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Summary The epidemiology of iron deficiency anaemia in sub-Saharan Africa differs from that in other parts of the world. The low-quality diets prevalent in this region are a poor source of iron, the population is frequently exposed to infection, and demographic characteristics result in a greater prevalence of people at high risk of iron deficiency anaemia than in other parts of the world. We herein review the causes, disease burden, and consequences of iron deficiency anaemia in the general population in this region, and current policies and interventions for its control. The current debate is dominated by concerns about the safety of iron interventions, namely regarding its effects on malaria and other infectious diseases. However, universal antenatal iron supplementation and delayed cord clamping are safe interventions and stand out for their potential to improve maternal and infant health. Effective infection control is a precondition to safe and efficacious iron interventions in children. Greater emphasis should be given to approaches aiming to reduce iron loss due to helminth infections and menstruation, alongside interventions to increase iron intake. Translation For the French translation of the abstract see Supplementary Materials section.

Summary: Background: WHO recommends daily iron supplementation for pregnant women, but adherence is poor because of side-effects, effectiveness is low, and there are concerns about possible harm. The iron-regulatory hormone hepcidin can signal when an individual is ready-and-safe to receive iron. We tested whether a hepcidin-guided screen-and-treat approach to combat iron-deficiency anaemia could achieve equivalent efficacy to universal administration, but with lower exposure to iron. Methods: We did a three-arm, randomised, double-blind, non-inferiority trial in 19 rural communities in the Jarra West and Kiang East districts of The Gambia. Eligible participants were pregnant women aged 18–45 years at between 14 weeks and 22 weeks of gestation. We randomly allocated women to either WHO's recommended regimen (ie, a daily UN University, UNICEF, and WHO international multiple-micronutrient preparation [UNIMMAP] containing 60 mg iron), a 60 mg screen-and-treat approach (ie, daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was

Summary For decades, folic acid has routinely been given to prevent or treat anaemia in children, pregnant women and people with sickle cell disease. However, there is no conclusive evidence that folate deficiency anaemia constitutes a public health problem in any of these groups. Industrial flour fortification is recommended and implemented in many countries to combat neural tube defects. Dietary folates or folic acid can antagonise the action of antifolate drugs that play a critical role in the prevention and treatment of malaria. Randomised trials have shown that folic acid supplementation increases the rate of treatment failures with sulfadoxine‐pyrimethamine. The efficacy of antifolate drugs against Plasmodium is maximized in the absence of exogenous folic acid, suggesting that there is no safe minimum dose of ingested folic acid. We here review the safety and benefits of interventions to increase folate status in malaria‐endemic countries. We conclude that formal cost‐benefit analyses are required.

Iron supplementation strategies in the developing world remain controversial because of fears of exacerbating prevalent infectious diseases. Understanding the conditions in which iron will be absorbed and incorporated into erythrocytes is therefore important. We studied Gambian children with either postmalarial or nonmalarial anemia, who were given oral iron supplements daily for 30 days. Supplements administered on days 1 and 15 contained the stable iron isotopes 57Fe and 58Fe, respectively, and erythrocyte incorporation was measured in blood samples drawn 14 days later. We investigated how the iron-regulatory hormone hepcidin and other inflammatory/iron-related indices, all measured on the day of isotope administration, correlated with erythrocyte iron incorporation. In univariate analyses, hepcidin, ferritin, C-reactive protein, and soluble transferrin receptor (sTfR) strongly predicted incorporation of 57Fe given on day 1, while hepcidin, ferritin, and sTfR/log ferritin correlated with 58Fe incorporation. In a final multivariate model, the most consistent predictor of erythrocyte isotope incorporation was hepcidin. We conclude that under conditions of competing signals (anemia, iron deficiency, and infection), hepcidin powerfully controls use of dietary iron. We suggest that low-cost point-of-care hepcidin assays would aid iron supplementation programs in the developing world.

