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The Zinc in Powders Trial: more than a "null finding"

The Zinc in Powders Trial: more than a "null finding"

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.

Inclusion of Micronutrient Biomarkers in National Surveys and Surveillance Systems: Barriers and Enablers

Inclusion of Micronutrient Biomarkers in National Surveys and Surveillance Systems: Barriers and Enablers

IZiNCG is pleased to share the report Inclusion of Micronutrient Biomarkers in National Surveys and Surveillance Systems: Barriers and Enablers. This work was conducted with the support of the Micronutrient Forum.

Including biomarkers of micronutrient status in existing or planned national surveys or surveillance systems would dramatically improve capacity to promote, design, monitor and evaluate micronutrient policies and programs. Ultimately, investing in better data would yield healthier populations, safer programs and cost savings. 

Yet, the availability of nationally representative micronutrient biomarker data in low- and middle income countries (LMICs) is scarce. Taking plasma/serum zinc concentrations among pre-school children as an example, only 26 LMICs have published data.

“Micronutrient deficiencies are estimated to impact a significant number of people around the world, but there remains far too little information on micronutrient status and deficiencies. More essential information and surveillance need to be gathered to make substantial progress on global targets.” 

Global Nutrition Report 2018

The objectives of this study were to identify barriers to, and enablers of, the inclusion of micronutrient biomarkers in national surveys and surveillance systems. IZiNCG conducted a series of key informant interviews with in-country and external representatives from six countries where national-level data on micronutrient status had been collected in the past five years: Cambodia, Pakistan, Malawi, Uganda, Ghana and Uzbekistan.

The most important and frequently reported barrier to inclusion of a more comprehensive panel of micronutrient biomarkers was inadequate funding to cover the analysis cost for all micronutrients considered at the planning stage. Government support and commitment was stressed as the most important enabling factor by all key informants. For the findings in full, please read the report here.

What can be done to address the barriers identified in the report, and see more countries including micronutrient biomarkers in national surveys? This project is part of a wider collaborative effort led by the Micronutrient Forum aimed at increasing the availability and utilization of high-quality data on micronutrient status at the national/sub-national levels in LMICs. Read more in this recent publication.

Last updated: June 9, 2021

Phytase added to SQ-LNS increased zinc absorption

Phytase added to SQ-LNS increased zinc absorption

In their guest blog for IZiNCG, Sarah Zyba and Ryan Wessells from UC Davis describe the findings from a randomized controlled trial where the addition of exogenous phytase to small-quantity lipid-based nutrient supplements (SQ-LNS) increased absorption of zinc from a meal of millet-based porridge containing SQ-LNS in young Gambian children.

Young children in low- and middle- income countries like The Gambia are at risk for zinc deficiency because of high rates of infection and dietary zinc inadequacy common in these settings (1). Additional zinc can be provided to young children through supplementation, large-scale food fortification of staple foods, or the home fortification of complementary foods with products such as multiple micronutrient powders, fortified blended foods (e.g. Supercereal Plus) or small-quantity lipid-based nutrient supplements (SQ-LNS). SQ-LNS are typically a peanut and milk powder-based paste, fortified with vitamins and minerals and designed to be added to complementary foods (2).

However, many of the complementary foods eaten with SQ-LNS are cereal-based and high in phytate. Phytate is a phosphorus storage molecule that also binds minerals such as calcium, iron and zinc (3). Phytate is not easily digested by humans, which causes low absorption of minerals, including zinc, from foods or meals that are high in phytate. Phytase, an enzyme which breaks down phytate, can free phytate-bound zinc in the diet making it more available for absorption. Phytase is naturally found in some foods, such as wheat, in small amounts. Phytase can also be added to foods during the manufacturing process. 

