The findings from IZiNCG’s Zinc in Powders Trial (ZiPT), conducted in collaboration with icddr,b, are published! ZiPT was a randomized, partially double-blind, controlled, community-based efficacy trial involving 2886 young children in Dhaka, Bangladesh. Children 9-11 months old were randomly assigned to one of six different intervention groups: a standard micronutrient powder (MNP) containing 4.1 mg zinc and 10 mg iron, daily; a high-zinc (10 mg), low-iron (6 mg) MNP, daily; high-zinc low-iron and high zinc, no-iron MNPs on alternating days; dispersible zinc tablet (10 mg), daily; dispersible zinc tablet (10 mg), daily for 2 weeks at enrollment and 12 weeks; and placebo powder, daily. The interventions were provided for 24 weeks, and intensive twice weekly morbidity surveillance occurred over the intervention period. To summarize the key findings, there were no differences in the incidence or prevalence of diarrhea across intervention groups, and only the high-zinc, low-iron MNP group had a slightly smaller decline in length-for-age z-score compared with the placebo powder group, prompting a corresponding editorial to ask “has zinc lost its shine?”.
ZiPT was designed to narrow a host of evidence gaps around preventive zinc supplementation and MNP formulations. Despite the consistency of evidence for preventive zinc supplementation in reducing the incidence of diarrhea and eliciting small but significant increases in height, no formal recommendations for preventive zinc supplementation exist. MNP programs are reaching over 10 million children globally, and the standard MNP formulation includes 15 micronutrients, including zinc. Hence MNPs are an attractive vehicle for delivery of preventive zinc and other essential vitamins and minerals to young children. At the time ZiPT was designed, there was some limited evidence that MNPs may be associated with an increase in diarrheal incidence and it was hypothesized that the iron content of the MNPs may be a contributing factor. Furthermore, the available evidence indicated that MNPs had minimal effects on child growth, and evidence was emerging that the amount of zinc in the standard MNP formulation (4.1mg) was probably insufficient in settings with a high prevalence of environmental enteric dysfunction (EED). Lastly, the effect of zinc-containing MNPs on serum zinc concentrations was inconclusive.
The findings from ZiPT underscore the reality that micronutrient supplementation is not a “silver bullet” to improving functional child health outcomes, and that several other factors such as EED, premature introduction of complementary food of poor nutritional quality and intrauterine growth restriction may have had a more substantial impact on diarrhea and linear growth in this study population. However, there are several important take-home messages from the ZiPT findings that deserve highlighting.
First, it was reassuring that MNPs did not cause a higher incidence or prevalence of diarrhea, as previously observed in some trials.
Second, the lack of an effect of stand-alone preventive zinc supplementation on rates of diarrhea was somewhat surprising and contrasts much of the literature, particularly given the high burden of diarrheal disease and high compliance to the study interventions in this population. However, a recent trial in Laos among children aged 6–23 months similarly found that neither preventive zinc nor MNPs significantly reduced the incidence or duration of diarrhea. It is possible that therapeutic zinc, received by all children according to WHO guidelines when experiencing a diarrhea episode, may have helped prevent future episodes of diarrhea among children in all groups. It is also possible that the higher doses of therapeutic zinc supplementation may have local, pharmacologic effects on the gastrointestinal tract, thereby reducing the risk of diarrhea in contrast to lower-dose preventive zinc supplementation.
Third, both the daily dispersible zinc tablet and the high-zinc, low-iron MNP formulation, which provided 10mg of zinc, did a remarkable job at improving serum zinc concentrations: the prevalence of low serum zinc concentrations fell from 48% to 6% and 29% to 12%, respectively. These marked improvements in zinc status in the absence of a response in functional outcomes raise the possibility that the 24-wk duration of ZiPT may have been insufficient to elicit a response in linear growth. However, the modest improvements in linear growth among children in the daily high-zinc, low-iron MNP group compared with the placebo powder group suggests that the zinc content in the standard MNP formulation may need to be increased, at least in populations at risk for EED.
Where to next? Should MNPs be recommended as an intervention to improve zinc status despite the lack of impact on diarrhea and linear growth? Given the need for targeted interventions to improve zinc intakes of children 6-23 months of age layered on top of population-based strategies such as large-scale food fortification, MNPs remain an attractive vehicle with potential benefits beyond simply delivering additional zinc and other micronutrients. Furthermore, there is no “one size fits all” approach. Ideally, micronutrient delivery approaches need to be designed and tailored according to local dietary practices, micronutrient deficiency prevalence data, and the existence of other interventions. We will be sharing more findings from ZiPT soon. Stay tuned for a deep dive.
The ZiPT trial is a collaboration between icddr,b, IZiNCG, the University of California, San Francisco, Johns Hopkins University, and the University of Colorado. Funding for the trial was provided from the Bill & Melinda Gates Foundation to IZiNCG.