Enablers and barriers of zinc fortification; experience from 10 low- and middle-income countries

The first publication from IZiNCG’s Zinc Fortification Task Force, Enablers and Barriers of Zinc Fortification; Experience from 10 Low- and Middle-Income Countries with Mandatory Large-Scale Food Fortification, is now available in Nutrients.

Food fortification presents an opportunity for enhancing zinc intakes. Despite data suggesting zinc deficiency as being a potential public health problem, only 29 out of 72 low- and middle-income countries with mandatory fortification programs for cereal grains include zinc as a mandatory fortificant.

To guide policy decisions, we investigated the factors enabling and impeding the inclusion of zinc as a fortificant by conducting a series of in-depth interviews with key informants from 10 countries. We learnt that the decision to include zinc was strongly influenced by guidance from international development partners. Enabling factors included the assessment of zinc deficiency, mandatory regional food fortification standards which included zinc, the World Health Organization (WHO) guidelines for zinc fortification, and the low cost of the zinc compound commonly used. Barriers included the absence of zinc from regional fortification standards, limited available data on the efficacy and effectiveness of zinc fortification, and the absence of national objectives related to the prevention of zinc deficiency.

Systematic review coming soon

More evidence about the impact of zinc fortification is available now compared with when many of the countries interviewed the planning of their zinc fortification programs. We have conducted a review of efficacy and effectiveness studies to ascertain the effect of zinc fortification - alone or with multiple micronutrients - on a range of health outcomes. The review has been accepted for publication in Advances of Nutrition.

IZiNCG’s Zinc Fortification Task Force

The objective of Phase 1 of the Task Force has been to assess the efficacy and effectiveness of zinc fortification interventions, and to identify opportunities to enhance impact. We are now moving into Phase 2 - watch this space. Our members represent the Food Fortification Initiative, the Global Alliance for Improved Nutrition, Nutrition International, and the Global Fortification Data Exchange.

Read more about strategies for promoting zinc nutrition here.

Portable X-ray fluorescence of zinc applied to human toenail clippings

Could toenail zinc content assessed by portable X-ray fluorescence be a field friendly biomarker of zinc status? Professor David Fleming of Mount Allison University describes where the science is at.

Zinc deficiency is a widespread problem which has been associated with a variety of serious health effects. Diagnosing zinc deficiency at the individual level is, unfortunately, a somewhat thorny issue. Currently, there is no single method of determining zinc status which is both simple and reliable. The best option is probably the measurement of plasma (or alternatively serum) zinc concentration [1,2]. This approach, however, requires a sequence of non-trivial steps pertaining to the sample acquisition, storage, and analysis (usually at a distant lab). Other reliable or potentially useful biomarkers of zinc status have been noted, including zinc concentration in urine and hair [1,2]. These approaches also have drawbacks.

Zinc concentration in nail was recently described as an “emerging biomarker” by the Biomarkers of Nutrition for Development (BOND) zinc expert panel [2]. This designation indicates that nail zinc concentration has a theoretical association with zinc status, but requires further study. This need for additional development was reinforced in a Technical Brief from IZiNCG, which provided an overview of assessing zinc exposure using hair or nail zinc [3]. 

Toenail clippings ready for measurement by portable X-ray fluorescence (Photo: David Fleming)

We recently conducted a study involving the measurement of zinc concentration in toenail clippings using two different methods: portable X-ray fluorescence (XRF) and inductively coupled plasma-mass spectrometry (ICP-MS) [4]. Of the two methods, portable XRF is a relatively new approach to zinc biomarker analysis, while ICP-MS may be considered a “gold standard”. We measured single toenail clippings from 60 different individuals living in Atlantic Canada (the population was drawn from the Atlantic PATH cohort [5]). The clippings were measured first by portable XRF, a non-destructive technique, and then by ICP-MS. The population average zinc concentration was found to be 85 µg/g from ICP-MS. The portable XRF technique was very sensitive to detecting zinc in the clippings and provided a reasonable estimate of zinc concentration. Using the XRF output spectrum to determine a normalized zinc signal, we found a correlation coefficient r = 0.68 between the XRF results and the ICP-MS zinc concentrations. Looking forward, correlation between the two methods might be improved by measuring multiple points on each clipping when using XRF – in our study, only a single point on each clipping was assessed by XRF.

