School-based deworming has been advocated as a highly cost-effective public health measure in less-developed countries (World Bank 1993). It is estimated that over 1 billion people are infected with Ascaris lumbricoides, 880 million with hookworms, and 770 million with Trichuris trichiura (Warren et al. 1993), and school children are the group most heavily infected with these geohelminths (Savioli et al. 1992). The expected benefits from deworming in this age group are improved school participation and performance, growth and iron status (Warren et al. 1993).

Improved growth of primary school children could result in greater adult height, which is associated with greater work capacity in men and women and with improved reproductive outcomes in women (WHO Expert Committee 1995). We previously published evidence that Zanzibari school children experience significant linear growth retardation compared with international growth references (Stoltzfus et al. 1997a). Because helminth infections are highly prevalent in Zanzibar, the growth of school children might be improved if helminth infections were controlled.

Several efficacy trials of antihelminthic therapies in school children have produced promising results (Kruger et al. 1996, Latham et al. 1990, Stephenson et al. 1989, 1993a and 1993b), especially in coastal East Africa, where helminth infections are prevalent and intense. In these controlled randomized trials, growth, appetite, fitness and iron status improved in children treated with antihelminthic drugs. However, evidence is lacking in the literature on the program effectiveness of large-scale school-based deworming efforts.

We report here the results of an evaluation of a school-based deworming program implemented by the Ministries of Health and Education of Zanzibar on Pemba Island. The evaluation measured the effect of the program on helminth infections, nutritional status and school attendance and compared the effects of two deworming schedules, twice-yearly and thrice-yearly. A single 500-mg dose of generic mebendazole was chosen as the antihelminthic treatment because of its simplicity and low cost (US$0.027 per dose, Albonico et al. 1994). We describe the effect of twice-yearly and thrice-yearly deworming on the height and weight gains of primary school children in Zanzibar.

METHODS

On the basis of a trial of antihelminthic drugs conducted in Pemba (Albonico et al. 1994), a single 500-mg dose of generic mebendazole was chosen as the regimen to be used in the program. Although mebendazole did not control hookworm infection as well as albendazole, its effect on A. lumbricoides and T. trichiura infections was similar to that of albendazole, and the cost of mebendazole was around 10% the cost of albendazole at that time. A thrice-yearly regimen was chosen because of the rapidity of reinfection with helminth infections (Albonico et al. 1995) and the limited efficacy of mebendazole against T. trichiura and the hookworms.

Of the 72 public primary schools on Pemba Island, 12 schools were randomly selected for evaluation (Fig. 1). Pemba is divided into four districts of roughly equal size, and the selection of schools was stratified by district, so that three schools in each district were chosen. Within districts, the schools were randomly allocated to the control, twice-yearly or thrice-yearly group. All children within a school received the same program regimen. For logistical reasons, only morning classes were selected for the survey. Although the deworming program was administered to all classes of grades 1-5, only classes of grades 1-4 were included in the evaluation of nutritional effect, because malnutrition was expected to be of greatest importance in younger children. Grades 1 and 2 were deliberately overrepresented for the same reason.

Baseline, 6-mo and 12-mo follow-up nutrition and parasitology surveys were conducted in March-May 1994, October-November 1994 and March-May 1995, respectively. The design was based on the comparison of within-individual changes in childrens' nutritional status from baseline to 12 mo in each treated group vs. the placebo group, and these are the analyses presented in this article. The 6-mo follow-up survey was planned to provide an interim measure of program effect for evaluation of whether a nontreated group could be maintained ethically. The full battery of assessments was not completed at 6 mo, and those data are not presented here. A sample size of 1000 children per group was estimated to be sufficient to compare the twice-yearly and thrice-yearly program groups with the control group, accounting for the design effect of randomizing at the school level and planning for subgroup analyses.

Before the study began, meetings were held at each school to inform parents of the deworming regimen that would be implemented in their school, the purpose of the evaluation, its risks and benefits, and alternatives to participation in the surveys. All children present in school on survey days were invited to participate in each survey. Children found to have hemoglobin <70 g/L (3.5% of children) were treated with mebendazole and oral iron supplements. Inclusion or exclusion of these children did not affect the growth results, and they are included in the analyses presented here. Overall, 91% of children listed on teachers' class registers participated in the baseline survey, and 85% of those children were assessed again at the 12-mo follow-up, in the following school year (Fig. 1). Compared with children who completed the study, those lost to follow-up were similar in all measured characteristics except that they were more likely to be boys (60.0% vs. 50.3%, P < 0.001) and less likely to be stunted (height-for-age Z-score < 2, 42.1 vs. 48.6%, P < 0.005). Both of these characteristics were associated with greater growth effect from deworming (see Results); thus, any bias caused by loss to follow-up would act to diminish the effect that we measured. The study was approved by the institutional review boards of The Johns Hopkins University, the World Health Organization and the Ministry of Health of Zanzibar.

