Summary Research conducted during the past years sugg - PDF document

SummarydeÞciency.We conducted a systematic literature search to identify relevant studiesevidence on the burden of disease related to zinc deÞciency would belimited to the results of randomized controlled trials (RCTs) conducteddiarrhoea, pneumonia and malaria illness among children aged 0Ð4other populations; however, the International Zinc Nutrition Consulta-of zinc in each countryÕs food supply.1.52 (95% CI 1.20Ð1.89) and malaria by 1.56 (95% CI 1.29Ð1.89). Weextended those results as best estimates of the risk of mortality fromthese causes as a result of zinc deÞciency. Following the IZiNCG tech-deÞciency was estimated to cause 176000diarrhoea deaths, 406000pneumonia deaths and 207000 malaria deaths. The associated loss ofdisability-adjusted life years (DALYs) attributable to zinc deÞciency Zinc deficiencyLaura E.Caulfield and Robert E.Black the world. Available evidence from RCTs on the strength of the associ-intakes in these other groups, research is needed to determine the mag-nitude of the potential health effects..IntroductionZinc is a trace mineral essential to all forms of life because of its fun-century, as a condition characterized by short stature, hypogonadism,deÞciency has hampered efforts to document prevalences of zinc deÞ-ciency. Despite this, RCTs of zinc supplementation in areas with habit-tant to attempt to quantify the prevalence of zinc deÞciency and itsdisease burden implications of zinc deÞciency..Nature and definition of the risk factorwith zinc deÞciency (Wood 2000). intakes of zinc may be acceptable, the levels of inhibitors (e.g. Þbre andabsorbed. For this reason, zinc requirements for dietary intake arePrevalence of zinc deÞciencyof the diet in various regions of the world. For example, the Worldmoderate bioavailability. For example, of 148 surveys conducted in pop-in populations with moderate zinc bioavailability, 40 indicated averageLaura E.Caulfield and Robert E.Black259 conducted in populations with low zinc bioavailability, none reportedestimated regional prevalences of zinc deÞciency.ing the bioavailability of zinc in the food supply. We used this secondapproachbecause of the improved methodology and more conservativeestimates of deÞciency, and were provided with estimated prevalences ofbelow.Agriculture Organization of the United Nations (FAO) on an annualtion, and population estimates for each country in 1998 (FAO 1999).Per capita zinc availability was estimated based on the zinc:energy ratio,which was derived using FAO values for energy for each food and valuesof the World Food Program (World Food Dietary Assessment System1997) for the estimated zinc content of each food. To examine thetotal protein content of the diet. This equation and information on thecentage absorbable zinc in the food supply, based on their main staplebution of animal protein to the energy available in the food supply.calculating the mean of the recommended zinc intakes for low, average1996), weighted by the sex and age distribution of the countryÕs popu- lation, as obtained from the WISTAT database (WISTAT 1994). To cal-assumptions of normality, they calculated the proportion of individualssidered only the phytate:zinc molar ratio in the food supply (Brown The method does not account for zinc intake from breast milk or fromdrinking water. However, breast milk is only an adequate source of zinca usual water intake of 2 l/day. the appropriate counterfactual (i.e. theoretical minimum exposure) forzinc deÞciency. Unlike some other exposures, zero prevalence of zincication of the zinc disease burden due to this risk factor. Thus, for pur-zinc deÞciency is 31%, and ranges from 4% to 73% (Table 5.1). TheHealth outcomes consideredTo proceed with a systematic investigation of the evidence regarding theimpairment or blindness and mortality. The target populations consistedof the literature described below, we concluded that there were few pub-Laura E.Caulfield and Robert E.Black261 262Comparative Quantification of Health Risks Table 5.1Estimated prevalence of inadequate zinc intakes by subregionAvailableMean % of%inadequateNumberPopulationEnergyZincPhytate:zinczincadjustedintakes Subregionof