Single toenail clipping in portable X-ray fluorescence instrument (Photo: David Fleming)

Single toenail clipping (Photo: David Fleming)

The portable XRF approach presents a number of potential advantages for the analysis of zinc concentration in nail clippings. Measurements could be made in a field setting and results provided quickly. Sample preparation is minimal, operating conditions are simple, and the technique is relatively inexpensive. If the correlation of XRF results with ICP-MS concentrations could be improved, portable XRF might therefore be an especially attractive approach for assessing zinc concentration in nail clippings. The other critical issue here, of course, is whether zinc concentration in nail is truly representative of an individual’s zinc status. That remains an open question which will require additional study to resolve. If zinc concentration in nail is eventually upgraded from “emerging biomarker” to “useful biomarker”, we anticipate that portable XRF will receive a great deal of attention and become a potentially important component of public health initiatives targeting zinc deficiency.

References

[1] N.M. Lowe, K. Fekete, T. Decsi, Methods of assessment of zinc status in humans: a systematic review, Am. J. Clin. Nutr. 89 (2009) 2040S-2051S.

[2] J.C. King, K.H. Brown, R.S. Gibson, N.F. Krebs, N.M. Lowe, J.H. Siekmann, D.J. Raiten, Biomarkers of nutrition for development (BOND) – zinc review, J. Nutr. 146 (2016) 858S-885S.

[3] International Zinc Nutrition Consultative Group (IZiNCG) Technical Brief No. 8, Assessing population zinc exposure with hair or nail zinc (2018), https://www.izincg.org/technical-briefs

[4] D.E.B. Fleming, S.L. Crook, C.T. Evans, M.N. Nader, M. Atia, J.M.T. Hicks, E. Sweeney, C.R. McFarlane, J.S. Kim, E. Keltie, A. Adisesh, Portable X-ray fluorescence of zinc applied to human toenail clippings, J. Trace Elem. Med. Biol. 62 (2020) 126603.

[5] E. Sweeney, Y. Cui, V. DeClercq, P. Devichand, C. Forbes, S. Grandy, J.M.T. Hicks, M. Keats, L. Parker, D. Thompson, M. Volodarsky, Z.M. Yu, T.J.B. Dummer, Cohort profile: the Atlantic partnership for tomorrow’s health (Atlantic PATH) study, Int. J. Epidemiol. 46 (2017) 1762-1763i.

Preventive and Therapeutic Zinc Interventions and Diarrhea Outcomes in Laotian Children

In this guest blog for IZiNCG, Dr Maxwell A Barffour and Dr Guy-Marino Hinnouho provide insights from a recent publication titled Effects of therapeutic zinc supplementation for diarrhea and two preventive zinc supplementation regimens on the incidence and duration of diarrhea and acute respiratory tract infections in rural Laotian children: A randomized controlled trial.

Background

Over 500,000 young children die from complications of diarrhea each year, with a disproportionately higher burden (>90%) in low- and middle-income countries. Since, 2004, the World Health Organization and UNICEF have recommended the use of therapeutic zinc, along with oral rehydration therapy (ORS), for the treatment of acute diarrhea episodes [1, 2]. This strategy, which requires the use of 20 mg zinc, given daily for 10-14 days during diarrhea episodes, is supported by results of several trials and reviews, which collectively indicate that in children 6 months and older, adjunctive treatment of diarrhea with zinc reduces diarrhea severity. Specifically, the evidence suggests that therapeutic zinc shortens the duration of diarrhea and reduces the number of episodes progressing to persistent diarrhea [3]. Limited evidence also suggests that therapeutic zinc may reduce the incidence of new diarrhea episodes in the 2-3 months following treatment initiation [4].

There are several limitations to a therapeutic approach to zinc supplementation. Because this strategy requires appropriate recognition of diarrhea, motivation to seek treatment and access to a health care facility, coverage is often low [5, 6]. In addition, this strategy has not been shown to affect other functional outcomes related to zinc deficiency, such as physical growth and risk of pneumonia. Hence a goal of this study was to compare the health benefits of therapeutic and preventive strategies for delivering zinc. Furthermore, when delivered as a preventive supplement, zinc may be given as a single zinc-alone supplement, or as part of a multiple micronutrient powder (MNP). Generally, MNP formulations are deemed more desirable because of the ability to target multiple micronutrient deficiencies. However, some evidence suggests that because zinc interacts with other nutrients, zinc delivered as  part of  MNP may not be as effective as zinc delivered alone. Therefore, an additional goal of this study was to compare  two preventive zinc strategies (i.e. zinc alone or MNP) with respect to their effect on diarrhea outcomes.

