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Division of Nutritional Sciences, Cornell University, Ithaca, NY;
* UNICEF, Zanzibar, Tanzania;
Communicable Diseases Prevention and Control, World Health Organization, Geneva, Switzerland;
** Department of International Health, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD;
Public Health Laboratory Ivo de Carneri, Wawi, Chake Chake, Pemba Island, Zanzibar, Tanzania; and
Ivo de Carneri Foundation, Milan, Italy
2To whom correspondence should be addressed. E-mail: rjs62{at}cornell.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • anemia • iron • growth • appetite • helminths
Iron deficiency and helminth infections are two of the most common conditions afflicting children in less-developed countries. Iron deficiency is estimated to affect about one fifth of the world’s population, and young children are among the most severely affected (1). Evidence is mounting that iron deficiency anemia adversely affects brain development (2,3), with measurable effects on children’s behavior, motor development and cognition (4–6). Severe anemia also contributes to mortality in children (7). For these reasons, the provision of iron-fortified weaning foods or low dose iron supplements is advocated by the WHO and UNICEF (8). However the efficacy of low dose daily iron supplementation according to current international recommendations is not well documented in malaria-endemic settings.
On a global basis the geohelminths, Ascaris lumbricoides, Trichuris trichiura, and the hookworms, are perhaps the most common chronic subclinical infections of childhood, with widespread geographic distribution (9). The health consequences of chronic helminth infections are believed to be proportional to the intensity of infection (10). Therefore, the main programmatic focus of helminth control has been school-age children, who harbor the greatest number of worms. Studies have found that anthelminthic treatment of school-age children has improved iron status, growth and cognition, although study findings were not entirely consistent for any of these outcomes (11). This inconsistency is not surprising, given the diversity of ages, nutritional risk, helminth species and helminth transmission intensities in the populations studied.
The health consequences of helminth infections in preschool-age children have been studied less frequently, because the worm burdens in young children are not as great as in school children and are therefore assumed to be less detrimental. However, young children are at much greater risk of iron deficiency anemia and growth retardation than their school-age counterparts.
Coastal East Africa is a setting in which geohelminth transmission is intense, and children acquire worms at relatively young ages. Anemia is also prevalent and severe because of iron deficiency, malarial infection and perhaps, helminth infections. In this environment we aimed to achieve the following: 1) measure the efficacy of anthelminthic treatment (mebendazole) every 3 mo and/or low dose daily iron supplementation to improve anemia and growth of preschool children; 2) test whether iron or mebendazole improves appetite of preschool children, based on mother’s perception; and 3) compare the effects of iron and mebendazole in younger and older preschool children. Our prior expectation was that mebendazole would confer more benefit on older preschool children because of their greater worm burdens, whereas iron supplementation would benefit both older and younger preschool children. The effects of iron and mebendazole on children’s language and motor development were published previously (12).
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The study was carried out in Kengeja village, Pemba Island, Zanzibar, The United Republic of Tanzania. Kengeja was selected because it is a relatively large rural village, accessible by road, and with access to a spacious primary health care center that became the base of our field activities. Pemba Island is densely populated and mostly rural, with subsistence farming as the main economic activity. Plasmodium falciparum malaria is holoendemic, as are the geohelminths, A. lumbricoides, T trichiura, Ancylostoma duodenale, and Necatur americanus. Nearly all children are breast-fed, but complementary feeding typically begins at a few months of age. By 2 y of age, children are weaned onto the family diet. which consists mainly of rice and cassava, eaten with vegetables and small amounts of fish or meat.
We estimated that 68 children per group would be sufficient to detect a 5 g/L difference in hemoglobin response in two age subgroups, assuming an SD of 9 g/L, 
= 0.05 and ß = 0.10. Using a factorial design, both interventions could be evaluated with a total sample of 136 children. We multiplied this number of 1.5 to allow for analysis of treatment interactions, doubled this estimate to examine two age groups separately, added 20% for loss to follow-up, and added 20% again, expecting that one fifth of the sample would have to be excluded and treated for severe anemia. Thus, we planned to screen 640 children for enrollment.