countries(millions)(kcal/d)(mg/d)ratio(mg)requirement(95% CI)AFR-D25278.7245310.025.81.1457.336.5(327)(2.1)(2.6)(0.20)(10.8)(26.4Ð46.6)AFR-E20322.620758.627.90.9446.761.6(370)(1.6)(3.7)(0.20)(12.4)(49.3Ð73.9)AMR-A3315.7351412.112.62.8585.36.3(234)(1.0)(0.8)(0.37)(7.4)(0Ð16.1)AMR-B26418.6282810.420.61.6665.426.0(244)(1.8)(5.7)(1.15)(14.8)(17.9Ð34.1)AMR-D668.522417.524.70.9144.568.4(223)(1.0)(6.6)(0.15)(5.6)(54.7Ð82.1)EMR-B10130.429468.522.01.1260.925.2(195)(1.1)(2.7)(0.40)(6.1)(21.1Ð29.3)EMR-D9339.725447.825.00.9152.251.8(460)(1.9)(3.4)(0.19)(11.7)(33.8Ð69.8) Laura E.Caulfield and Robert E.Black263EUR-A22409.4337812.611.53.5392.03.9(154)(1.1)(1.8)(0.93)(8.4)(2.8Ð5.0)EUR-B16213.6307310.218.41.6373.212.7(433)(1.5)(4.6)(0.62)(10.1)(8.9Ð16.5)EUR-C6247.0302011.213.82.1883.55.7(109)(0.7)(1.1)(0.37)(4.7)(4.4Ð7.0)SEAR-B3285.126169.126.91.0056.933.5(203)(1.1)(3.4)(0.06)(6.0)(14.7Ð52.3)SEAR-D61198.023567.927.50.8543.572.5(127)(0.7)(0.4)(0.07)(4.8)(62.3Ð82.7)WPR-A4148.9295411.816.62.1391.23.6(122)(0.9)(3.4)(1.27)(2.9)(3.2Ð4.0)WPR-B131498.3270510.719.01.4780.58.5 (159)0.9)(1.3)(0.23)(8.7)(3.6Ð13.4)World1725874.327069.921.31.5166.531.3(434)(2.0)(6.0)(0.90)(19.4)(26.7Ð35.9) Presented as means (standard deviations). Source:IZiNCG (forthcoming). Risk factorÐdisease relationshipSearch strategyArticles related to zinc deÞciency in human populations were identiÞedducted using combinations of the following keywords: zinc, deÞciency,mortality, death, morbidity, acute respiratory infection, pneumonia, diarrhoea, measles, malaria, child, pregnancy, infant, neonatal, fetal, premature, congenital, abortion, stillbirth, miscarriage, birth weight,health outcomes of interest in human populations. These health out-excluded from review were animal studies and case reports.Methods for combining risk estimates from individual studiesposes would be a prospective cohort study. Unfortunately, no suchstudies were identiÞed despite an exhaustive search. Certainly this relatesindividuals discussed above. There have been, however, a signiÞcantnumber of RCTs of zinc supplementation examining morbidity outcomescalculations are summarized in Table 5.2.The studies included were RCTs of zinc supplementation for the pre- Laura E.Caulfield and Robert E.Black265 Table 5.2Studies contributing data on the effect of zinc deÞciency on morbidity among children,aged 0Ð4 years AgeSample sizeOutcomes measured Country (reference)Study designSupplement(months)Zinc groupControl groupEnrolment criteriaDiarrhoeaPneumoniaMalariaBurkina Faso (MŸller Continuous 12.5mg zinc as6Ð31356353Community-basedet al.2001)supplementation (6 days/sulfate(included forweek) over a 6-month diarrhoea only)period.Malaria deÞned based on community-basedactive case detectionEthiopia (Umeta etContinuous 10mg zinc as6Ð129292StratiÞed based on al.2000)supplementation (6 days/sulfatelength-for-age week) for 6 months2SDGambia (Bates et al.Twice weekly70mg zinc as 6Ð285554Matched on age ÑÑ1993)supplementation over azinc acetateand sex1.25-year period.Supplement provided in a fruit-ßavoured drink;by microscopic evaluationGuatemala (Ruel etDaily supplementation 10mg zinc as6Ð94544Community-basedal.1997)for 28 weekssulfateIndia (Bhandari et al.Daily supplementation 10mg zinc to6Ð3512411241Community-basedÑ2002)for 16 weeksinfants;20mgchildren;as gluconate 266Comparative Quantification of Health Risks Table 5.2Studies contributing data on the effect of zinc deÞciency on morbidity among children,aged 0Ð4 years ( AgeSample sizeOutcomes measured Country (reference)Study designSupplement(months)Zinc groupControl groupEnrolment criteriaDiarrhoeaPneumoniaMalariaIndia (Sazawal et al.Daily supplementation 10mg zinc as6Ð35286293Recovered from 1997,forthcoming)for 26 weeksgluconate,acute diarrhoeaA,B,D,EJamaica (Meeks-Daily supplementation 5mg zinc as6Ð243130Weight-for-heightGardner et al.1998)for 12 weekssulfate,vitamin2SDA,B,C,DMexico (Rosado etContinuous 20mg zinc as18Ð369797Community-basedal.1997)supplementation (5 days/methionate,week) for 54 weekshalf with ironPapua New GuineaContinuous 10mg zinc as6Ð60136138Community-based(Shankar et al.1997,supplementationgluconate2000)(6 days/week) over a 46Ð7week period.MalariadeÞned based on activecase detection as well asclinic visits,conÞrmed bymicroscopic evaluationPeru (Penny et al.Daily supplementation 10mg zinc as6Ð358079Recovered from 1999)for 26weeksgluconatepersistent diarrhoeaViet Nam (Ninh Daily supplementation for 10mg zinc as4Ð367373Weight-for-age et al.1996)22 weekssulfateand height-for-age2SD Measured. ÑNot measured. Laura E.Caulfield and Robert E.Black267malaria. In addition, there are numerous RCTs in which zinc supplementsÞndings on zinc