Published online February 1, 2006
PEDIATRICS Vol. 117 No. 3 March 2006, pp. e396-e404 (doi:10.1542/peds.2005-1129)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Baggett, H. C.
Right arrow Articles by Gessner, B. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Baggett, H. C.
Right arrow Articles by Gessner, B. D.
Related Collections
Right arrow Blood

Endemic Iron Deficiency Associated With Helicobacter pylori Infection Among School-Aged Children in Alaska

Henry C. Baggett, MD, MPHa,b, Alan J. Parkinson, PhDb, Pam T. Muth, MPHa, Benjamin D. Gold, MDc and Bradford D. Gessner, MD, MPHa

a Alaska Division of Public Health, Anchorage, Alaska
b Centers for Disease Control and Prevention, Anchorage, Alaska
c Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Rural Alaska Natives have a high prevalence of iron deficiency and Helicobacter pylori infection. The objective of this study was to estimate the prevalence of iron deficiency, iron-deficiency anemia, and active H pylori infection among school-aged children in rural Alaska.

METHODS. We enrolled 68% (688) of the 7- to 11-year-old children from 10 predominantly Alaska Native villages in southwestern Alaska. We collected venous blood samples to assess iron deficiency and anemia. Each child was tested for active H pylori infection by 13C-urea breath test (UBT). Evaluated risk factors included age, gender, village of residence, number of household members, number of household members who were younger than 5 years, recent antibiotic use, and household water source.

RESULTS. Of 688 enrolled children, iron deficiency was present in 38%, iron-deficiency anemia was present in 7.8%, and H pylori infection by UBT was present in 86%. Iron deficiency was independently associated with living in a household with >6 people and village of residence. H pylori infection by UBT was independently associated with child's age ≥10 years and village of residence. Ninety-one percent of children with iron deficiency had H pylori infection by UBT, and children with active H pylori infection were more likely to be iron deficient than uninfected children. Children with H pylori infection by UBT were also more likely to have iron-deficiency anemia than uninfected children.

CONCLUSIONS. In this study of nearly 700 children in 10 different villages in Alaska, we confirmed that the high prevalence of iron deficiency persists among school-aged children. We found that active H pylori infection was independently associated with iron deficiency and iron-deficiency anemia among children in this region. H pylori infection may account for a portion of the iron deficiency and iron-deficiency anemia in rural Alaska and other areas with high prevalences of both conditions. Innovative approaches are critically needed to address the iron deficiency in high prevalence areas such as rural Alaska and most of the developing world.

Key Words: Helicobacter pylori • children • iron deficiency • infection • Alaska

Abbreviations: CI—confidence interval • PR—prevalence ratio • OR—odds ratio

Iron deficiency adversely affects cognitive development and behavior in infants and children1 and is the most common micronutrient deficiency among children worldwide.2 The prevalence of iron deficiency among children in developing countries exceeds 50% and is usually attributed to inadequate nutrition.2 Although the iron deficiency prevalence among school-aged children in the United States is only 4%,3 the prevalence among Alaska Native children approaches 30%,4–6 similar to that seen in developing nations and other arctic populations.7,8

Iron deficiency among children in most high-prevalence areas has been attributed primarily to poor nutritional intake or parasitosis.2,9 In Alaska, however, evidence has not supported a substantial role for either of these common causes of iron deficiency. Three separate studies found that the average daily iron intake among Alaska Natives in rural Alaska was very near or above the US recommended dietary allowance.5,10,11 Excessive parasitosis among this population has not been reported by the Alaska Division of Public Health, and a prevalence study in Alaska found the incidence of hookworm infection, an important cause of anemia in developing countries, to be well below the US average.12

Many areas of the world with high iron deficiency prevalences also have high Helicobacter pylori prevalences,13–15 including western Alaska, where seroprevalence among adults exceeds 80%.6 Recent investigations among Alaska Natives5,6,11 and other populations worldwide16–21 found an association between iron deficiency and H pylori infection. Previous studies were limited by small sample sizes or the use of anti–H pylori immunoglobulin G antibody positivity as a surrogate marker of infection. Serologic testing in children often leads to false-positive and -negative results and does not distinguish between past and current infection.22 These data raise the possibility that H pylori infection may contribute to global iron deficiency, but no large or population-based studies have been conducted to evaluate the association between iron deficiency and active H pylori infection (ie, infection documented by breath and/or stool testing) among children.