Background: Iron deficiency is the most prevalent nutritional deficiency worldwide. WHO recommends daily iron supplementation for all pregnant women where anaemia exceeds 40%, but adherence is limited by side-effects, effectiveness is low, and there are concerns around possible harm. The iron-regulatory hormone, hepcidin, signals 'ready-and-safe' to receive iron. We tested a hepcidin-guided screen-and-treat (S&T) approach to combat iron deficiency anaemia (IDA) aimed at achieving equivalent efficacy to universal administration but at lower levels of supplemental iron exposure. Methods: We conducted a 3-arm randomised-controlled double-blind trial in rural Gambia to assess non-inferiority of two ST b) daily UNIMMAP containing 60mg iron for 7d if weekly hepcidin was

Serum ferritin concentration is the preferred biomarker to assess population iron status in the absence of inflammation. Interpretation of this biomarker is complicated in populations with a high burden of infection, however, because inflammation increases serum ferritin concentration independently of iron status. We aimed to compare estimates of iron status of Kenyan pregnant women, with circulating ferritin concentrations adjusted for inflammation using newly proposed methods by the BRINDA project, or using previously proposed adjustment methods. We re-analyzed data from pregnant Kenyan women living in a rural area where malaria is highly endemic (n = 470) or in an urban area (n = 402). As proposed by the BRINDA group, we adjusted individual ferritin concentration by internal regression for circulating concentrations of C-reactive protein (CRP) and &alpha, 1-acid glycoprotein (AGP). Other adjustment methods comprised: (a) arithmetic correction factors based on CRP or AGP, (b) exclusion of subjects with inflammation (CRP &gt, 5 mg/L or AGP &gt, 1 g/L), and (c) higher ferritin cut-off value (&lt, 30 &mu, g/L). We additionally adjusted for Plasmodium infection as appropriate. Lastly, we assessed iron status without adjustment for inflammation. All correction methods increased prevalence of iron deficiency compared to the unadjusted estimates. This increase was more pronounced with the internal regression correction method. The iron deficiency prevalence estimate increased from 53% to 87% in rural Kisumu study and from 30% to 41% in the urban Nairobi study after adjusting for inflammation (CRP and AGP) using the BRINDA internal regression method. When we corrected for both inflammation and Plasmodium infection using the regression correction, it resulted in lower prevalence estimates compared to uninfected women. Application of linear regression methods to adjust circulating ferritin concentration for inflammation leads to markedly decreased point estimates for ferritin concentration and increased estimates for the prevalence of iron deficiency in pregnancy.

Low birth weight (LBW) and preterm birth (PTB) are major contributors to infant mortality and chronic childhood morbidity. Understanding factors that contribute to or protect against these adverse birth outcomes is an important global health priority. Anaemia and iron deficiency are common in malaria-endemic regions, but there are concerns regarding the value of iron supplementation among pregnant women in malaria-endemic areas due to reports that iron supplementation may increase the risk of malaria. There is a lack of evidence on the impact of iron deficiency on pregnancy outcomes in malaria-endemic regions.We determined iron deficiency in a cohort of 279 pregnant women in a malaria-endemic area of Papua New Guinea. Associations with birth weight, LBW and PTB were estimated using linear and logistic regression. A causal model using sequential mediation analyses was constructed to assess the association between iron deficiency and LBW, either independently or mediated through malaria and/or anaemia.Iron deficiency in pregnant women was common (71% at enrolment) and associated with higher mean birth weights (230 g; 95% confidence interval, CI 118, 514; p 0.001), and reduced odds of LBW (adjusted odds ratio, aOR = 0.32; 95% CI 0.16, 0.64; p = 0.001) and PTB (aOR = 0.57; 95% CI 0.30, 1.09; p = 0.089). Magnitudes of effect were greatest in primigravidae (birth weight 351 g; 95% CI 188, 514; p 0.001; LBW aOR 0.26; 95% CI 0.10, 0.66; p = 0.005; PTB aOR = 0.39, 95% CI 0.16, 0.97; p = 0.042). Sequential mediation analyses indicated that the protective association of iron deficiency on LBW was mainly mediated through mechanisms independent of malaria or anaemia.Iron deficiency was associated with substantially reduced odds of LBW predominantly through malaria-independent protective mechanisms, which has substantial implications for understanding risks for poor pregnancy outcomes and evaluating the benefit of iron supplementation in pregnancy. This study is the first longitudinal study to demonstrate a temporal relationship between antenatal iron deficiency and improved birth outcomes. These findings suggest that iron supplementation needs to be integrated with other strategies to prevent or treat infections and undernutrition in pregnancy to achieve substantial improvements in birth outcomes.