Photo credit: Sonja Hess

Study Design and Study Population

This blog summarizes a study published in the Journal of Global Health which aimed to assess the benefits of two preventive zinc supplementation regimens and a therapeutic zinc supplementation for diarrhea, on the incidence and duration of diarrhea episodes [7]. The trial was implemented from September 2015 through April 2017 in rural communities in Khammouane Province, Lao PDR. The province was selected because of the  high prevalence of stunting [8], a proxy indicator of zinc deficiency. In addition, the province had no existing programs delivering micronutrient interventions at the time of the study. A pilot survey completed in 2015 found that ~62% of children (6- 23 months) were zinc deficient (plasma zinc concentrations <65 μg/dL).

The study included children 6-23 months at enrollment [9]. Children were randomly assigned to one of four groups, namely a preventive zinc group (7mg zinc /d as dispersible tablet), a therapeutic zinc group (20 mg/d for 10 days) given in relation to diarrhea episodes, and a daily preventive MNP group (containing 10 mg zinc, 6 mg iron + 13 other micronutrients). A fourth group, the control group, received a daily placebo powder, and in addition, a placebo tablet during diarrhea episodes. Each child was followed for up to 9 months, or until lost to follow-up. Reported diarrhea episodes were assessed during weekly home visit. Diarrhea was defined as 3 or more lose stools in a 24-hr period. 

Photo credit: Maxwell Barffour

Photo credit: Maxwell Barffour

Relevant baseline characteristics and compliance

Overall, 3407 eligible children were enrolled and randomized into one of the four groups (i.e. therapeutic zinc (n=851), preventive zinc (n=852), MNP (n=852) and control (n=852)). About 87% of the children enrolled completed the scheduled 9 months of follow-up. The participants who completed the study were similar to those who did not with respect to age and other baseline characteristics including anemia. 

The mean age of participating children was 14 months, and the prevalence of stunting (40%), and anemia (55%) suggested a population with a high prevalence of chronic malnutrition. Most of the children (>70%) were breastfed at the time of the baseline survey. Reported adherence to the daily preventive supplements was 92%. Diarrhea treatment was initiated for ~87% of all diarrhea episodes, and on average, 7 out of the 10 tablets were given to children who needed treatment for diarrhea. 

Main results

Overall, 2013 children (representing ~60% of the study population) experienced at least one diarrhea episode during the course of the follow-up. The overall incidence of acute diarrhea was low ( <1 episode per 100 days at risk) and each episode lasted about 2 days. There was no overall difference in either the diarrhea incidence or duration across the four groups. Because previous studies have established that the impact of zinc on diarrhea tended to vary by age, a goal of this study was to also assess evidence of such age variation. We found that older children (i.e. those 18 months of age and above) tended to benefit from the therapeutic zinc supplementation. In this age group, the duration of diarrhea was significantly lower in those who received the therapeutic zinc compared to the control group. Similarly, the incidence of recurrent diarrhea episodes (i.e. episodes occurring after a prior diagnosis) was significantly reduced among the therapeutic zinc group compared to the control group. The preventive zinc and the MNP  had no impact on diarrhea incidence or duration, regardless of the child’s age. Also, noteworthy, the MNP was not associated with an overall adverse effect on diarrhea incidence or duration.

Concluding remarks

Finding of this study suggest that therapeutic zinc may confer protective benefits against diarrhea in this population, especially if delivered to older children. It is plausible that the observed impact seen in older children may be due to a zinc-dependent enhancement in adaptive immune response. Contrary to evidence from several prior studies and systematic reviews, preventive zinc did not have an impact on diarrhea in this population. This lack of effect may have been due to the fact that the overall incidence of diarrhea in this population was relatively lower than those observed in other populations. Finally, the  MNP, which contained a daily iron dose of 6 mg was not associated with an overall increase in the diarrhea incidence. It is worth mentioning that in children with genetic hemoglobinopathies, the MNP was associated with a small increase in diarrhea incidence. Overall, the findings from this study highlight the need for continuing research to find optimal strategies for improving nutritional and health status in this population.

Additional findings  from the Lao Zinc Study

The Lao zinc study was also designed to assess  treatment effect on micronutrient status, anemia and physical growth.  Below is a summary of findings as published in the Journal of Pediatrics [10]:

• Therapeutic zinc had no impact on zinc, iron or vitamin A status.

• Preventive zinc significantly improved zinc status.

• MNP improved zinc  and iron status.

• MNP had a marginal positive impact on hemoglobin and anemia, with a significant impact among children who were anemic at baseline.

Photo credit: Maxwell Barffour

Relevant references

1.         WHO, U., Clinical management of acute diarrhoea in children: WHO/UNICEF joint statement. Geneva: World Health Organization; 2004. http://www.who.int/maternal_child_adolescent/documents/who_fch_cah_04_7/en/, 2004.