The primary objective of this study was to assess the effect that adding phytase to SQ-LNS had on zinc absorption. We did this by using a dual stable zinc isotope tracer method (4,5). Two SQ-LNS products were manufactured by Nutriset SAS; one was a standard formulation without phytase and one was the same formulation with 550 FTU (phytase units) of phytase added at the point of manufacture. In a collaboration between the University of California, Davis Institute for Global Nutrition, and the Medical Research Council Unit, The Gambia, we conducted a crossover double-blind randomized controlled trial in Keneba, The Gambia to test these two products.

Field staff during a training session before data collection began. Photo credit: Sarah Zyba

Field staff during a training session before data collection began. Photo credit: Sarah Zyba

Thirty healthy young children 18 – 24 months of age participated in the study. For two consecutive days, children received a standard breakfast and lunch, which both consisted of a millet-based porridge and 10 g SQ-LNS.  On one day, they received the SQ-LNS product with phytase, and the other day they received SQ-LNS without phytase; the order that they received the two products was randomly assigned. To measure zinc absorption from the test meals, we gave the children oral doses of two different stable zinc isotopes (Zn-67 and Zn-70) while they ate the meals; one stable zinc isotope was given with meals containing SQ-LNS with phytase, and the other stable zinc isotope was given with meals containing SQ-LNS without phytase. At the end of the second day, children received an IV infusion of a third stable zinc isotope (Zn-68). Urine samples were then collected for several days.

Field staff preparing test meals. Photo credit: Sarah Zyba

Field staff preparing test meals. Photo credit: Sarah Zyba

The ratio of the oral isotopes to the IV isotope (i.e. Zn-67:Zn-68 and Zn-70:Zn-68) in the urine was used to determine the fraction, or percent, of zinc absorbed from each of the test meals. By collecting weighed food records, we were also able to calculate the total amount of zinc absorbed (in mg) from millet-based porridge test meals containing SQ-LNS with or without phytase.

A study participant being fed a test meal by his mother. Photo credit: Sarah Zyba.

A study participant being fed a test meal by his mother. Photo credit: Sarah Zyba.

A study participant receiving an oral zinc stable isotope from a study fieldworker. Photo credit: Sarah Zyba

A study participant receiving an oral zinc stable isotope from a study fieldworker. Photo credit: Sarah Zyba

We found that the addition of phytase increased the fractional absorption of zinc from test meals containing a millet-based porridge and SQ-LNS from 8.6% to 16.0%. The total amount of zinc absorbed from the test meals more than doubled from 0.5 mg to 1.1 mg when phytase was added to the SQ-LNS.  

This shows that reducing the amount of phytate in the diet by adding phytase to SQ-LNS at the point of manufacture may be an important strategy to increase zinc absorption among young children. Further studies should be conducted to determine the longer-term impact of SQ-LNS with phytase on biomarkers of zinc status and functional outcomes of zinc deficiency.

A publication with more details of the methods and results from this study can be found here.

For more information, please contact Dr. Ryan Wessells, University of California, Davis at krwessells@ucdavis.edu

References

1.     Brown KH, Rivera JA, Bhutta Z, Gibson RS, King JC, Lönnerdal B, Ruel MT, Sandtröm B, Wasantwisut E, Hotz C. International Zinc Nutrition Consultative Group (IZiNCG) technical document #1. Assessment of the risk of zinc deficiency in populations and options for its control. Food Nutr Bull 2004;25:S99–203.

2.     Arimond M, Zeilani M, Jungjohann S, Brown KH, Ashorn P, Allen LH, Dewey KG. Considerations in developing lipid-based nutrient supplements for prevention of undernutrition: experience from the International Lipid-Based Nutrient Supplements (iLiNS) Project. Matern Child Nutr 2015;11 Suppl 4:31–61.

3.     Lonnerdal B. Phytic acid-trace element (Zn, Cu, Mn) interactions. Int J Food Sci Tech 2002;37:749–58.

4.     Lopez de Romana D, Salazar M, Hambidge KM, Penny ME, Peerson JM, Krebs NF, Brown KH. Longitudinal measurements of zinc absorption in Peruvian children consuming wheat products fortified with iron only or iron and 1 of 2 amounts of zinc. Am J Clin Nutr 2005;81:637–47.