A community census was conducted in June 1996 to determine the number of age-eligible children. Based on parental report of age, 684 children 6–59 mo of age in 451 households were identified. Allocation to iron or placebo was carried out by household rather than by child, so that mothers would not be responsible for administering different bottles of supplement to different children within the household. Households were grouped into three strata: those with children <36 mo, those with children 
36 mo, and those with children in both age subgroups. Within these strata, households were randomly assigned to iron or placebo, in blocks of four. Children were randomly allocated to mebendazole or placebo, stratified by iron allocation and household, in blocks of four.
In September 1996, 614 children were assessed and were administered randomized treatments (Fig. 1). Of those children, 76 were lost to follow-up before the 12-mo assessment; thus 538 completed the 12-mo trial. The children lost to follow-up and those who completed the trial were similar on a wide of variety of characteristics. including anthropometry, appetite and hemoglobin. All children with severe anemia (hemoglobin < 70 g/L) at the baseline assessment were treated with a therapeutic course of oral iron plus mebendazole and were excluded from these analyses. This was the sole exclusion criterion.
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Interventions.
The iron supplement was a liquid preparation containing 20 g/L iron as ferrous sulfate or an identical placebo (ALPharma, Baltimore, MD) in 50-mL opaque bottles with child-proof dropper caps. The placebo was matched in color, packaging and flavor. Each bottle was labeled with one of six batch numbers assigned by ALPharma, three corresponding to iron and three to placebo. At the baseline clinic. mothers were trained how to give a 0.5-mL dose (10 mg iron) to the study child each day. For the 12-mo period between the baseline and follow-up clinics, local staff visited mothers once weekly. At these weekly visits, the worker asked mothers how many days in the past week she gave the supplement to the child, and attempted to address any compliance problems using a problem-solving algorithm. She also replaced nearly empty bottles with full bottles as needed. Mothers who reported giving the supplement fewer than 5 d in a week were reported to the supervisor, who visited the household to further motivate compliance. The potency of the supplement was monitored by the manufacturer, and was found to be 80% potent after 12 mo of storage at room temperature.
In spite of child-proof packaging, two children consumed a large portion of a bottle of iron supplement. These children were monitored closely for toxic sequelae, and none were found. They are included in these analyses. After these events, the amount of iron supplement in each bottle was reduced to 25 mL, thereby reducing the total amount of elemental iron in one bottle from 1000 to 500 mg.
Anthelminthic treatment consisted of 500 mg mebendazole as orange-flavored chewable tablets, or identical placebo tablets (Pharmamed, Zejtun, Malta). These pills were packaged in 6 bottles with unique treatment codes, 3 corresponding to mebendazole and 3 to placebo. The first treatment dose was given at the baseline clinic; thereafter study staff made home visits to all children at 3-mo intervals to administer anthelminthic treatments. For children too young to chew, the tablet was crushed, suspended in water. and given by spoon.
At the conclusion of the trial, severely anemic children were treated with therapeutic oral iron, and all children were provided with mebendazole.
Assessment methods.