2.         World Health Organization; UNICEF., Zinc supplementation in the management of diarrhoea.http://www.who.int/elena/titles/zinc_diarrhoea/en/ 2016. Accessed 2016 September 28.

3.         Lazzerini, M. and H. Wanzira, Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev, 2016. 12: p. Cd005436.

4.         Baqui, A.H., et al., Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial. BMJ, 2002. 325(7372): p. 1059.

5.         Sabot, O., et al., Scaling up oral rehydration salts and zinc for the treatment of diarrhoea. Bmj, 2012. 344: p. e940.

6.         Ram, P.K., et al., Declines in case management of diarrhoea among children less than five years old. Bull World Health Organ, 2008. 86(3): p. E-f.

7.         Barffour MA, Hinnouho GM, Wessells KR, et al. Effects of therapeutic zinc supplementation for diarrhea and two preventive zinc supplementation regimens on the incidence and duration of diarrhea and acute respiratory tract infections in rural Laotian children: A randomized controlled trial. J Glob Health. 2020;10(1):010424. doi:10.7189/jogh.10.010424

8.         Bureau., M.o.H.a.L.S., Lao People's Democratic Republic Special, 2011–12 - Lao Social Indicator Survey (MICS/DHS) Final Report (English) Vientiane: Ministry of Health and Lao Statistics Bureau. 2012.

9.         Wessells, K.R., et al., Comparison of two forms of daily preventive zinc supplementation versus therapeutic zinc supplementation for diarrhea on young children’s physical growth and risk of infection: study design and rationale for a randomized controlled trial. BMC Nutrition, 2018. 4(1): p. 39.

10.       Barffour, M.A., et al., Effects of Daily Zinc, Daily Multiple Micronutrient Powder, or Therapeutic Zinc Supplementation for Diarrhea Prevention on Physical Growth, Anemia, and Micronutrient Status in Rural Laotian Children: A Randomized Controlled Trial. J Pediatr, 2018.

Contact:

Maxwell A Barffour, Missouri State University, MaxwellABarffour@missouristate.edu

Read more on this topic:

Preventive zinc supplementation in children

Zinc as part of the treatment of diarrhea

The ZiPT trial

Zinc Fortification Task Force initiates efforts to enhance the impact of zinc fortification interventions

Why a Zinc Fortification Task Force?

Fortification of staple foods and/or condiments with zinc appears to be a promising strategy for improving zinc status at the population level in low- and middle-income countries because of its relatively low cost and long-term sustainability. The motivation for establishing a Zinc Fortification Task Force is to progress IZiNCG’s position and recommendations related to zinc fortification, taking into account recent evidence, existing global guidelines, and the fact that mandatory zinc fortification is in place in more than 30 countries. The Task Force harnesses the perspectives of the Food Fortification Initiative, the Global Alliance for Improved Nutrition and Helen Keller International together with IZiNCG.

IZiNCG’s current stance on zinc fortification 

A review in IZiNCG’s 2009 Technical Document no. 2 summarised evidence showing that fortifying staple foods with zinc increases total daily zinc absorption, does not adversely affect the absorption of other minerals, is not associated with adverse effects and is a relatively low-cost intervention (1). Therefore, IZiNCG’s recommendation following this review was that countries should consider including zinc in mass and targeted fortification programs in populations at high risk of zinc deficiency. However, the review also pointed to the paucity of evidence on the efficacy and effectiveness of fortification programs, and that only a few studies had found a positive impact on plasma/serum zinc or functional indicators of zinc status.

Recent reviews

A 2016 Cochrane review of zinc fortification concluded the same: given the relatively small number of trials and participants, further investigation of the effects of zinc fortification was needed (2). However, the Cochrane review excluded many studies on the basis that zinc was not the only nutrient which differed between intervention and control groups, despite plasma/serum zinc being measured as an outcome. While such comparisons may be useful from an epidemiological perspective, they may not fully capture the real-world context.  For example, 34 countries have mandatory zinc fortification in place, with zinc being part of a premix with several other micronutrients. In a very recent review of large-scale food fortification on vitamin A, iodine, iron and folic acid status and health outcomes, this “real-world impact” was at the centre (3). However, this latter review excluded trials with less than 1000 participants, which would be too limiting in the case of available publications on zinc fortification.

Planned work of the taskforce 

The overarching goal of the task force is to assess the efficacy and effectiveness of zinc fortification interventions, and to identify opportunities to enhance impact. The first activity is to produce an update to the previous zinc fortification systematic reviews, summarising the additional evidence now available on zinc fortification. In addition to determining the impact of zinc fortification on zinc-related biochemical and functional outcomes, the review will attempt to answer the following other questions: 

• What is the adequate dosage and duration of exposure required to show an effect?

