The main question examined in this review was the effect of anthelmintics on growth and cognitive performance. Therefore we did not examine drug effects on intermediate outcomes such as worm infection. Head to head comparisons of different drugs are not included as these are not relevant until benefits in placebo controlled comparisons have been shown. We did not consider intermediate laboratory variables such as haemoglobin concentration. In fact, of the trials that met our inclusion criteria only three reported this outcome in a manner that could be used in the meta-analysis, and the evidence of an effect is limited.50
We intended to analyse effects by prespecified factors that could influence these estimates, including the presence of malnutrition, infection species, and intensity of infection. We also intended to stratify our analysis by age, as this will strongly influence the size of many growth outcomes. The data available from individual trials, however, were insufficient to allow subgroup analysis or meta-regression by any of these factors. Analysis of data from individual patients might start to unravel these subgroup effects but would be a large task.
Not unexpectedly, and probably related to the factors mentioned above, several meta-analyses showed heterogeneity between the results from different trials. We considered presenting only those results with no heterogeneity. Most growth outcomes are correlated within patients, however, so we judged that reporting only those meta-analyses where heterogeneity was absent would be a bias in itself. For this reason, we present all meta-analyses, and, where there was significant heterogeneity, we have provided analysis using both fixed and random effects models. The wide confidence intervals with random effects reflect the heterogeneity in the available data. Full details of individual trial data are available from the Cochrane Library.50
The analysis highlighted several methodological issues that should be examined in future trials. Firstly, trial quality varied. Most trials were small, and few reported that they concealed allocation.
Secondly, most researchers obtained multiple growth measures, but their reporting of these was inconsistent. Authors variously reported absolute values, changes in values, indices of values (such as weight for height, height for age), and comparison of values with accepted international reference data. Researchers did not indicate their a priori primary outcome. We were therefore unable to assess whether the data presented were the intended primary outcomes or whether a number of growth outcomes were measured with the authors reporting only on significant results. This bias, termed selective reporting, may be done unwittingly by researchers but is potentially an important unresearched source of bias in systematic reviews of published literature.
Thirdly, growth is an indirect measure of health outcome, and only one study examined more direct measures such as illness or mortality. Evans et al attempted to examine morbidity measures such as episodes of diarrhoea, respiratory infection, or measles.20
The results of their study indicated that there were fewer episodes of measles in treated children.
Finally, policy makers assume that these interventions improve school attendance, and we specifically sought this outcome. Two studies measured this, and neither found an effect. Other studies used cognitive tests, but what these mean and how they relate to a child's wellbeing is not clear. Researchers used a wide range of tests, which made direct comparison difficult. Even when the same test was used, such as the digit span (forwards) and verbal fluency test, the effects were not consistent between studies. Again, the hypothesis that routine anthelmintic treatment will benefit a subgroup of the population could not be explored with the data available to us. A further difficulty is that most tests for cognitive performance have not been validated outside Western countries.51,52
On the other hand, the real problems in implementing these trials should not be underestimated, and difficulties can result in contamination, which mitigates against the detection of true effect differences between groups. In the study by Evans et al, in which fortnightly assessments were carried out, the researchers found that a proportion (>30%) of children in the placebo group had actually received intermittent anthelmintic treatment.20
The reported crossover rate in the Awasthi trial further indicates the difficulty in maintaining treatment groups within a study population (S Awasthi, unpublished data).
Our interpretation of these findings is that the evidence of benefit for mass treatment of children related to positive effects on growth and cognitive performance is not convincing. In the light of these data, we would be unwilling to recommend that countries or regions invest in programmes that routinely treat children with anthelmintic drugs to improve their growth or cognitive performance.
There is a need for good quality, properly concealed, placebo controlled trials to investigate the impact on these outcomes. It is inefficient, unjustified, and irrelevant to carry out head to head comparisons of different anthelmintic drugs. A large cluster, randomised trial in India is currently examining mortality as an outcome, and the results of this work will be an important contribution. International coordination, possibly through the WHO, is required to ensure that future trials are similar in design and that researchers agree in advance to pool individual patients' data in a meta-analysis and to explore hypotheses about subgroup effects in relation to age, worm load, and exposure to infection.
What is already known on this topic
Many children in developing countries are infected by intestinal helminths and infection is associated with poor nutrition
In endemic areas the World Bank and others widely promote routine regular mass treatment of children with anthelmintics
What this study adds
There is little evidence to support the use of routine anthelmintic treatment to improve growth and cognitive performance in children in developing countries