The trial profile is shown in . Baseline characteristics were similar between intervention groups (). The prevalence of zinc deficiency was high (67%). Giardia infection was detected in 192 children (31%), and 426 children (70%) were stunted.
Baseline characteristics of study participants, by intervention group.
Twenty children (3%) did not complete the trial: three died, two were withdrawn by parents, and 15 emigrated from the area (). Another two children discontinued the intervention but were available for follow-up. Compliance was high (96%) and similar in all four groups.
Effect of supplementation with zinc (left panel) or multi-nutrients (right panel) on selected morbidity outcomes.
There were 3,268 clinic visits during the study period, of which 2,462 (75%) were accompanied by guardian-reported fever and 1,572 (48%) classified as malaria. Among the non-malarial fever cases, 658 were accompanied by diarrhea, cough, or other localizing signs, either alone or in combination, while 232 fever cases were without localizing signs (). For 223 children (36%), parents or caretakers reported at least one episode of diarrhea. A total of 390 diarrhea episodes were recorded, with an incidence rate of 0.74/child-year. There were 1,333 episodes of reported cough, but only few (181) fulfilled criteria of ALRI as established by the World Health Organization 
. The number of severe pneumonia cases (24) was insufficient for meaningful analysis. There were 744 visits for other reasons, mainly abscesses and symptoms involving skin, ears, and eyes.
Incidence rates for various illnesses, stratified by the presence of fever.
Upon examination of interaction effects (), we found no evidence that concurrent supplementation with multi-nutrients influenced the magnitude of the effect of zinc on rates of diarrhea, respiratory illness, fever without localizing signs, or other illness. Thus in the remainder of this report, we will present marginal effects whereby the effect of multi-nutrients is assessed by comparing the pooled groups receiving placebo or zinc with the pooled groups receiving multi-nutrients, and the effect of zinc is assessed by comparing the pooled groups receiving no zinc (with or without multi-nutrients) and the pooled groups receiving zinc (with or without multi-nutrients).
Incidence of various illnesses, by treatment group.
Zinc supplementation reduced the rate of diarrhea by 24% (95% CI: 4% to 40%) (), while multi-nutrients seemed to increase rates by 19% (–6% to 50%). We found similar effects when restricting the analysis to cases of diarrhea with ≥3 loose stools/24 h (). The protective effect appeared more evident for cases of diarrhea that were accompanied by fever (HR 0.73; 0.55–0.98) than for those not accompanied by fever (HR 0.80; 0.55–1.16), but the difference in effect was small.
There was no evident effect of either intervention on episodes of respiratory illness, whether defined as reported cough or as cough with fast breathing, or on episodes of other illnesses (). By contrast, zinc reduced the rates of fever without localizing signs by 25% (4%–43%; adjusted for age class and distance between homestead and research clinic).
Age was strongly predictive for all morbidity outcomes, but there was no evidence that age class influenced the magnitude of the effect of the interventions for any of the outcomes considered (not shown). We found weak evidence that the zinc-induced reduction in diarrhea rates was more pronounced in stunted children (0.66; 0.49–0.90) than in those with a lesser degree of stunting (0.95; 0.62–1.45; interaction effect: 0.68 (0.41–1.15); ; upper panel, left).
Subgroup analysis of effects of supplementation with zinc or multi-nutrients on diarrhea (top panels) and fever without localizing signs (bottom panels).
The effect of multi-nutrient supplementation on diarrhea depended on the presence of Giardia
infection at baseline (; upper panel): multi-nutrient supplementation doubled the rate of diarrhea among those with Giardia
at baseline (2.03; 1.24–3.32), whereas it had no obvious effect among those without Giardia
infection (1.03; 0.78–1.36). This difference in intervention effect between Giardia
-positive and Giardia
-negative children was independent of age and stunting, and unlikely to have occurred by chance (interaction effect: 1.98; 1.13–3.47; p
With regards to the effects of multi-nutrients on fever without localizing signs, patterns observed in the subgroup analysis largely resembled those observed for diarrhea (; lower panel). Both Giardia infection and being stunted at baseline determined the magnitude of the effect of multi-nutrients on disease rates. Multi-nutrients resulted in increased rates (1.39; 0.82–2.36) in children with Giardia infection and decreased rates in those without (0.74; 0.53–1.03) (interaction effect: 1.86; 1.00–3.47). In stunted children, however, multi-nutrients decreased rates (0.67; 0.46–0.97), whereas in children with a lesser degree of stunting, multi-nutrients seemed to increase rates (1.46; 0.93–2.28; interaction effect: 0.47; 0.26–0.83).
Lastly, multi-nutrients also increased the rate of reported cough among stunted children, but not so in their less stunted counterparts (HR: 1.34; 1.06–1.69 versus 0.98; 0.82–1.17; p-value for interaction: 0.05). When analyzing effects on ALRI, a similar pattern was seen (1.41; 0.79–2.52 versus 0.99; 0.65–1.50 among stunted and less stunted children respectively), but the number of cases was lower and thus the statistical evidence for this interaction weaker (p