Background The efficacy of home fortification with iron-containing micronutrient powders varies between trials, perhaps in part due to population differences in adherence. We aimed to assess to what extent adherence measured by sachet count or self-reporting forms is in agreement with adherence measured by electronic device. In addition, we explored how each method of adherence assessment (electronic device, sachet count, self-reporting forms) is associated with haemoglobin concentration measured at the end of intervention; and to what extent baseline factors were associated with adherence as measured by electronic device. Methods Three hundred thirty-eight rural Kenyan children aged 12-36 months were randomly allocated to three treatment arms (home fortification with two different iron formulations or placebo). Home fortificants were administered daily by parents or guardians over a 30 day-intervention period. We assessed adherence using an electronic device that stores and provides information of the time and day of opening of the container that was used to store the fortificants sachets in each child’s residence. In addition, we assessed adherence by self-reporting and sachet counts. We also measured haemoglobin concentration at the end of intervention. Results Adherence, defined as having received at least 24 sachets (≥ 80%), during the 30-day intervention period was attained by only 60.6% of children as assessed by the electronic device. The corresponding values were higher when adherence was assessed by self-report (83.9%; difference: 23.3%, 95% CI: 18.8% to 27.8%) or sachet count (86.3%; difference: 25.7%, 95% CI: 21.0% to 30.4%). Among children who received iron, each 10 openings of the electronic cap of the sachet storage container were associated with an increase in haemoglobin concentration at the end of intervention by 1.2 g/L (95% CI: 0.0 to 1.9 g/L). Adherence was associated with the age of the parent but not with intervention group; with age, sex or anthropometric indices of the child; or with age or sex of the parent or guardian. Conclusions The use of self -reporting and sachet count may lead to overestimates of adherence to home fortification. Trial registration The trial was registered with ClinicalTrials.gov (NCT02073149) on 25 February 2014. Electronic supplementary material The online version of this article (10.1186/s12889-018-5097-2) contains supplementary material, which is available to authorized users.

Background Zinc protoporphyrin (ZPP) has been used to screen and manage iron deficiency in individual children, but it has also been recommended to assess population iron status. The diagnostic utility of ZPP used in combination with haemoglobin concentration has not been evaluated in pre-school children. We aimed to a) identify factors associated with ZPP in children aged 12–36 months; b) assess the diagnostic performance and utility of ZPP, either alone or in combination with haemoglobin, to detect iron deficiency. Methods We used baseline data from 338 Kenyan children enrolled in a community-based randomised trial. To identify factors related to ZZP measured in whole blood or erythrocytes, we used bivariate and multiple linear regression analysis. To assess diagnostic performance, we excluded children with elevated plasma concentrations of C-reactive protein or α 1-acid glycoprotein, and with Plasmodium infection, and we analysed receiver operating characteristics (ROC) curves, with iron deficiency defined as plasma ferritin concentration 5.93120) correctly ruled out iron deficiency in 37.4%–53.7% of children screened, depending on the true prevalence, with both specificity and negative predictive value ≥90%. Conclusions In young children, whole blood ZPP and erythrocyte ZPP have added diagnostic value in detecting iron deficiency compared to haemoglobin concentration alone. A single diagnostic score based on haemoglobin concentration and whole blood ZPP can rule out iron deficiency in a substantial proportion of children screened. Trial registration ClinicalTrials.gov NCT02073149 (25 February 2014). Electronic supplementary material The online version of this article (doi:10.1186/s12878-017-0082-z) contains supplementary material, which is available to authorized users.

In 2016, the World Health Organization (WHO) recommended point-of-use fortification of complementary foods with iron-containing micronutrient powders to improve iron status and reduce anaemia in children at risk of anaemia. This recommendation continues to be debated. In a recent trial among Kenyan children aged 12–36 months, we found no evidence that daily point-of-use fortification was efficacious in improving haemoglobin concentration or plasma iron markers. An updated meta-analysis indicated that, on average, in an arbitrarily selected setting and with adherence as obtained under trial conditions, one may expect a small increase in haemoglobin concentration in preschool children, with the upper limit of the 95% CI virtually excluding an effect beyond 5.5 g/L. In the present paper, we elaborate on the interpretation of these findings and the meta-analyses that formed the basis for the WHO guidelines. In particular, we draw attention to the phenomenon that small group differences in the distribution of continuous outcomes (haemoglobin concentration, ferritin concentrations) can give a false impression of relatively large effects on the prevalence of the dichotomised outcomes (anaemia, iron deficiency). Please see related articles: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0839-z , https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0867-8