We conducted a population-based, cross-sectional study to estimate the prevalence of iron deficiency, iron-deficiency anemia, and active H pylori infection among school-aged children in rural Alaska. We evaluated risk factors for each of these conditions and hypothesized that iron deficiency was independently associated with active H pylori infection.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Setting
The current study was the preliminary screening phase of a randomized clinical trial to evaluate the effect of H pylori therapy on iron deficiency and was conducted in the Bristol Bay and Yukon-Kuskokwim regions of southwestern Alaska. These regions have a combined population of ~30000, which is 85% Alaska Native (Yup'ik Eskimo) and which lives predominantly in isolated and small villages (outside of the 2 main regional centers, the population per village ranges from 75 to 1014 people). At the time of the study, most village residents had a subsistence lifestyle, and 20% to 30% of household incomes fell below the federal poverty level.23 Seven of the 10 study villages had piped water and sewer services to most households.23 The remaining villages had running water available for public use only at a central location, such as a washeteria. Primary health care delivery occurred at village health clinics staffed by community health aides, who provided basic acute and preventive care services. None of the villages was accessible by road.

Participants
We selected the 8 most-populous villages in the Yukon-Kuskokwim region and the 2 most populous in the Bristol Bay region, not including the 2 regional centers (population range per village: 471–1014; median: 734). During November and December 2002, we invited all resident children who were 7 to 11 years of age to participate in this investigation. We actively sought participation by contacting all families with eligible children by mail and telephone using lists that were generated by local assistants. Children were excluded when they were receiving iron therapy.

We conducted in-person interviews with the child or the parent using a standard questionnaire to collect information on the number and ages of people in the household and the household water source. Each child's medical chart was reviewed to determine whether he or she had been prescribed antibiotics in the 30 days before enrollment. A venous blood sample was collected in a serum separator tube from each participant.

Iron Deficiency and Iron-Deficiency Anemia
Immediately after blood collection, a drop of blood was drawn into a microcuvette for hemoglobin measurement using a portable hemoglobinometer (HemoCue AB; HemoCue, Ängelholm, Sweden). The remaining blood was stored at room temperature for 30 to 60 minutes, centrifuged, and poured into a separate plastic tube. The serum was refrigerated for 1 to 4 days and transported in a cold box to the Centers for Disease Control and Prevention, Arctic Investigations Program laboratory (Anchorage, AK). Serum samples then were frozen at –30°C until processed for testing.

Serum ferritin concentrations were determined by using a radioimmunometric assay (ICN Pharmaceuticals Diagnostic Division, Orangeburg, NY). Iron deficiency was defined as a serum ferritin concentration of <10 µg/L and iron-deficiency anemia as a ferritin level of <10 µg/L and a hemoglobin concentration <115 g/L.24 Transferrin saturation was determined as a secondary measure of iron stores using standard methods at a local hospital laboratory, and a value of <15% was considered abnormal. All participants with iron deficiency (ferritin < 10 µg/L) were offered iron replacement therapy. Those with anemia but without iron deficiency were referred to their local provider for treatment.

Detection of H pylori
We assessed active H pylori infection using the urea breath test (UBT) (BreathTek; Meretek Diagnostics Inc, Lafayette, CO), a sensitive (>95%) and specific (>95%) measure of infection.25–27 After the children fasted for ≥1 hour, a baseline breath sample was collected in the manufacturer's breath collection bag. The participant then ingested 3 g of Pranactin-Citric (75 mg of 13C-urea, citric acid, aspartame, and mannitol) reconstituted in 100 mL of bottled water. A second breath sample was collected 15 minutes later. This method has not been shown to cause false-positive results in pediatric populations as a result of urease-producing oral flora.27,28 Breath samples were stored at room temperature for 1 to 4 days before being transported to Anchorage for analysis. The urea hydrolysis rate was determined using the UbiT-IR300 mass spectrophotometer (Otsuka Pharmaceutical Co, Ltd, Tokyo, Japan). Infection was defined as a calculated urea hydrolysis rate of >10 from the suggested {delta} over baseline for 13CO2 cutoff of 2.4 after adjustment for weight, height, and gender on the basis of the manufacturer's recommendation for pediatric patients.28 Using an unadjusted cutoff value of 2.4 for {delta} over baseline did not change results for any participants, whereas using an unadjusted cutoff value of 4.5 resulted in a change in infection status from positive to negative for only 2 of 578 children. We conducted serologic testing for H pylori–specific antibodies using the HM-CAP enzyme immunoassay (E-Z-EM, Lake Success, NY) to detect immunoglobulin G antibodies against high molecular weight cell-associated proteins of H pylori.29

Statistical Analysis
Analysis was performed by using Stata 8.0 (Stata Corp, College Station, TX). We estimated the prevalence of iron deficiency, iron-deficiency anemia, and H pylori infection as the proportion of tested children with the given condition; 95% confidence intervals (CIs) were calculated adjusting for the cluster sampling by village. Binary exposures were compared by using the {chi}2 test. Age and household size (number of people living in the home) were dichotomized for analysis at the median value for all participants. Potential risk factors for iron deficiency, iron-deficiency anemia, and H pylori infection were evaluated in univariate analysis, and prevalence ratios (PRs) and 95% CIs were calculated.