Parasitological methods are described in greater detail elsewhere (Stoltzfus et al. 1997b), and are briefly recounted here. Stool containers were given to children on the day before the survey, and they were instructed to bring a sample of their stool to school the next day. About 95% of children returned stool samples in each survey. Quantitative counts of helminth eggs in feces were determined by the Kato-Katz method (WHO 1994). Urine samples were collected from 100% of children. Microhematuria was determined using Hemastix test strips (Ames Laboratories, Elkhart, IN) and was used as a proxy indicator of urinary schistosomiasis (Savioli et al. 1990). Thick and thin blood films were stained with giemsa, and malaria parasites were counted against leukocytes using standard methods (WHO 1991).

First, baseline characteristics of the treatment groups and the placebo group were compared using simple linear regression. Characteristics that differed to a potentially biologically important degree were controlled for in subsequent tests of program effect.

The measures of program effect on growth were the 12-mo weight and height increments for each child. All analyses were performed at the individual level and were adjusted for within-school correlations using the generalized estimating equations approach (Diggle et al.). Some baseline characteristics of children in the three program groups differed at baseline (Table 1). Thus, the overall 1-y program effects on weight and height increments of children in twice-yearly and thrice-yearly dewormed schools were compared with those in control schools, using multiple linear regression to adjust for characteristics that differed at baseline.

Table 1. Baseline characteristics of study children by program group1 [View Table]

Given the heterogeneity of school children, we expected that some subgroups of children would benefit more from deworming than others. Multiple linear regression models with program group interaction terms were used to test whether program effects were greater in children with certain baseline characteristics. Baseline characteristics associated with greater benefit from the program are termed predictors of benefit. Interactions with program group were considered potentially important if they were significant at P levels <0.15 and if they were consistent in both program groups.

Analyses were conducted separately for children <10 y and 10 y of age, to separate the effects on pre-pubertal and pubertal growth. Sexual maturation was not assessed. Height-for-age Z-scores were determined using the anthropometric subroutines of EpiInfo, version 6 (Centers for Disease Control and Prevention, Atlanta, GA). Weight-for-height Z-scores and body mass index [BMI, weight (kg)/height² (m²)] percentiles were considered as indicators of thinness. Body mass index is presented here because it is recommended for assessing children >10 y of age, whereas weight-for-height Z-score is not (WHO Expert Committee 1995), and there are no recommendations for assessing thinness in children 6-10 y old. The BMI percentiles were defined by the sex and race-specific tables of Must et al. (1991a and 1991b). Analyses were performed using Systat (SPSS, Chicago, IL) and SAS (SAS Institute, Carey, NC) statistical software.

RESULTS

There were several significant differences among the three program groups at baseline (Table 1). This is not surprising, because only 12 schools were randomly allocated. Both program groups had more hookworm and T. trichiura infection than the control group, but the twice-yearly group had less A. lumbricoides infection than the other groups. In terms of anthropometry, the twice-yearly group was less stunted than the other two groups at baseline.

Table 2. Prevalence and intensity of helminth infections by program group at 12-mo follow-up survey [View Table]

Table 3. Overall adjusted 12-mo growth increments in children in control, twice-yearly or thrice-yearly deworming program schools [View Table]

Among children 10 y old, shortness-for-age again predicted weight gain from deworming (Fig. 3). Children who were less stunted (higher height-for-age Z-score) at baseline gained more weight in response to deworming. Also, in this age group, age and sex predicted height gain from deworming. Girls grew less than boys in response to deworming, and the growth response was greatest in younger boys. Ten-year-old boys gained 0.31 cm more in the twice-yearly group (P < 0.020) and 0.49 cm more in the thrice-yearly group (P < 0.025) compared with the control group.

The presence or intensity of the three geohelminth infections at baseline did not predict benefit from the deworming program for either weight or height gain, nor did iron deficiency or anemia.