All of the following assessments were carried out at baseline and at the 12-mo follow-up. Parents were asked to bring a small sample of their child’s feces to the village clinic, and were given a container for this purpose. Fecal samples were stained on the same day and examined within 1 h of staining by the Kato Katz method (13). Helminth egg counts were obtained on 95.3% of study children. A 3-mL venous blood sample was collected into a vacutainer tube with serum separator gel. Drops of whole blood were dispensed immediately to make a blood film, and for deteiinination of hemoglobin using a HemoCue hemoglobinometer (HemoCue, AB, Angelhom, Sweden) and erythrocyte protoporphrin using a hematofluorometer (Aviv Biomedical, Lakewood, NY). The remaining blood was centrifuged at 1000 x g for 20 min at room temperature and serum was collected. Thick blood films were fixed with ethanol and stained with Giemsa, and malaria parasites were counted against leukocytes. The microscopist counted fields containing >200 leukocytes. If <10 parasites were seen, counting continued up to 500 leukocytes. Parasite densities were calculated by assuming 8 x 109 leukocytes/L blood (14). Sera were stored in Pemba at -10°C for up to 3 mo, then transported in liquid nitrogen to Baltimore, MD where they were stored at -70°C until analysis. Ferritin was assayed using a fluorescence-linked immunoassay (DELFIA System by Wallac, Gaithersburg, MD). The mean CV for this assay was 3% (range: 0.2–7.0%).
Weight was measured to the nearest 0.1 kg using a digital scale (Seca, Columbia, MD). Supine length was measured in triplicate to the nearest 0.1 cm using a wooden length board (Shorr Productions, Olney, MD), and the mean value was used for analysis. Mid-upper arm circumference was measured in triplicate and the mean value was used for analysis. Age was ascertained by examination of birth certificate or another official document, and was frequently found to differ from the age reported by the parents in the census. Therefore the actual age range of the children was 6–71 mo rather than the 6–59 mo age range selected from the census.
Appetite was assessed by maternal report, a method shown to be valid in Lima. Peru (15). Mothers were asked in the local language, "Lately, how has your child’s appetite been?" The answer was rated on a 5-point scale from very bad to very good. At the follow-up visit, 84% of mothers answered "very good." Therefore the other four categories were combined to create the variable "poor appetite." Mothers were asked to recall all foods and drink given to the child in the past 24 h including breast milk, and this was used to classify current breast-feeding status. Mothers were also asked if their child had illness symptoms in the past week (i.e., fever, cough, diarrhea, dysentery. rapid or difficult breathing), using standard and specific terms in Swahili.
Data analysis.
The effects of mebendazole on wasting malnutrition differed by age and therefore the results are displayed in two age groups, <30 mo and 30 mo. The age cut-off of 30 mo was chosen because it most strongly differentiated preintervention relationships between iron status and parasitic infections (16), and it also differentiated mebendazole treatment effects on the outcomes reported here. Although 30 mo was nearly the median age in the entire baseline sample, it was below the median age of the sample reported in this paper because at baseline, severe anemia was much more common in the younger age group (16) and those children are excluded from analysis. Treatment effects on hemoglobin, serum ferritin and erythrocyte protoporphyrin, severe anemia and poor appetite are reported without age stratification because they were similar in the two age groups. Data are presented with children grouped by the two factors in this factorial trial. that is, children who received iron vs. no iron, and children who received mebendazole vs. no mebendazole. This is appropriate because we found no treatment interaction between iron and mebendazole on any outcome. Thus, the results of interest are the main effects of the interventions. However, we present the primary outcomes (i.e., wasting, stunting, anemia and poor appetite) for each treatment cell (i.e., double placebo, iron only, and so on), thus making potential interactions apparent.
Helminth and malaria infection densities are reported as geometric means because of their highly skewed distributions. Children with no parasites are included in these geometric means by setting their values (for helminth eggs/g feces or malaria parasites/µL blood) equal to 1 before making the logarithmic transformation.