We used multiple logistic regression to evaluate the independent effect of risk factors for iron deficiency, iron-deficiency anemia, and H pylori infection by calculating adjusted odds ratios (OR). We evaluated all exposure variables that were associated with the outcome of interest at a level of P ≤ .1 in univariate analysis. Exposure variables were tested individually using a forward addition approach and kept in the model when they were associated with the outcome of interest with a 2-sided P ≤ .1. In a separate analysis, we specifically tested the a priori hypothesis that H pylori infection was an independent risk factor for iron-deficiency and iron-deficiency anemia. In this analysis, we kept potentially confounding variables in the final model when they changed the OR describing the association between iron deficiency and H pylori infection by ≥10%. We included demographic variables (village of residence, gender, and a categorical age variable [7, 8, 9, and ≥10 years]) in all logistic-regression models as potential confounders. A 2-sided P < .05 was considered statistically significant.

Ethical Approval
This study was approved by the Institutional Review Boards of the Centers for Disease Control and Prevention and the Alaska Area Research and Publications Committee, the Human Subjects Committee at the Yukon-Kuskokwim Regional Health Corporation, and the village or tribal councils in each of the 10 study villages. Written assent was obtained from all participants, and written consent was obtained from their guardians.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Participants
We enrolled 688 children (range: 40–110 per village), which represented 68% of all age-eligible children in the study villages based on the 2000 census (range: 45–92% by village). No children were excluded for taking iron replacement therapy at the time of testing. Participants had a mean age of 9.5 years, 51% were male, and 99.6% were Alaska Native (Table 1).


View this table:
[in this window]
[in a new window]
  		TABLE 1 Demographic and Household Characteristics of all Children Enrolled in the Investigation (N = 688)

 
Prevalence of Iron Deficiency and Iron-Deficiency Anemia
Of 686 tested children, 263 (38.3%) were iron deficient as defined by a ferritin level of <10 µg/L (95% CI: 30.5–46.1%; Table 2), and the median serum ferritin level was 11.8 µg/L. Iron deficiency prevalence differed by village, from 19.7% to 56.1% (P < .001). Transferrin saturation was low in 332 (48.4%) of 686 children tested (95% CI: 42.5–54.3%), and the median was 15.2%. Serum ferritin and transferrin saturation both were low in 145 (21.1%) children (95% CI: 15.4–26.9%). Anemia was present in 104 (15.2%) of 683 tested children (95% CI: 10.0–0.4%), and the median hemoglobin level was 123 g/L. Iron-deficiency anemia was present in 53 (7.77%) children (95% CI: 4.20–11.3%).


View this table:
[in this window]
[in a new window]
  		TABLE 2 Estimated Prevalence of Iron Deficiency, Anemia, and H pylori Infection Among Children Aged 7 to 11 Years: Southwestern Alaska, 2001

 
Risk Factors for Iron Deficiency and Iron-Deficiency Anemia
During univariate analysis, iron deficiency, as measured by low ferritin, was associated with residing in a household of at least 6 people or with a child age <5 years and residence in the Yukon-Kuskokwim region (Table 3). Results were similar when the measure of iron deficiency was low transferrin saturation, except that the association with household size was not statistically significant (P = .39, data not shown). During multivariate logistic-regression analysis, children who were living in homes with ≥6 people were more likely to be iron deficient than those in homes with <6 people (OR: 1.5; 95% CI: 1.1–2.2). Iron deficiency prevalence also differed by village of residence (P = .0017) but was no longer significantly associated with residence in the Yukon-Kuskokwim region.


View this table:
[in this window]
[in a new window]
  		TABLE 3 Characteristics of Children With Iron Deficiency (Ferritin <10 µg/L), Iron-Deficiency Anemia (Ferritin <10 µg/L and Hemoglobin <115 g/L), and H pylori Infection by UBT: Southwestern Alaska, 2001

 
Of evaluated risk factors, iron-deficiency anemia was associated only with residence in the YukonKuskokwim region in univariate analysis (Table 3). However, the association was not statistically significant in multiple logistic-regression modeling; only village of residence remained significantly associated with iron-deficiency anemia (P = .04).

Prevalence of H pylori Infection
UBTs were completed successfully for 668 (97%) of the 688 participants; samples from the remaining 20 children were inadequate for testing. H pylori infection prevalence was 86.5% (95% CI: 78.4–94.7%; Table 2). Serologic evidence of H pylori infection was present in 446 (67.2%) of 664 children with interpretable results (95% CI: 60.6–73.8%). Among children with positive UBTs, 65.1% (419 of 644) also had a positive H pylori serology (95% CI: 57.4–72.7%).

Risk Factors for H pylori Infection
During univariate analysis, H pylori infection based on UBT results was associated with older age, residing in a household of at least 6 people or in a household with a child aged <5 years, residence in the Yukon-Kuskokwim region, household water source, and living in a village without piped water services (Table 3). During multivariate analysis, age ≥10 years (OR: 2.0; 95% CI: 1.2–3.4) and village of residence (P < .001) remained significantly associated with H pylori infection. After controlling for village of residence, we could not evaluate effectively the risk for H pylori associated with living in a village without piped water services, because these services did not vary within villages.