5.     Islam MM, Woodhouse LR, Hossain MB, Ahmed T, Huda MN, Peerson JM, Hotz C, Brown KH. Total zinc absorption from a diet containing either conventional rice or higher-zinc rice does not differ among Bangladeshi preschool children. J Nutr 2013;143:519–25.

Further reading on strategies to increase zinc absorption:

Gibson RS, Anderson VP. A review of interventions based on dietary diversification or modification strategies with the potential to enhance intakes of total and absorbable zinc. Food Nutr Bull. 2009 Mar;30(1 Suppl):S108-43.

Gibson RS, Raboy V, King JC. Implications of phytate in plant-based foods for iron and zinc bioavailability, setting dietary requirements, and formulating programs and policies. Nutr Rev. 2018 July 13.

Fortified Rice for School Children in Cambodia. The FORISCA project.

Fortified Rice for School Children in Cambodia. The FORISCA project.

In their guest blog for IZiNCG, Khov Kuong (DFPTQ, Fisheries Administration, Ministry of Agriculture, Forestry and Fisheries) and Frank Wieringa (the French National Research Institute for Sustainable Development (IRD)) share the findings from the newly published FORSICA project.

Zinc deficiency is highly prevalent in Cambodia. The 2014 Micronutrient Survey in Cambodia found that >60% of the women of reproductive age and under-five children had plasma zinc concentrations <9.9 mmol/L, indicative of zinc deficiency [1]. Other indicators for zinc deficiency, such as stunting prevalence, are highly prevalent too, which the latest Demographic Health Survey (2014) reporting 1 in 3 children being stunted [2]. Although there are few data available, it is likely that zinc status is poor in other age groups in Cambodia, such as in school-aged children. 

To improve zinc status of the Cambodian population, the use of zinc-fortified rice is a tempting solution. The consumption of rice in Cambodia is very high, with >60% of daily energy intake coming from rice. Also, zinc-fortified rice is very stable, without zinc being lost over time, or when using different rice cooking techniques [3]. And rice fortified with zinc, iron, and B-vitamins was found to be highly acceptable in Cambodia [4]. Before the start of the FORISCA ((Fortified Rice for School Children in Cambodia) project, we tested the organoleptic qualities of different types of fortified rice on mothers and school teachers. Interestingly, over 80% of the mothers were capable of picking out correctly the fortified rice out of a sample of 3 plates of rice. But the fortified rice scored high on different aspects of organoleptic qualities, such as smell and taste. 

As the United Nations World Food Program (WFP) in Cambodia was exploring possibilities to improve nutritional status of school children in Cambodia through use of fortified foods in school meal programs, we took the opportunity to test the impact of introducing fortified rice on micronutrient status, morbidity and cognitive development in school children. Together with the US-based NGO PATH, and co-funded by the United States Department of Agriculture (USDA), WFP-DSM consortium and IRD, we recruited almost 10,000 school children within the FORISCA project. The FORISCA project was developed together with the Government of Cambodia’s Ministry of Education, Youth and Sports, The Ministry of Agriculture, Forestry and Fisheries and the National Fortification Board. The aim of the project was two-fold. First, to test whether a daily breakfast with multiple-micronutrient fortified rice could reduce anemia prevalence, improve micronutrient status and improve functional outcomes such as cognitive development and incidence of infectious diseases. The second aim was to test whether different types of fortified rice (i.e. cold extruded vs hot extruded) had different efficacy in improving micronutrient status. For this aim, 3 different types of fortified rice where tested, with different micronutrient composition and different fabrication techniques. 

The micronutrient content of the different fortified rice groups tested in the FORISCA project, per 100 g of uncooked blended rice.

The micronutrient content of the different fortified rice groups tested in the FORISCA project, per 100 g of uncooked blended rice.