Treatment effects on primary outcomes are reported with and without adjustment for baseline values and other important covariates, using the generalized estimating equation approach (17) to account for the intrahousehold clustering introduced by household-level randomization of the iron intervention. Anthropometric Z-scores were computed using Anthro version 3.0 (CDC, Atlanta, GA). We defined underweight as weight-for-age Z-score less than -2, stunting as height-for-age Z-score less than -2. and wasting as weight-for-age less than -2. Wasting was too rare to analyze as an outcome variable, and therefore mild wasting (weight-for-height Z-score less than -1) was used. This is biologically relevant because the excess morbidity and mortality risk associated with malnutrition occur in mild-to-moderate malnutrition as well as severe malnutrition, and in sub-Saharan Africa, most of the excess mortality attributable to malnutrition stems from mild-to-moderate malnutrition (18). For mid-upper aim circumference, values below the 5th centile of sex- and age-specific reference data of the WHO were considered to reflect malnutrition (19). For anemia as an outcome, we used the WHO anemia definition for this age group (<110 g/L. termed mild anemia in this paper), and also two alternative cut-off points, <90 g/L (moderate anemia) and <70 g/L (severe anemia), because the effects of anemia on child health and development become more profound as anemia becomes more severe (20).
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Stunting occurred in 38% of children and 31.2% were underweight. Wasting occurred in only 3.8% of children, and was most common in 1-y-olds (12–23 mo, 10% prevalence). Nevertheless, the children were thinner than the reference population, with 33% of the sample having weight-for-height Z-scores less than -1 compared with an expected proportion of 16%. Another indication of the thinness of the children was their small arm circumferences, with 16% of values falling below the 5th centile of the international reference. Small arm circumference was more prevalent in older infants (6–12 mo) and 1-y-olds (
25%) than in children > 24 mo old (12.3%).
Rates of breast-feeding were 97% in older infants, 75% in 1-y-olds, and 3% in 2-y-olds. Only one child in the 30 mo age group was being breast-fed at baseline. Appetite, reported by mothers on a 5-point scale (higher values being worse) was worse in younger children (<30 mo, n = 183, 2.3 ± 1.0) than older children (30 mo, n = 275, 1.9 ± 0.9, P < 0.001). As expected (15), appetite was worse in children whose mothers reported a recent fever (n = 204, 2.3 ± 1.1) than in those with no recent fever (n = 252, 1.8 ± 0.8, P < 0.001).
At baseline 94% of children had mild anemia and 78% had elevated ervthrocvte protoporphyrin (>90 µmol/mol heme), but only 23% had low serum ferritin (<15 µg/L). In this study population, serum ferritin was elevated by subclinical infection, including malaria, as described previously (16).
Most characteristics of the children were similar across the treatment groups (Tables 1, 2, 3, 4), with height-for-age in the younger age group as an exception. Stunting was more common in children who received iron compared with no iron, and more common in children who received mebendazole compared with no mebendazole (Table 1). This was driven by a high rate of earlier stunting in the children assigned to the iron - mebendazole group. The rates of stunting in children <30 mo old in the four treatment cells were: double placebo, 14/55 (29%); iron only, 14/43 (33%, P = 0.44 compared with double placebo), mebendazole only 9/33) (27%, P = 0.85); iron + mebendazole, 24/49 (49%, P < 0.02).
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Mothers and children generally liked the iron supplement. According to mothers’ weekly report, >90% of children received at least 70% of the intended doses. The serum ferritin concentrations at the end of the trial confirm that children actually consumed the iron supplement (Table 2). Serum ferritin, which is both an iron storage protein and an acute phase protein, increases with iron consumption or with recent illness. However, at the 12-mo assessment when blood was collected for serum ferritin and other assays, reported rates of recent illness were not higher in the iron-supplemented children. For example, fever in the past week was reported in 27% (63/232) of children who received iron and 37% (85/227) of children who did not (P = 0.09). The mebendazole was also accepted well by mothers and children; >92% of children received at least 3 of the 4 intended doses during the 12-mo study period.
Parasitic infections.
Helminth infections were prevalent, and increased strikingly with age (Table 3). Mebendazole was highly effective in controlling A. lumbridoides, somewhat less effective against T. trichiura and least effective against hookworms, especially in older children. The relative effectiveness of a single dose of mebendazole on the three geohelminths in this trial was consistent with other reports in the literature (21,22).
Malaria infection is strongly associated with anemia in young children in this sample (16). Malaria infection was very common, but its prevalence and intensity were similar across treatment groups, both before and after treatment (data not shown).