Relationship Between H pylori Infection and Iron Deficiency
Ninety-one percent (235 of 257) of children with iron deficiency had H pylori infection. Children with H pylori infection based on the UBT were more likely to be iron deficient than uninfected children (Table 4); however, iron deficiency prevalences were similar among H pylori–seropositive (39%) and –seronegative (36%) children. The association between breath test positivity and iron deficiency differed by age and was present only for children who were at least 9 years of age (Table 5). During multivariate analysis, iron deficiency remained associated with H pylori infection after adjustment for age, gender, village of residence, and household size; this relationship was modified by age and was statistically significant only for children who were ages 9 and ≥10 years.


View this table:
[in this window]
[in a new window]
  		TABLE 4 Association Between H pylori Infection by UBT and Various Measures of Iron Status and Anemia: Southwestern Alaska, 2001

 

View this table:
[in this window]
[in a new window]
  		TABLE 5 Prevalence of Iron Deficiency Among H pylori–Positive and H pylori–Negative Children According to Age Group: Southwestern Alaska, 2001

 
Results were similar when iron deficiency was defined as having a serum ferritin level of <12 µg/L or as a combination of a ferritin level of <10 µg/L and transferrin saturation of <15% (Table 4). When iron deficiency was defined as a low ferritin and low transferrin saturation, prevalence ratios were higher for children aged 9 (PR: 3.8; 95% CI: 0.55–27.0) and ≥10 years (PR: 3.3; 95% CI: 0.87–13.0). Logistic-regression analysis also revealed a stronger association among older children (9 years old: OR: 4.4 [95% CI: 0.56–34.0]; 10 years old: OR: 3.6 [95% CI: 0.78–16.0]), but the 95% CIs included 1. Low transferrin saturation alone did not differ among H pylori–infected and –uninfected children.

Children with H pylori infection on the basis of the UBT were more likely to have iron-deficiency anemia than uninfected children (Table 4). The association remained after adjustment for age, gender, and village of residence, but the 95% CI included 1 (OR: 4.1; 95% CI: 0.92–8.0; P = .06). We could not assess effect modification by age because only 2 uninfected children had iron-deficiency anemia. Iron-deficiency anemia was also more common among H pylori–seropositive (9%) versus H pylori–seronegative (5%) children (PR: 2.0; 95% CI: 1.0–4.0). We calculated the percentage of iron deficiency in the population that potentially was attributable to H pylori infection (population-attributable fraction) as the difference in the prevalence of iron deficiency among 7- to 11-year-old children overall and those without H pylori infection divided by the prevalence overall.30 Up to 36% of iron deficiency was potentially attributable to H pylori infection, and among children who were aged 9 and ≥10 years, this fraction increased to 70% and 73%, respectively.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
For almost 5 decades, studies have documented the high prevalence of iron deficiency and iron-deficiency anemia in rural Alaskan communities.4–6,10,11,31 In this study of nearly 700 children in 10 different villages, we confirmed that the high prevalence of iron deficiency persists among school-aged children, a group that normally is considered to be at very low risk for iron deficiency in the United States. The prevalence in the current study exceeds estimates for similarly aged children in the United States overall by nearly 10 times3 and is similar to prevalences seen in developing countries and other arctic pediatric populations.2,7,8 Unlike developing country populations, though, previous data collected from Alaska Natives do not support poor nutritional iron intake5,10,11 or parasitosis12 as causes for iron deficiency, suggesting that other causes must exist.

We found that H pylori infection was independently associated with iron deficiency and iron-deficiency anemia among children in this region, with high prevalences of all 3 conditions. This association has been observed in previous studies in rural Alaska5,6,11 and elsewhere,16–21 but never in a study that was population based, had a relatively large cohort of children, and used a validated measure of active H pylori infection. Our findings suggest that H pylori infection may be an important risk factor for iron deficiency and iron-deficiency anemia among children in rural Alaska and possibly in other areas of the world where these conditions are highly prevalent. In contrast to previous studies,5,6 we did not find an association between iron deficiency and H pylori seropositivity. Serologic testing for H pylori in children lacks sensitivity and specificity22 and does not distinguish between past and current infection; this may have led to misclassification of H pylori status and subsequent attenuation of the association.

In the current investigation, the association between iron deficiency and H pylori infection was modified by age, with the strongest association in children who were aged ≥9 years. In this age group, iron deficiency was 3.7 to 4 times more prevalent among H pylori–infected than –uninfected children. We did not anticipate this effect modification given the narrow age range of our sample, but the increased risk in older children seems biologically plausible. Older children likely have been infected longer than younger children, allowing more time for iron deficiency to develop. Furthermore, older children may be less likely to have iron deficiency related to other causes, such as insufficient dietary intake, leaving H pylori infection to account for a greater proportion of iron deficiency.