• What proportion reduction in zinc deficiency can we expect to see as a result of zinc fortification, and which groups may require additional/complementary interventions? 

• Which indicators should be recommended for evaluating zinc fortification programs?

• What do we know about novel/alternative vehicles for zinc fortification? 

In parallel, the Zinc Fortification Task Force also wants to capture the lessons learnt and identify knowledge and resource gaps in countries with existing national zinc fortification programs. Which evidence did they act on? Which barriers are they facing? Likewise, the Task Force plans to explore the perspectives of countries with a high burden of zinc deficiency without zinc fortification in place, and the feasibility of zinc fortification as a successful strategy in such settings. 

We hope that the results from the activities in this first phase of the Zinc Fortification Task Force will be available by July 2020, and that this effort will help inform renewed global commitments to food fortification. 

References

1. Hess SY, Brown KH. Impact of zinc fortification on zinc nutrition. Food Nutr Bull. 2009 Mar;30(1 Suppl):S79-107. 

2. Shah D, Sachdev HS, Gera T, De-Regil LM, Peña-Rosas JP. Fortification of staple foods with zinc for improving zinc status and other health outcomes in the general population. Cochrane Database Syst Rev. 2016 Jun 9;(6):CD010697.

3. Keats EC, Neufeld LM, Garrett GS, Mbuya MNN, Bhutta ZA. Improved micronutrient status and health outcomes in low- and middle-income countries following large-scale fortification: evidence from a systematic review and meta-analysis. Am J Clin Nutr. 2019 Jun 1;109(6):1696-1708.

Read more about strategies for promoting zinc nutrition here.

Recent publication: A dynamic model for predicting growth in zinc-deficient stunted infants given supplemental zinc

Zinc deficiency limits infant growth and increases susceptibility to infections, which further compromises growth. Zinc supplementation improves the growth of zinc-deficient stunted infants, but the amount, frequency, and duration of zinc supplementation required to restore growth in an individual child is unknown. A dynamic model of zinc metabolism that predicts changes in weight and length of zinc-deficient, stunted infants with dietary zinc would be useful to define effective zinc supplementation regimens.

A model of zinc metabolism was developed using data on zinc kinetics, tissue zinc, and growth requirements for healthy 9 month old infants. The model suggests that frequent, smaller doses (5–10 mg Zn/d) are more effective for increasing growth in stunted, zinc-deficient 9-mo-old infants than are larger, less-frequent doses.

In the future, the model predictions of zinc supplementation need to be evaluated in homogenous groups of stunted infants with respect to age, sex, and zinc status. That information will improve predicted amounts of supplemental zinc, and it will identify the population subgroups (e.g., infants with plasma zinc and length-for-age z score below defined thresholds) most likely to respond to zinc supplementation.

The publication can be found here.

Study in progress: Reference methods for biological sample preparation and zinc analysis

The accurate determination of the prevalence of zinc deficiency is essential for effective design, targeting, and evaluation of interventions. Hence, methodological knowledge gaps are important to understand and address.

The concentration of zinc in biological samples, such as plasma, serum, hair, or urine, varies considerably between populations. While part of this variation is attributable to differences in diet or inflammation – i.e. what we want to measure – part may also be due to the different methods and equipment used to process and analyze the samples. 

Instruments commonly used for zinc analysis include atomic absorption spectrometry (AAS), inductively couple plasma optical (atomic) emission spectrometry (ICP-OES / ICP-AES), and ICP mass spectrometry (ICP-MS). 

IZiNCG has earlier published reference methods for collecting plasma and serum for zinc analysis, but reference methods for sample preparation and zinc analysis have not yet been developed. 

The goals of this project are to:

a)    Establish a set of reference methods for zinc analysis, applicable to new or established laboratories using each major type of instrument; and 

b)    Develop reference data that document analytical accuracy and precision among different instruments and different types of samples under ideal conditions at multiple sites. 

The results, anticipated early-mid 2019, will be communicated as an IZiNCG technical brief following publication in a peer-reviewed scientific journal.

Participating labs:

AAS

University of Colorado Denver, USA

ETH Zurich, Switzerland

Aga Khan University, Pakistan

International Centre for Diarrhoeal Disease Research, Bangladesh

National Institute of Nutrition, Hanoi, Vietnam

ICP-OES

Children’s Hospital Oakland Research Institute, USA

ICP-MS

University of Colorado, Denver, USA

ETH Zurich, Switzerland

Oklahoma State University, USA