Anthropometry and appetite outcomes.
Iron had no significant effects on mild wasting or stunting malnutrition in either age group after adjusting for baseline anthropometric status (Table 4). Mebendazole significantly decreased mild wasting malnutrition in the younger age group only. This was evident in both indicators of thinness. In children <30 mo old, mebendazole decreased mild wasting malnutrition by 62% (95% CI: 10, 84) and prevalence of small arm circumference by 71% (95% Cl: 9, 81).
The adjusted odds ratios (AORs) for stunting in children <30 mo old were >1, indicating that there were more stunted children in the treated groups, although the CI included 1 after adjustment for baseline characteristics (Table 4). The pattern of stunting in the four treatment cells was nearly identical to the pattern at baseline (see baseline characteristics, above), with similar rates in the double placebo, iron only and mebendazole only groups, and a higher rate in the iron + mebendazole group. When an iron by mebendazole treatment interaction term was entered in this model, the iron and mebendazole AOR in the younger age group were close to 1 [iron AOR: 0.92, 95% CI: 0.25, 3.36; mebendazole AOR: 1.29, 95% CI: 0.32, 5.15], and the treatment interaction term was positive but not significant (1.66, 95% CI: 0.26, 10.60).
We also explored further the mebendazole treatment effects on mild wasting by age because the effect was highly protective in the younger children, but appeared to be adverse in the older age group. This possible adverse effect of mebendazole was limited to children 48 mo old, in whom the AOR was 2.88 (95% CI: 0.82, 10.14). In children 24–48 mo old, the AOR was 1.06 (0.47, 2.38).
Both interventions reduced poor appetite in the children, by 40%, according to mothers’ report. This effect was consistent across age groups; thus the combined results are presented in Table 5.
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The prevalence of mild anemia (<110 g/L) remained high (66–87%) at the end of the intervention period in all study groups, and there were no treatment effects on this outcome in either age group. Similarly, there were no treatment effects on mean hemoglobin concentration, despite large and significant improvements in serum ferritin and erythrocyte protoporphyrin (Table 2). The effect of iron supplementation in children <30 mo old was potentially biologically important (mean ± SD for iron vs. no iron, 99 ± 16 vs. 95 ± 19), but this finding was not significant (P = 0.113).
Neither iron nor mebendazole significantly reduced moderate anemia in either age group (Table 5). However the prevalence in mebendazole-treated children was 30% lower than in children who did not receive mebendazole. We explored this effect further by dividing the sample into three age groups. The protective effect of mebendazole occurred exclusively in children <24 mo old and was significant in this age group (Fig. 2). To determine whether this effect was explained by improved iron status, we examined mebendazole’s effects on within-child changes in serum ferritin in the three age subgroups. A strong age modification was apparent, but in children <24 mo old, mebendazole treatment decreased the serum ferritin increments.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Iron supplementation did not affect mild or moderate anemia or growth retardation. but reduced the prevalence of severe anemia at the final assessment by 66% (95% CI: -2, 89, P = 0.066). This large effect was marginally significant because of the small number of severely anemic children at the end of the trial, but is consistent with the trial conducted by Menendez et al. (23) in Ifakara, Tanzania. In that trial, low dose daily iron was provided to infants from 2 to 6 mo of age, and it reduced the incidence of severe anemia (hemoglobin < 80 g/L) in the second half of infancy by 29%. Although we treated and excluded severely anemic children at baseline, and the incidence of severe anemia was not a primary outcome of this study, our result is consistent with the conclusion that low dose daily iron supplementation substantially prevents severe anemia in young children exposed to intense transmission of P. falciparum malaria.