Our findings highlight the potential public health impact of H pylori infection in this region of Alaska, as up to 70% of the iron deficiency in children who are ≥9 years of age may be attributable to H pylori infection. However, measures of excess risk assume a causal relationship between exposure and disease, which cannot be established from a single cross-sectional study. Therefore, our estimates of population-attributable risk must be interpreted with caution.

This study included 1 of the largest cohorts of children who have been evaluated for active H pylori infection in the world and demonstrated that >85% of subjects were infected. The epidemiology of H pylori in rural Alaska is similar to that in developing country settings, where infection occurs at an early age and prevalence is high.13–15 Risk factors for H pylori acquisition and transmission are poorly understood but may be related to conditions that are associated with low socioeconomic status, such as crowded housing or relatively poor water and septic systems. In the current investigation, H pylori infection was associated with living in a village without piped water and sewer services. We could not evaluate this association independent of village of residence because utility services do not vary within villages. Other studies have documented an epidemiologic association between H pylori infection and contaminated water and have found evidence of the organism in water sources using molecular laboratory methods (eg, polymerase chain reaction).14,32–34 However, the laboratory methods in these investigations are not well validated for testing environmental samples.

We found that 15% of children had a hemoglobin level <115 g/dL, but only 8% also had a low ferritin, suggesting that important causes of anemia beyond iron deficiency exist. Similar trends have been described in population-based studies among young children in the United States,35 Great Britain,36 and New Zealand.37 Hemoglobinopathies are relatively uncommon among Alaska Natives and are unlikely to account for a substantial portion of the anemia seen in this study; routine newborn screening has revealed no substantial difference in the prevalence of overall or specific hemoglobinopathies between Alaska Native and non–Alaska Native subjects (Alaska Division of Public Health, unpublished data). Anemia of chronic disease (also known as anemia of inflammation) is caused by chronic or acute immune activation and is the second most common cause of anemia after iron deficiency.38,39 Alaska Natives experience a disproportionately high incidence of several infectious diseases and other inflammatory conditions compared with the US population overall, including respiratory syncytial virus bronchiolitis,40 chronic lung disease,41 otitis media,42 and invasive bacterial infections,43 which may contribute to anemia in some children in this region. Inflammatory processes can also cause elevated serum ferritin levels, which may have led to underestimation of the proportion of anemic children with iron deficiency.44 Among the 104 children in our study with low hemoglobin, 82 (79%) had at least 1 measure of low iron stores (ferritin or transferrin saturation).

The relatively modest overall association between H pylori infection and iron deficiency indicates that other causes of iron deficiency must be considered. Previous studies in rural Alaska concluded that insufficient iron intake was an unlikely cause of disease.5,10,11 However, the last large nutritional survey was conducted in this area during 1988. Since that time, access to commercially prepared foods has increased in rural areas, which may have led to decreased intake of traditional, iron-rich foods, such as red meat and fish. Inherited abnormalities in iron absorption can cause iron deficiency despite sufficient dietary intake.45 However, data from Alaska's Women, Infants, and Children Program show that Alaska Native children who were aged <5 years and living in the 4 largest cities in Alaska had hemoglobin levels similar to non–Alaska Natives (Alaska Department of Health and Social Services, unpublished data), which suggests that environmental rather than genetic factors play a key role in iron deficiency in rural settings. Iron absorption can also be inhibited by excessive dietary intake of items such as starch and phytates,45 but there is no evidence that these inhibitors are common in subsistence diets in rural Alaska.10

An important strength of this study was the high participation rate (68%). Although we cannot be sure that volunteers were representative of the entire population of 7- to 11-year-old children, nonparticipants were similar to participants in terms of age (mean: 9.4), gender (51% male), and race (99% Alaska Native), and living conditions were relatively homogeneous within study villages. Our study also had several limitations. We defined iron deficiency solely on the basis of ferritin levels, whereas studies that used the National Health and Nutrition Examination Survey defined iron deficiency as low values for 2 of the following: ferritin, transferrin saturation, or free erythrocyte protoporphyrin.3 However, 21% (145 of 686) of children in the current study had both a low ferritin level (<10 µg/L) and low transferrin saturation, still well above the 4% prevalence of iron deficiency among US children aged 6 to 11 years found in the National Health and Nutrition Examination Survey.3 We defined iron deficiency using a low cutoff for serum ferritin (10 µg/L) to increase the specificity of our case definition, although this may have led to an underestimation of the iron deficiency prevalence (eg, prevalence = 51% if iron deficiency is defined as a ferritin level of <12 µg/L). The cross-sectional design of this study limits inference about the causal relationship between H pylori infection and iron deficiency. In addition, the modest association between iron deficiency and H pylori infection (PR: 1.65) raises concern about confounding by unmeasured exposures. For instance, poor nutrition could cause iron deficiency and potentially increase susceptibility to H pylori infection. However, the association was much stronger in children who were 9 years or older (PR: 3.7–4.0) and among those with iron-deficiency anemia, and our findings are consistent with previous studies that evaluated the relationship between H pylori and iron deficiency in Alaska and in other settings.5,6,11,16–21 Confounding by unmeasured socioeconomic factors could also have occurred, but there is relatively little variation in socioeconomic status among Alaska Natives from southwestern Alaska, particularly within villages. Finally, our study was conducted in small villages in rural Alaska, which may limit the generalizability of our findings. However, H pylori infection and iron deficiency are highly prevalent in other indigenous arctic populations and many areas of the developing world, and similar associations between H pylori and iron deficiency have been found in smaller studies in diverse populations.16–19,21