DISCUSSION

The fact that control of helminth infections improved the linear growth of children <10 y old also provides support for our previous inference that Zanzibari children experience linear growth retardation during their early school years (Stoltzfus et al. 1997a). If these children were achieving their genetic potential for linear growth in the absence of intervention, then antihelminthic treatment would not have increased their rate of linear growth.

However, the magnitude of the growth response to deworming was small. This can be illustrated in several ways. In children <10 y of age, the growth responses in the thrice-yearly program group were 0.2 kg/y and 0.3 cm/y. Compared with the control group gains, these represent improvements of 10% in weight and 7% in height. The largest height responses to deworming, seen in less stunted children receiving thrice-yearly deworming, were around 0.5 cm/y, or 12% of control height gains. These gains do not bring the growth of Zanzibari school children in line with the international growth reference. An average 9-y-old child tracking at the median of the WHO reference for height would gain 3.7 kg/y and 5.7 cm/y (average of values for boys and girls, from WHO 1983).

Because Zanzibari children will benefit from the school-based deworming program throughout their primary school years, the effect on growth has a long period of time to accumulate. If children gained an extra 0.3 cm/y from the thrice-yearly deworming program, over a 5-y period they might accumulate a height benefit of 1.5 cm. For an 11-y-old boy, this represents an improvement in height-for-age of 0.22 Z-scores (WHO 1983). Even the largest height benefit we observed in a subgroup, 0.5 cm/y, would mean an improvement of only 0.37 Z-scores if sustained over a 5-y period.

A series of smaller randomized placebo-controlled efficacy trials conducted in Kenya, where the epidemiology of geohelminths is very similar to that in Zanzibar, found larger growth responses to antihelminthic treatment than we did. A single 400-mg dose of albendazole improved height gains by 0.6 cm and weight gains by 1.3 kg in a 6-mo trial in 150 first and second graders (Stephenson et al. 1989). Treatment with metrifonate (which treats both hookworms and S. haematobium) or praziquantel (which treats only S. haematobium) improved height gains by 0.2 cm in a 5-wk trial in 48 pre-pubescent boys infected with both parasites (Latham et al. 1990). A single 600-mg dose of albendazole improved height gains by 0.6 cm and weight gains by 1.0 kg in 53 boys after 4 mo (Stephenson et al. 1993b). However, those boys were part of a larger trial comparing one dose of albendazole in a 8-mo period to two 4-mo doses in 284 boys and girls (Stephenson et al. 1993a). In the larger and longer trial, weight gains improved by 1.0 kg, but there was no effect on height gains.

There are several possible reasons why the growth effect we observed was small. First, there might be other factors limiting the growth of these children in addition to helminth infections, i.e., helminth control is necessary but not sufficient to improve substantially the growth of Zanzibari school children. This explanation is supported by the consistent finding that less stunted children had the greatest growth response to deworming. This effect modification was apparent in both program groups for height and weight gains of children <10 y of age and for weight gains of children 10 y of age. If helminth infection were the only factor holding back the linear growth of children, then we would expect to see the most stunted children having the greatest growth response to antihelminthic treatment. We found the opposite to be true, which is consistent with the idea that something in addition to geohelminth infections is slowing the growth of stunted children.

Under conditions found in areas such as Zanzibar, additional zinc or iron may be needed for children to achieve normal growth. A potential role of vitamin A deficiency can be ruled out, because the serum retinol distribution of first-graders in this sample was nearly identical to that of children in the United States (data not shown). These children were significantly iron deficient (Stoltzfus et al. 1997b), and iron supplementation improved the growth of Kenyan school children (Lawless et al. 1994). We have not evaluated zinc status in this population, but zinc deficiency has been reported in other parts of sub-Saharan Africa (Ferguson et al. 1993). In addition to geohelminths, chronic malarial infection or strongyloidiasis might limit the growth of school children. An effective bednet program improved the growth of preschool children in an area of mainland Tanzania with malaria epidemiology similar to that in Zanzibar (Shiff et al. 1996). The prevalence of Strogyloides stercoralis infection in a subsample of this study cohort at baseline was 41.2% (Albonico, M., and Cancrini, G., unpublished data), but the nutritional consequences of this infection are largely unknown (Stephenson 1987).

A second possible reason for the small growth effect is that anthelminthic treatment might cause a temporary growth spurt that is not sustained. These school children may have multiple "gates", growth inhibitors or missing growth factors, that limit their rate of growth. Geohelminths may be one such growth inhibitor, but when this burden is alleviated the child can grow at a normal rate only until bumping into the next gate. Thus, when evaluated over a 1-y period, the growth effect we observed seems relatively small compared with results from shorter trials.