At the same time, iron supplementation was remarkably ineffective in preventing mild-to-moderate anemia, despite the fact that iron status improved. Although a lack of hemoglobin response to iron supplementation is sometimes taken as evidence that iron deficiency does not exist, we did not draw this conclusion from our data, for three reasons. First, the evidence from multiple iron status indicators measured in these children at baseline (16) confirmed severe iron deficiency. Second, iron treatment had a large preventive effect on severe anemia, and it is implausible that only the severely anemic children were iron deficient. Third, in the same sample of children, iron treatment significantly improved motor and language development (12), which can be explained only by a correction of iron deficiency severe enough to limit the biological systems involved in learning and behavior. Thus, we conclude that other anemia-causing factors such as malaria, vitamin deficiencies, ineffective erythropoiesis due to inflammatory processes, or hemoglobinopathies imposed a ceiling on the children’s hematologic response to iron.
Other trials of iron supplementation to children 6 mo old in malaria endemic parts of sub-Saharan Africa had greater effects on hemoglobin than did our trial. Trials in the Gambia (24) and Ethiopia (25) used daily iron doses at least three times greater than we did, and both observed significant increases in mean hemoglobin. A recent trial in Kenya (26) administered twice weekly doses [6 mg/(kg · wk)] of iron to children 6–36 mo old, approximated the weekly dose in our trial, although our supplement was given in smaller daily doses (10 mg/d). They reported a 12.5 g/L significant increase in hemoglobin in the iron supplemented group compared with the placebo group. All three of these trials were carried out in sites with less intense malaria transmission than Zanzibar. We found a 4 g/L increase in hemoglobin concentration in the younger age group, which was not significant. Although we achieved our estimated required sample size in each age subgroup, our actual statistical power was only 67% because the variation in hemoglobin response within children was larger than we had anticipated (16 vs. 9 g/L). Nonetheless, the hemoglobin response to iron supplementation in this study was lower than expected and, from a public health standpoint, disappointing.
The low daily iron dose that we used was equal to the U.S. recommended daily allowance (10 mg/d) (27), and similar to the WHO-recommended dose of 12.5 mg/d for children <24 mo old (8). However, the WHO recommends a higher dose (20–30 mg/d) for children 2–5 y of age, and it is possible that a higher iron dose would have yielded more benefit in Pemban children. Our dose was intentionally kept at dietary levels because of the concern that supplemental iron at higher doses given for 12 mo might exacerbate malarial infection. However, no exacerbation was observed. It is possible that a higher iron dose would have been more efficacious.
It is noteworthy that two children consumed potentially toxic amounts of iron in the context of a supervised research trial, despite child-proof packaging and safety information provided to mothers. Our recourse was to reduce the maximum amount of iron in a household to <800 mg. In our opinion, iron supplementation programs should follow a similar guideline. Although treatment with mebendazole is not routine in children <2 y old, we observed no adverse effects from this treatment, as we reported previously (28).
As expected, the benefits of mebendazole treatment were modified by age, but the direction of the differential effects by age were contrary to our earlier expectations. Mebendazole improved growth only in children <30 mo old and reduced moderate anemia only in children <24 mo old at the start of the trial. The benefits thus occurred in the age group at highest risk for anemia and growth retardation, but in the age group with the lowest intensity of helminth infections. The magnitude of reduction in mild wasting malnutrition was similar to or greater than the benefits observed from dietary interventions in young children (29).
In addition to these significant benefits in mebendazole-treated young children, mebendazole was associated with higher rates of stunting in younger children and higher rates of mild wasting (weight-for-height Z-score less than -1) in older children, although neither effect was significant. We believe that the higher rates of stunting in younger children represent residual confounding, evidenced by the nearly identical pattern of stunting seen in the treatment cells at baseline. The excess mild wasting in mebendazole treated children was found to be limited to children 48 mo old, but this odds ratio was not significant in any age subgroup. It seems implausible that mebendazole would harm 4- and 5-y-old children but not younger children, and we conclude that this elevated odds ratio was observed by chance.