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Within the FORISCA project, school children were given a standard breakfast, 6 days per week, for 6 months. The breakfast consisted of rice (~100 g dry rice per child per day), with a sauce of tomatoes, oil (fortified with vitamin A) and fish (~5 g per child per day). Breakfast was prepared every morning in the school kitchen, and meals were distributed over the classes. 

Schools were allocated to receive either normal rice, or one of the 3 different types of fortified rice tested. Children would receive their breakfast at 7 in the morning, and class would start thereafter. Children were assessed for anthropometry, cognitive development and micronutrient status at baseline, midline (after 3 months) and at endline. 

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Baseline micronutrient status confirmed our suspicion that zinc status was poor in school-aged children in Cambodia, with >80% of the school children having low plasma zinc concentrations [5]. Severe zinc deficiency, defined as a plasma zinc concentration <7.6 mmol/L) was present in ~50% of the school children. Six-month consumption of rice fortified with zinc significantly reduced the prevalence of zinc deficiency in the children, with the fortified rice with the highest zinc content, (Nutri-Rice) having the greatest reduction. At endline of the study, the prevalence of zinc deficiency and severe deficiency had not changed in the group receiving ordinary rice, and remained very high at 93% and 54% respectively. In contrast, in the Nutri-Rice group, the prevalence of zinc deficiency and severe zinc deficiency had decreased to 66% and 25% respectively. In the Ultra-Rice Improved group of school children, which was the fortified rice with the lowest fortification level of zinc, the prevalence of zinc deficiency and severe zinc deficiency was reduced too as compared to the placebo group, but to a lesser extent than in the Nutri-Rice group (to 83% and 37% respectively). 

We calculated that the zinc fortified rice contributed between 29% (Ultra-Rice improved) and 53% (Nutri-Rice) of the Recommended Daily Allowance (RDA) of the school children over the 6 month intervention period. Clearly, the higher zinc content of the Nutri-Rice contributed to the greater impact on zinc status. But even with ~50% of the RDA covered by the fortified breakfast, 25% of the children remained severely zinc deficient. Given the very high prevalence of zinc deficiency in this population, the amount of zinc in the fortified rice could easily be doubled, to cover 100% of the RDA. Vitamin A status was improved also in the children who received rice fortified with vitamin A, with children in the Ultra-Rice improved and Nutri-Rice groups having a risk for marginal vitamin A status that was 1/5 and 1/4 respectively of children receiving normal rice [6].

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The prevalence of anemia in the school children was lower than expected, at 16% [6]. Surprisingly, the prevalence of iron deficiency was very low, with <2% of the children having iron deficiency, and hence, the fortified rice had little impact on anemia prevalence or on improving iron status. Sub-clinical inflammation also played a role here, as in children without inflammation, there was a tendency towards higher haemoglobin concentrations in all the groups receiving fortified rice. 

Another surprising outcome of the FORISCA project was the increase in hookworm infection in the children receiving fortified rice. At baseline, all children were dewormed. However, after 6 months, up to 30% of the children were re-infected, and the re-infection rate was higher in the children receiving fortified rice than in the children receiving normal rice[7]. The re-infection rate was highest in the children receiving the fortified rice with the highest iron content, making us believe that the iron in the fortified rice played a role in enabling the re-establishment of the hookworm infection. Also, as hookworm re-infection rate tended to be higher in the cold-extruded fortified rice groups, bioavailability of iron might have been different between the cold- and hot-extruded rice varieties. 

Finally, despite the differences in zinc content of the 3 groups of fortified rice, both types of extruded fortified rice (cold vs hot extruded rice) were effective in improving zinc status and therefore production method appears not to be an important factor in determining the impact on zinc status of fortified rice. 

The WFP in Cambodia is currently assessing the expanded use of fortified rice in the school meal program, and the aim is to have a rice fortified breakfast for all the children participating in the school meal program, meaning that almost 250,000 children will hopefully receive a fortified rice meal soon.

REFERENCES

1.         Wieringa FT, Dahl M, Chamnan C, Poirot E, Kuong K, Sophonneary P, Sinuon M, Greuffeille V, Hong R, Berger J, et al: The High Prevalence of Anemia in Cambodian Children and Women Cannot Be Satisfactorily Explained by Nutritional Deficiencies or Hemoglobin Disorders. Nutrients 2016, 8.