Background We aimed to show the non-inferiority of home fortification with a daily dose of 3 mg iron in the form of iron as ferric sodium ethylenediaminetetraacetate (NaFeEDTA) compared with 12.5 mg iron as encapsulated ferrous fumarate in Kenyan children aged 12–36 months. In addition, we updated a recent meta-analysis to assess the efficacy of home fortification with iron-containing powders, with a view to examining diversity in trial results. Methods We gave chemoprevention by dihydroartemisinin-piperaquine, albendazole and praziquantel to 338 afebrile children with haemoglobin concentration ≥70 g/L. We randomly allocated them to daily home fortification for 30 days with either placebo, 3 mg iron as NaFeEDTA or 12.5 mg iron as encapsulated ferrous fumarate. We assessed haemoglobin concentration (primary outcome), plasma iron markers, plasma inflammation markers and Plasmodium infection in samples collected at baseline and after 30 days of intervention. We conducted a meta-analysis of randomised controlled trials in pre-school children to assess the effect of home fortification with iron-containing powders on anaemia and haemoglobin concentration at end of intervention. Results A total of 315 children completed the 30-day intervention period. At baseline, 66.9% of children had inflammation (plasma C-reactive protein concentration >5 mg/L or plasma α 1-acid glycoprotein concentration >1.0 g/L); in those without inflammation, 42.5% were iron deficient. There was no evidence, either in per protocol analysis or intention-to-treat analysis, that home fortification with either of the iron interventions improved haemoglobin concentration, plasma ferritin concentration, plasma transferrin receptor concentration or erythrocyte zinc protoporphyrin-haem ratio. We also found no evidence of effect modification by iron status, anaemia status and inflammation status at baseline. In the meta-analysis, the effect on haemoglobin concentration was highly heterogeneous between trials (I 2: 84.1%; p value for test of heterogeneity

Summary The World Health Organization recommends universal iron supplementation of 30–60 mg/day in pregnancy but coverage is low in most countries. Its efficacy is uncertain, however, and there has been a vigorous debate in the last decade about its safety, particularly in areas with a high burden of malaria and other infectious diseases. We reviewed the evidence on the safety and efficacy of antenatal iron supplementation in low‐income countries. We found no evidence that daily supplementation at a dose of 60 mg leads to increased maternal Plasmodium infection risk. On the other hand, recent meta‐analyses found that antenatal iron supplementation provides benefits for maternal health (severe anaemia at postpartum, blood transfusion). For neonates, there was a reduced prematurity risk, and only a small or no effect on birth weight. A recent trial showed, however, that benefits of antenatal iron supplementation on maternal and neonatal health vary by maternal iron status, with substantial benefits in iron‐deficient women. The benefits of universal iron supplementation are likely to vary with the prevalence of iron deficiency. As a consequence, the balance between benefits and risks is probably more favourable in low‐income countries than in high‐income countries despite the higher exposure to infectious pathogens.

Introduction: Home fortification powders containing iron and other micronutrients have been recommended by World Health Organisation to prevent iron deficiency anaemia in areas of high prevalence. There is evidence, however, that home fortification at this iron dose may cause gastrointestinal adverse events including diarrhoea. Providing a low dose of highly absorbable iron (3 mg iron as NaFeEDTA) may be safer because the decreased amount of iron in the gut lumen can possibly reduce the burden of these adverse effects whilst resulting in similar or higher amounts of absorbed iron. Objective: To show non-inferiority of home fortification with 3 mg iron as NaFeEDTA compared with 12.5 mg iron as encapsulated ferrous fumarate, with haemoglobin response as the primary outcome. Design: 338 Kenyan children aged 12–36 months will be randomly allocated to daily home fortification with either: a) 3 mg iron as NaFeEDTA (experimental treatment), b) 12.5 mg iron as encapsulated ferrous fumarate (reference), or c) placebo. At baseline, after 30 days of intervention and within 100 days post-intervention, blood samples will be assessed for primary outcome (haemoglobin concentration), iron status markers, Plasmodium parasitaemia and inflammation markers. Urine and stool samples will be assessed for hepcidin concentrations and inflammation, respectively. Adherence will be assessed by self-reporting, sachet counts and by an electronic monitoring device. Conclusion: If daily home fortification with a low dose of iron (3 mg NaFeEDTA) has similar or superior efficacy to a high dose (12.5 mg ferrous fumarate) then it would be the preferred choice for treatment of iron deficiency anaemia in children. Keywords: Adherence, Anaemia, Child, Preschool, Dietary supplements, Iron, Non-inferiority, Fortification