The young children in this study had very light helminth infections, which is why we expected that they would not benefit from anthelminthic treatment. It is therefore important to hypothesize how mebendazole might have improved growth and hematopoiesis in these young children. Several pathways have been proposed to explain the potentially adverse effects of helminth infection on malnutrition. These include decreased intake, consumption of nutrients by the worms themselves, impaired absorption, increased nutrient loss or altered metabolism (30–32). Mebendazole did improve children’s appetites in this study, but this effect is unlikely to fully explain our results because appetite improved in both age groups and also with iron treatment, whereas the effects on mild wasting malnutrition and anemia were limited to mebendazole treatment in children <30 mo old. The mechanisms by which helminths impair nutrient absorption, increase losses or consume nutrients needed by the child are most plausibly linked to the number of worms inhabiting the gut. It is difficult to believe that worms would affect intestinal absorption or leakage more in young children than in older children, who were only 50% bigger by weight than their younger counterparts but harbored 5 times more Ascaris worms, and 10 times more Trichuris and hookworms.
We therefore hypothesize that the surprising benefit to young children might be explained by a combination of two things. Children in this age period are at highest risk for the outcomes of anemia and wasting malnutrition and thus are most vulnerable to the deleterious effects of worms. Second, children during the same period are acquiring first time helminth infections, which we speculate may induce proinflammatory mediators that are detrimental to protein metabolism (33,34), appetite (35,36) and erythropoiesis (37,38). This hypothesis is consistent with the observation that mebendazole decreased increments of serum ferritin (an acute phase protein) with the same differential age response. However, it is also possible that mebendazole acted directly on the intestinal microflora or intestinal immune function through pathways that do not involve worms.
Our assessment of appetite yielded interesting findings, because mothers reported greater improvements in children’s appetites after treatment with iron or mebendazole. Because this study was randomized and double-blind, we conclude that some real change occurred in mother-child feeding interactions due to the interventions. However, our appetite question was not validated against actual intakes, and it is clear from the distribution of responses that mothers did not fully appreciate the meaning of the five- point Likert scale. From this and other experiences interviewing Pemban mothers, we found that they are averse to reporting that anything is "bad" about their children. Future studies of appetite in this setting will require development of more informative methods.
Several other randomized trials of anthelminthic treatment in preschool children were reported. These trials employed a variety of drugs and treatment schedules, included children of various ages with different degrees of nutritional risk, and had divergent results. Studies in Tanzania (39), Myanmar (40) and India (41) reported benefits to growth, studies in Bangladesh (42,43), Ethiopia (44), Guatemala (45) and Brazil (46) reported no benefit to growth, and one study in Zaire (47) reported poorer growth in children treated for worms. It seems likely that there are certain conditions in which anthelminthic treatment can improve growth of children, but further research is required to elucidate those conditions. It is noteworthy that nearly all other randomized trials were conducted in populations affected mainly by ascariasis. It is possible that the worm species being treated affects the growth benefit from treatment. and that the large benefit to young children in our study was due to the presence of Trichuris or hookworm infection. It is also remarkable that all four of the positive trials (including ours) reported benefits in ponderal growth, but only one reported a benefit to linear growth (40). In our study, the youngest children benefited exclusively from mebendazole, and many other trials did not include children <2 y old. Indeed, if we had not designed this study to look for differing effects by age subgroup, we would have missed the important benefits to toddlers.
In summary, we observed unexpected benefits of anthelminthic treatment to very young African children. Iron supplementation prevented severe anemia, but did not reduce mild or moderate anemia in this population. Control of anemia in this population clearly requires a more comprehensive intervention than only low dose daily iron. The reductions in mild wasting malnutrition and anemia that we observed after mebendazole treatment are large and potentially important to the development and survival of these children. This observation should be replicated. If it is true, helminth control programs currently targeted to school-age children should be expanded to include young children.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 23 May 2003. Initial review completed 30 June 2003. Revision accepted 22 October 2003.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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