This explanation is supported by two trials in the literature. First is that of Stephenson et al. (1993a), in which results after 4 mo showed significant height and weight gains; however, when the 8-mo trial was completed, the weight gain had not increased further and the height gain had disappeared (Stephenson et al. 1993b). However, it should be noted that the 4-mo results were reported on a subgroup of boys who may have responded differently from the total group of boys and girls combined. A recent trial conducted north of Cape Town, South Africa (Kruger et al. 1996) also suggests that the effect of deworming on growth velocity abates over time. Iron-deficient 6- to 8-y-old children who received two 200-mg doses of albendazole 4 mo apart had height gains about 0.6 cm greater after 5 mo than children receiving placebo. After 11 mo, the relative height gain remained around 0.6 cm. This study must be interpreted with caution in this context, because the children were also given iron-fortified soup in a factorial design with deworming, and only 73 children composed the iron-deficient subsample.

To explore this possibility in our own data, we compared the observed growth effect using the 6-mo follow-up data to the 12-mo effects. In children <10 y of age, the weight effects (difference between weight increments in the treated vs. control group) after 6 mo were 0.32 kg (P < 0.01) in the twice-yearly group and 0.18 kg (P = 0.12) in the thrice-yearly group. These values are similar to the effects observed after 12 mo (see Table 2). The 6-mo height effects from deworming were 0.15 cm (P = 0.23) in the twice-yearly group and 0.19 cm (P = 0.48) in the thrice-yearly group, values that rather support the assumption that the height effect observed in the thrice-yearly deworming group was gradual throughout the year. These comparisons provide some supporting evidence that deworming causes an immediate increase in weight gain that is not sustained beyond 6 mo. The same does not seem to be true for height. In children 10 y of age, the 6-mo weight and height effects were trivial, and none was statistically significant.

A third possible explanation is that mebendazole controlled hookworms and T. trichiura too poorly to induce a large growth response. Neither of the benzimidazole antihelminthic drugs is very effective against T. trichiura (Albonico et al. 1994). However, the trials conducted by Latham and Stephenson and colleagues in Kenya (Latham et al. 1990, Stephenson et al. 1989, 1993a and 1993b) used antihelminthic treatments that are more effective against hookworms, and larger reductions in the prevalence and intensity of hookworm infection were attained. This explanation is supported by the dose response in the effect of twice-yearly and thrice-yearly deworming on height gains. The height gains of children <10 y of age increased with frequency of deworming, both in terms of the overall group effects (Table 2) and the subgroup analyses (Fig. 2 and 3). However, a similar dose response was not seen in weight gains.

If poor control of helminth burdens is the reason for the small growth effects, then hookworms or T. trichiura rather than A. lumbricoides must be mainly responsible, given that ascariasis was controlled quite effectively by mebendazole. The lack of effect of A. lumbricoides on growth is also suggested by the finding that the growth response to antihelminthic treatment did not differ between children with and without A. lumbricoides infection at baseline (i.e., ascariasis was not a predictor of benefit from deworming). Over 30% of children did not have ascariasis at baseline; thus we had reasonable statistical power to observe this effect if it existed. This is in contrast to the hookworms and T. trichiura, which infected the vast majority of children at baseline.

Finally, the small effect we observed might be due to chance in the particular sample that we used. It is possible that the growth response in this sample of children was at the lower end of effects that will usually result from school-based deworming programs or that the large growth response in the Kenyan trials represents the upper expectation and will probably not be repeated. Additional evaluations of the growth effect of deworming programs are needed to provide reliable expectations of effect for program planners.

In summary, controlling A. lumbricoides infection and reducing the intensity of T. trichiura and hookworm infections in Zanzibari school children brought about small improvements in weight and height gains, particularly in children <10 y of age and in children who were less stunted. The public health relevance of the growth effect we observed is questionable. It is possible that helminth control is necessary but not sufficient to substantially improve the growth of school children in areas such as Zanzibar, and additional interventions or combinations of interventions should be tested. Antihelminthic regimens that are more effective against hookworms should be evaluated in programmatic settings and over time frames of at least 1 y. Improved growth is only one potential benefit from school-based deworming programs, and a final appraisal of the worth of such programs must also consider school participation, educational performance and effect on iron status.

ACKNOWLEDGMENTS