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
A significant disparity persists in the prevalence of iron deficiency between Alaska Native and other US school-aged children, with Alaska Native children more closely resembling children from developing countries. Our data suggest that H pylori infection may be an important contributor to the disparity in this region, where endemic iron deficiency persists despite apparent adequate nutritional intake and lack of parasitosis. Innovative approaches in rural Alaska and other areas are critically needed to address the high prevalence of iron deficiency, one of the most common causes of disability worldwide.46 Future strategies may include prevention or treatment of H pylori infection. Additional study is needed to determine whether treating H pylori infection facilitates resolution of iron deficiency and whether the benefits of therapy outweigh the risks.


   ACKNOWLEDGMENTS
 
Funding for this project was provided through a US federal grant, Directed Source 02079 for the Alaska Anemia Intervention and Treatment Program. TAP Pharmaceuticals provided lansoprazole for an additional phase of this study, during which some children received H pylori therapy.

We acknowledge Michael Bruce, Jay Butler, and Ken Petersen for expert opinion on study design; Eitel Dunaway for database management; Helen Peters for assistance with study implementation; Lyn Zanis, Karen Miernyk, and Julie Morris for laboratory work; Joe Klejka, Gayle Jones, and Dana Hall for assistance with activities in the Yukon-Kuskokwim villages; Gina Carpenter for assistance in the Dillingham villages; Ken Southerland for data entry; and members of the traditional and city councils of all participating villages for interest in the project.


   FOOTNOTES
 
Accepted Sep 1, 2005.

Address correspondence to Henry C. Baggett, MD, MPH, CDC, DGMQ MS E-03, 1600 Clifton Rd, Atlanta, GA 30333. E-mail: hbaggett{at}cdc.gov

Dr Baggett assisted with study design, was the primary person responsible for study implementation during the first study year, conducted all data analysis, and was the primary manuscript author. Dr Gessner was the study primary investigator, wrote the study protocol, was the primary person responsible for study implementation during the second study year, and assisted with data analysis and preparing the manuscript. Dr Parkinson was responsible for all components of laboratory analysis, assisted with study design, and provided critical input into the final manuscript. Ms Muth assisted with study design and writing the study protocol, was the primary person responsible for administrative project management, and reviewed the final manuscript. Dr Gold contributed to the study design, data analysis, and interpretation and provided critical input into the final manuscript.

Dr Gold has served as a consultant for TAP Pharmaceuticals, Astra Zeneca, and Romark Laboratories. Dr Gessner receives research support from Sanofi Pasteur. The remaining authors have indicated they have no financial relationships relevant to this article to disclose.