deÞciency and risk of diarrhoea (Meeks-Gardner et al.Sazawal et al. 1998), and three contributed Þndings on risk of malariaassociated with zinc deÞciency. This was calculated as the inverse of theodds ratio or relative risk estimated from RCTs given two assumptions:subjects in the study population have some level of zinc deÞciency, andsupplementation with zinc eliminated zinc deÞciency. Because the Þrst ofThe results of the nine RCTs with Þndings on zinc deÞciency and diar-rhoea incidence are presented in Table 5.3. The results are presented for Table 5.3Zinc deÞciency and risk of diarrhoea incidence Zinc groupControl groupRelative risk Country (reference)EpisodeFollow-upFollow-upBurkina Faso (MŸller 32249126374478441.19 (1.03Ð1.39)et al.2001)Ethiopia (Shankar et al.1997)271679059167902.22 (1.39Ð3.45)Guatemala (Ruel et al.1997)387848246783611.22 (1.08Ð1.41)India(Sazawal et al.1997)934448661033455551.09 (1.00Ð1.31)Jamaica (Meeks-Gardner 3926043722651.09 (0.69Ð1.72)et al.1998)Mexico (Rosado et al.1997)8242322132427511.59 (1.20Ð2.13)Papua New Guinea (Umeta 632749077294651.14 (0.82Ð1.59)et al.2000)Peru (Penny et al.1999)56413178661136481.14 (1.01Ð1.27) Viet Nam (Ninh et al.1996)5611242100112421.79 (1.28Ð2.50)All1.28 (1.10Ð1.49) Episode refers to an episode of diarrhoea as per the case deÞnition in the individual study. Follow-up refers to the total number of child-days of follow-up or disease surveillance in each study. relative risk of diarrhoeal disease incidence due to zinc deÞciency. AsIn 1999, a pooled analysis was conducted of published RCTs of zincchildren (Zinc InvestigatorsÕ Collaborative Group 1999); at that time,The results of the Þve RCTs with Þndings on zinc deÞciency and pneu-monia incidence are presented in Table 5.4. The results are presented forWith the exception of the study by Bhandari et al. (2002), the studies Table 5.4 Zinc groupControl groupRelative risk Country (reference)EpisodeFollow-upFollow-upIndia (Bhandari et al.2002)881320001181344001.32 (1.01Ð1.72)India (Sazawal et al.1998)244486643455551.76 (1.08Ð2.94)Jamaica (Meeks-Gardner 02604122653.13 (0.16Ð100.0)Peru (Penny et al.1999)91317811136481.22 (0.51Ð2.86) Viet Nam (Ninh et al.1996)451124281112421.79 (1.25Ð2.56)All1.52 (1.20Ð1.89) Episode refers to an episode of pneumonia as per the case deÞnition in the individual study. Follow-up refers to the total number of child-days of follow-up or disease surveillance in each study. Three RCTs of zinc supplementation to prevent malaria morbidity wereeffect of zinc deÞciency on malarial attack rates. However, Shankar et al. (2000) obtained the original data from the study (Bates et al. 1993)MŸller et al. (2001) from further analysis. Instead we used ShankarÕsMortalityClearly, zinc deÞciency contributes to increased risk of incidence forfatality or severity of these diseases, the risk of mortality due to zincdue to zinc deÞciency. For this reason, we have proposed that the rela-tive risk of mortality related to diarrhoea, pneumonia and malaria asso-ciated with zinc deÞciency, are 1.28, 1.52 and 1.56, respectively (TableGroup 1999, 2000). There are three pieces of direct evidence that zincLaura E.Caulfield and Robert E.Black269 Bangladeshi children who received supplements of 20mg/d zinc as adju-in the study by MŸller et al. (2001). With respect to malarial deaths, itstudy by MŸller et al. (2001). Finally, it should be noted that infectionsDisease causation mechanismschildren. There is no doubt, however, that zinc is a critical nutrient formild deÞciencies of zinc is the immune system, reßecting the profoundof immune function, including barrier and non-speciÞc immunity, spe-Table 5.5Estimated effect of zinc deÞciency on morbidity andmortality due to diarrhoea,pneumonia and malaria in children aged 0Ð4 years MorbidityMortality IllnessRelative risk (95% CI)Relative risk (95% CI)Diarrhoea1.28 (1.10Ð1.49)1.28 (1.10Ð1.49)Pneumonia1.52 (1.20Ð1.89)1.52 (1.20Ð1.89) Malaria1.56 (1.29Ð1.89)1.56 (1.29Ð1.89) as glucocorticoid and thymulin activity, and cytokine function. Given theZinc deÞciency also results in reduced growth rates in animals, andthere is ample evidence from RCTs that the provision of supplementalchildren. Recently, Brown et al. (1998a) published a meta-analysis ofmore than 52 RCTs investigating the effect of supplemental zinc onweight-for-age and height-for-age respectively. It is heuristic to conclude that some of the improved growthduration/severity.Burden of