2.         Cambodia Demographic and Health Survey 2014. [https://dhsprogram.com/pubs/pdf/FR312/FR312.pdf]

3.         Kuong K, Laillou A, Chea C, Chamnan C, Berger J, Wieringa FT: Stability of Vitamin A, Iron and Zinc in Fortified Rice during Storage and Its Impact on Future National Standards and Programs-Case Study in Cambodia. Nutrients 2016, 8.

4.         Khanh Van T, Burja K, Thuy Nga T, Kong K, Berger J, Gardner M, Dijkhuizen MA, Hop le T, Tuyen le D, Wieringa FT: Organoleptic qualities and acceptability of fortified rice in two Southeast Asian countries. Ann N Y Acad Sci 2014, 1324:48-54.

5.         Kuong K, Tor P, Perignon M, Fiorentino M, Chamnan C, Berger J, Burja K, Dijkhuizen MA, Parker M, Roos N, Wieringa FT: Multi-Micronutrient Fortified Rice Improved Serum Zinc and Folate Concentrations of Cambodian School Children. A Double-Blinded Cluster-Randomized Controlled Trial. Nutrients 2019, 11.

6.         Perignon M, Fiorentino M, Kuong K, Dijkhuizen M, Burja K, Parker M, Chamnan C, Berger J, Wieringa FT: Impact of Multi-Micronutrient Fortified Rice on Hemoglobin, Iron and Vitamin A Status of Cambodian Schoolchildren: a Double-Blind Cluster-Randomized Controlled Trial.Nutrients 2016, 8:doi:10.3390/nu8010029.

7.         de Gier B, Campos Ponce M, Perignon M, Fiorentino M, Khov K, Chamnan C, de Boer MR, Parker ME, Burja K, Dijkhuizen MA, et al: Micronutrient-Fortified Rice Can Increase Hookworm Infection Risk: A Cluster Randomized Trial. PLoS One 2016, 11:e0145351.

Plasma/serum zinc in national surveys - barriers and enablers

Plasma/serum zinc in national surveys - barriers and enablers

“Micronutrient deficiencies are estimated to impact a significant number of people around the world, but there remains far too little information on micronutrient status and deficiencies. More essential information and surveillance need to be gathered to make substantial progress on global targets.” 

Global Nutrition Report 2018

There is an urgent need for more and better data on the zinc status of vulnerable populations to effectively target and monitor zinc intervention programs. Plasma/serum zinc concentration is endorsed as the best available biomarker of zinc status, particularly for assessing the risk of zinc deficiency in target population groups such as preschool-aged children and women of reproductive age. But to date, national level plasma/serum zinc data for any population group exist for only 26 countries:

Percentage of pre-school children with low plasma or serum zinc concentrations (map generated using data from WHO Micronutrient Database)

Percentage of pre-school children with low plasma or serum zinc concentrations (map generated using data from WHO Micronutrient Database)

In an effort to increase the availability and utilisation of high-quality data on zinc status at the national level in low- and middle-income countries, IZiNCG will carry out key informant interviews with survey representatives from countries where a national nutrition survey has recently been carried out. We want to better understand the hurdles and enabling factors to the inclusion of plasma/serum zinc in national surveys, and plan to talk with both those who included the assessment of plasma/serum zinc, and those who omitted it.  

Plasma/serum zinc is not the easiest of biomarkers to collect. By identifying factors that have enabled plasma/serum zinc assessment along with challenges that remain, we hope to facilitate the sharing of knowledge between countries and to promote the inclusion of plasma/serum zinc in future surveys. Findings from this project are expected early-2020.

Which form? How much? How often?

Which form? How much? How often?

Multiple Micronutrient Powder (MNP) programs are being scaled up globally and present a golden opportunity for delivering preventive zinc to older infants and young children.