Dr Baggett's current address is Centers for Disease Control and Prevention, DGMQ MS E-03, 1600 Clifton Rd, Atlanta, GA 30333.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Grantham-McGregor S, Ani C. A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr. 2001;131 :649S –668S[Abstract/Free Full Text]
  2. United Nations Administrative Committee on Coordination, SubCommittee on Nutrition (ACC/SCN). Fourth Report on the World Nutrition Situation. Geneva, Switzerland: ACC/SCN in Collaboration with International Food Policy Research Institute; 2000. Available at: www.unsystem.org/scn/Publications/4RWNS/4rwns.pdf. Accessed January 12, 2005
  3. Centers for Disease Control and Prevention. Iron Deficiency—United States, 1999–2000. MMWR Morb Mortal Wkly Rep. 2002;51 :897 –899[Medline]
  4. Centers for Disease Control and Prevention. High prevalence of iron deficiency anemia among Alaskan Native children. MMWR Morb Mortal Wkly Rep. 1988;37 :200 –202[Medline]
  5. Centers for Disease Control and Prevention. Iron deficiency anemia in Alaska Native children–Hooper Bay, Alaska, 1999. MMWR Morb Mortal Wkly Rep. 1999;48 :714 –716
  6. Parkinson AJ, Gold BD, Bulkow L, et al. High prevalence of Helicobacter pylori in the Alaska native population and association with low serum ferritin levels in young adults. Clin Diagn Lab Immunol. 2000;7 :885 –888[CrossRef][Medline]
  7. Willows ND, Dewailly E, Gray-Donald K. Anemia and iron status in Inuit infants from northern Quebec. Can J Public Health. 2000;91 :407 –410[ISI][Medline]
  8. Whalen EA, Caulfield LE, Harris SB. Prevalence of anemia in First Nations children of northwestern Ontario. Can Fam Physician. 1997;43 :659 –664[ISI][Medline]
  9. Stoltzfus RJ, Chwaya HM, Tielsch JM, Schulze KJ, Albonico M, Savioli L. Epidemiology of iron deficiency anemia in Zanzibari schoolchildren: the importance of hookworms. Am J Clin Nutr. 1997;65 :153 –159[Abstract/Free Full Text]
  10. Petersen KM, Parkinson AJ, Nobmann ED, Bulkow L, Yip R, Mokdad A. Iron deficiency anemia among Alaska Natives may be due to fecal loss rather than inadequate intake. J Nutr. 1996;126 :2774 –2783[Abstract/Free Full Text]
  11. Yip R, Limburg PJ, Ahlquist DA, et al. Pervasive occult gastrointestinal bleeding in an Alaska Native population with prevalent iron deficiency. Role of Helicobacter pylori gastritis. JAMA. 1997;277 :1135 –1139[Abstract]
  12. Kappus KK, Juranek DD, Roberts JM. Results of testing for intestinal parasites by state diagnostic laboratories, United States, 1987. MMWR CDC Surveill Summ. 1991;40 :25 –45[Medline]
  13. Torres J, Perez-Perez G, Goodman KJ, et al. A comprehensive review of the natural history of Helicobacter pylori infection in children. Arch Med Res. 2000;31 :431 –469[CrossRef][ISI][Medline]
  14. Klein PD, Graham DY, Gaillour A, Opekun AR, Smith EO. Water source as risk factor for Helicobacter pylori infection in Peruvian children. Gastrointestinal Physiology Working Group. Lancet. 1991;337 :1503 –1506[CrossRef][ISI][Medline]
  15. Bardhan PK. Epidemiological features of Helicobacter pylori infection in developing countries. Clin Infect Dis. 1997;25 :973 –978[ISI][Medline]
  16. Choe YH, Kim SK, Son BK, Lee DH, Hong YC, Pai SH. Randomized placebo-controlled trial of Helicobacter pylori eradication for iron-deficiency anemia in preadolescent children and adolescents. Helicobacter. 1999;4 :135 –139[CrossRef][ISI][Medline]
  17. Choe YH, Kwon YS, Jung MK, Kang SK, Hwang TS, Hong YC. Helicobacter pylori-associated iron deficiency anemia in adolescent female athletes. J Pediatr. 2001;139 :100 –104[CrossRef][ISI][Medline]
  18. Konno M, Muraoka S, Takahashi M, Imai T. Iron-deficiency anemia associated with Helicobacter pylori gastritis. J Pediatr Gastroenterol Nutr. 2000;31 :52 –56[CrossRef][ISI][Medline]
  19. Barabino A, Dufour C, Marino CE, Claudiani F, De Alessandri A. Unexplained refractory iron-deficiency anemia associated with Helicobacter pylori gastric infection in children: further clinical evidence. J Pediatr Gastroenterol Nutr. 1999;28 :116 –119[CrossRef][ISI][Medline]
  20. Choe YH, Kim SK, Hong YC. The relationship between Helicobacter pylori infection and iron deficiency: seroprevalence study in 937 pubescent children. Arch Dis Child. 2003;88 :178[Free Full Text]
  21. Yang YJ, Sheu BS, Lee SC, Yang HB, Wu JJ. Children of Helicobacter pylori-infected dyspeptic mothers are predisposed to H. pylori acquisition with subsequent iron deficiency and growth retardation. Helicobacter. 2005;10 :249 –255[CrossRef][ISI][Medline]
  22. Khanna B, Cutler A, Israel NR, et al. Use caution with serologic testing for Helicobacter pylori infection in children. J Infect Dis. 1998;178 :460 –465[ISI][Medline]
  23. State of Alaska, Department of Commerce, Community and Economic Development. Available at: www.dced.state.ak.us/dca/commdb/CF_COMDB.htm. Accessed February 1, 2005
  24. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. Prevalence of iron deficiency in the United States. JAMA. 1997;277 :973 –976[Abstract]