disease estimatesThe estimated deaths and DALYs attributable to zinc deÞciency areshown in Tables 5.6Ð5.7.When examined by region, the burden of zincLaura E.Caulfield and Robert E.Black271Table 5.6Deaths in children aged 0Ð4 years from zinc deÞciency,by subregion Deaths (000s) SubregionDiarrhoeaPneumoniaMalariaAFR-D175074AFR-E4791107AMR-A000AMR-B230AMR-D360EMR-B120EMR-D314810EUR-A000EUR-B130EUR-C000SEAR-B260SEAR-D7018716WPR-A000 WPR-B2100 World176406207 We estimated that zinc deÞciency in children aged 176000diarrhoea deaths, 406000pneumonia deaths, and 207000malaria deaths. The associated DALYs attributable to zinc deÞciencyrhoea, pneumonia and malaria occur. This places zinc deÞciency as a keyfactor conferring risk of morbidity and mortality to young children, onebecause it results from RCTs conducted in areas of the world with Table 5.7Disease burden attributable to zinc deÞciency,by subregion DALYs (000s) SubregionDiarrhoeaPneumoniaMalariaAFR-D60417052729AFR-E163131053978AMR-A110AMR-B691432AMR-D1092022EMR-B36931EMR-D10711679371EUR-A000EUR-B191020EUR-C170SEAR-B8424421SEAR-D24566579560WPR-A000 WPR-B613615 World6142142237669 RCTs, respectively. The estimated increased risk for malaria is less wellstudied. Our risk estimate was based on two RCTs with similar risk esti-mates in which clinic attack rates were the outcome of interest. Weof the consequences of zinc deÞciency, yet much work needs to be donein order to describe the magnitude and distribution of zinc deÞciencymined from food balance sheet data compiled by FAO. This is far fromchemical indicators. As stated earlier, however, there is no clear choicecited indicator of zinc status) would be limited to restricted samples ofstudy participants conducted in selected regions of the world. To ourfrom 172 countries, representing all 14 subregions. Further, because zincfeatures of the diet (total energy content, animal protein availability,mine the bioavailability of the zinc present in the food supply, the imate the prevalence of zinc deÞciency. There are multiple uncertaintiesof the composition of foods with respect to zinc, calcium, Þbre andLaura E.Caulfield and Robert E.Black273 validity of the assumptions made, and judge the certainty with which effect, however, may be countered by underestimation of intake in theFAO data which do not always account for subsistence production.Second, the groups for which these numbers are likely to be most con-health in the Þrst year of life due to maternal prenatal zinc deÞciency.therefore, newborn zinc deÞciency (assessed as low serum zinc concen-around six months of age, however, breast milk intake no longer pro-and persists until changes in the diet are made. Thus, it must be recog-nized that removal of the global burden of disease due to zinc deÞciencythis chapter, we have considered only the burden of disease for children Laura E.Caulfield and Robert E.Black275be true that zinc deÞciency contributes greatly to death and disabilityority area for future research.Because low weight-for-age (usually described as underweight) alsoempirically, but evidence from studies can provide insight in this issue.In the meta-analysis of zinc RCTs (Zinc InvestigatorsÕ Collaborativescore in the study subjects. However, the study by Umeta et al. (2000)limited evidence shows that the efÞcacy of zinc supplementation forare also studies in the literature in which improvements in immune func-pometric status appears to exert more generalized effects. With theseIn summary, the available evidence suggests that zinc deÞciency con-and disability, it is clear that further research on the role of zinc in mor-bidity, mortality and disability due to other causes and in other age Projections of exposureCurrently, there are no programmes or policy initiatives in place toimprove intakes of animal products which are good sources of zinc orto reduce phytates in foods which impair zinc absorption). Further, thereor programmatic initiatives to address zinc deÞciency, we project thatAcknowledgementsWe are grateful for the support of Kenneth H. Brown in providing usdimensions of malarial morbidity.Department of International Health, and by the World Health 1See preface for an explanation of this term.Bhandari N, Bahl R, Taneja S et al. (2002) Routine zinc supplementation onchildren in developing countries: a review of current scientiÞc knowledge.World Health Organization, Geneva. 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