  25. Gold BD, Colletti RB, Abbott M, et al. Helicobacter pylori infection in children: recommendations for diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2000;31 :490 –497[CrossRef][ISI][Medline]
  26. Rowland M, Lambert I, Gormally S, et al. Carbon 13-labeled urea breath test for the diagnosis of Helicobacter pylori infection in children. J Pediatr. 1997;131 :815 –820[CrossRef][ISI][Medline]
  27. Megraud F. European Paediatric Task Force on Helicobacter pylori. Comparison of non-invasive tests to detect Helicobacter pylori infection in children and adolescents: results of a multicenter European study. J Pediatr. 2005;146 :198 –203[CrossRef][ISI][Medline]
  28. Klein PD, Malaty HM, Czinn SJ, Emmons SC, Martin RF, Graham DY. Normalizing results of 13C-urea breath testing for CO2 production rates in children. J Pediatr Gastroenterol Nutr. 1999;29 :297 –301[CrossRef][ISI][Medline]
  29. Evans DJ, Evans DG, Graham DY, Klein PD. A sensitive and specific serologic test for detection of Campylobacter pylori infection. Gastroenterology. 1989;96 :1004 –1008[ISI][Medline]
  30. Koepsell TD, Weiss NS. Measures of excess risk. In: Koepsell TD, Weiss NS, eds. Epidemiologic Methods: Studying the Occurrence of Illness. New York, NY: Oxford University Press; 2003:196 –208
  31. Scott EM, Wright RC, Hanan BT. Anemia in Alaskan Eskimos. J Nutr. 1955;55 :137 –149[Abstract/Free Full Text]
  32. Hegarty JP, Dowd MT, Baker KH. Occurrence of Helicobacter pylori in surface water in the United States. J Appl Microbiol. 1999;87 :697 –701[CrossRef][Medline]
  33. Baker KH, Hegarty JP. Presence of Helicobacter pylori in drinking water is associated with clinical infection. Scan J Infect Dis. 2001;33 :744 –746[CrossRef][Medline]
  34. Benson JA, Fode-Vaughan KA, Collins ML. Detection of Helicobacter pylori in water by direct PCR. Lett Appl Microbiol. 2004;39 :221 –225[Medline]
  35. White KC. Anemia is a poor predictor of iron deficiency among toddlers in the United States: for heme the bell tolls. Pediatrics. 2005;115 :315 –320[Abstract/Free Full Text]
  36. Thane CW, Walmsley CM, Bates CJ, Prentice A, Cole TJ. Risk factors for poor iron status in British toddlers: further analysis of data from the National Diet and Nutrition Survey of children aged 1.5–4.5 years. Public Health Nutr. 2000;3 :433 –440[Medline]
  37. Soh P, Ferguson EL, McKenzie JE, Homs MYV, Gibson RS. Iron deficiency and risk factors for lower iron stores in 6–24 month-old New Zealanders. Eur J Clin Nutr. 2004;58 :71 –79[Medline]
  38. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352 :1011 –1023[Free Full Text]
  39. Abshire TC. The anemia of inflammation. a common cause of childhood anemia. Pediatr Clin North Am. 1996;43 :623 –637[CrossRef][ISI][Medline]
  40. Holman RC, Curns AT, Cheek JE, et al. Respiratory syncytial virus hospitalizations among American Indian and Alaska Native infants and the general United States infant population. Pediatrics. 2004;114 (4). Available at: www.pediatrics.org/cgi/content/full/114/4/e437
  41. Lewis TC, Stout JW, Martinez P, et al. Prevalence of asthma and chronic respiratory symptoms among Alaska Native children. Chest. 2004;125 :1665 –1573[Medline]
  42. Curns AT, Holman RC, Shay DK, et al. Outpatient and hospital visits associated with otitis media among American Indian and Alaska native children younger than 5 years. Pediatrics. 2002;109 (3). Available at: www.pediatrics.org/cgi/content/full/109/3/e41
  43. Galil K, Singleton R, Levine OS, et al. Reemergence of invasive Haemophilus influenzae type b disease in a well-vaccinated population in remote Alaska. J Infect Dis. 1999;179 :101 –106[CrossRef][ISI][Medline]
  44. Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep. 1998;47 :1 –29[Medline]
  45. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;34 :1986 –1895
  46. Murray CJL, Lopez AD. Global and regional descriptive epidemiology of disability: incidence, prevalence, health expectancies and years lived with disability. In: Murray CJL, Lopez AD, eds. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability From Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Boston, MA: Harvard University Press; 1996:201 –246
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



This article has been cited by other articles:


Home page
 Am J Trop Med HygHome page
L. J. Demma, R. C. Holman, J. Sobel, K. L. Yorita, T. W. Hennessy, E. L. Paisano, and J. E. Cheek
Epidemiology of Hospitalizations Associated with Ulcers, Gastric Cancers, and Helicobacter pylori Infection among American Indian and Alaska Native Persons
Am J Trop Med Hyg, May 1, 2008; 78(5): 811 - 818.
[Abstract] [Full Text] [PDF]

Home page
 Am J Trop Med HygHome page
T. H. FARAG, R. J. STOLTZFUS, S. S. KHALFAN, and J. M. TIELSCH
HELICOBACTER PYLORI INFECTION IS ASSOCIATED WITH SEVERE ANEMIA OF PREGNANCY ON PEMBA ISLAND, ZANZIBAR
Am J Trop Med Hyg, March 1, 2007; 76(3): 541 - 548.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Baggett, H. C.
Right arrow Articles by Gessner, B. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Baggett, H. C.
Right arrow Articles by Gessner, B. D.
Related Collections
Right arrow Blood