Background Sodium iron edetic acid (NaFeEDTA) might be a more bioavailable source of iron than electrolytic iron, when added to maize flour. We aimed to assess the effect, on children's iron status, of consumption of whole maize flour fortified with iron as NaFeEDTA or electrolytic iron. Methods 516 children, aged 3-8 years, from four schools in Marafa, Kenya, were randomly assigned to four groups. All were given the same amount of porridge five times a week. The porridge for one group was made from unfortified whole maize flour; for the other three groups it was fortified with either high-dose NaFeEDTA (56 mg/kg), low-dose NaFeEDTA (28 mg/kg), or electrolytic iron (56 mg/kg). Concentrations of haemoglobin, plasma ferritin, and transferrin receptor were analysed in samples taken at baseline and at the end of the 5-month intervention. The primary outcome was iron-deficiency anaemia. We analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00386074. Findings The prevalence of iron-deficiency anaemia in children given unfortified flour was 10%. Compared with placebo, the prevalence of iron-deficiency anaemia in children given flour fortified with high-dose NaFeEDTA, low-dose NaFeEDTA, and electrolytic iron changed by -89% (95% CI -97% to -49%), -48% (-77% to 20%), and 59% (-18% to 209%), respectively. Consumption of high-dose NaFeEDTA improved all measured iron-status indicators. Low-dose NaFeEDTA decreased the prevalence of iron deficiency but did not noticeably change the prevalence of anaemia. Electrolytic iron did not improve any of these iron-status indicators. Children who were iron-deficient at baseline benefited more from high-dose and low-dose NaFeEDTA than those with sufficient iron at baseline. Interpretation Consumption of whole maize flour fortified with NaFeEDTA caused modest, dose-dependent improvements in children's iron status. Fortification with electrolytic iron did not improve their iron status. Therefore, in high-phytate flours, NaFeEDTA is more suitable than electrolytic iron for supplementation of iron in the diet.

Background: Our group and many others have used the relativedose- response (RDR) test and the modified-RDR (MRDR) test as proxy indicators of liver stores of vitamin A. However, we have become concerned about the validity of these indicators. Objective: Simulation models were used to assess effects of random variations in serum retinol concentration on the RDR and to assess effects of group differences in serum retinol concentration on the distribution of RDR and MRDR values. Design: Random and independent samples were drawn from normally distributed, computer-generated numbers whose distributions simulated serum concentrations of retinol and 3,4-didehydroretinol as obtained from published reports. The resulting data sets were used to compute surrogateRDRorMRDRvalues. In model 1, the relation between serum concentrations of retinol and RDR was examined within a fictitious population. In models 2 and 3, fictitious populations with different distributions of serum retinol concentration were compared with respect to their RDR and MRDR values. Results: Simulated RDR values and serum retinol concentrations were negatively related. Models 2 and 3 showed that group differences in serum retinol concentrations necessarily produced group differences in mean RDR or MRDR values. A mathematical artefact may explain the negative relation reported between MRDR and serum retinol concentration, and it dictates that this relation will necessarily vary between populations with different degrees of vitamin A deficiency. Conclusion: A continued search for alternative blood indicators of liver stores of vitamin A is needed.

Objectives: Hematologic and non-hematologic benefits from iron supplementation are chiefly seen in iron deficient individuals; concerns that iron might promote infection especially in non-iron deficient individuals have complicated global anemia control policies, particularly in malaria-endemic settings. Iron homeostasis, including intestinal absorption, is controlled by hepcidin. Hepcidin is regulated by iron, erythropoietic drive, and inflammation, suggesting its potential utility to appraise iron status and thus guide iron supplementation. Methods: In 1338 African pre-school children we evaluated the Area Under the ROC Curve (AUCROC) for plasma hepcidin concentration as a diagnostic test of iron status, anemia type and erythrocyte incorporation of oral iron, determining and modeling the effects of cutoffs. Results: Hepcidin detected iron deficiency with an AUCROC = 0.85 (optimal sensitivity/ specificity at a cutoff of 5.5 ng/ml); this was not significantly affected by gender, wasting, malaria or carriage of inherited red cell disorders. In anemic children, hepcidin distinguished iron deficiency anemia from anemia of inflammation (AUCROC=0.89, optimal sensitivity/specificity cutoff 5.4 ng/ml). Hepcidin was the best predictor for >20% incorporation into erythrocytes of orally-administered 57Fe (AUCROC=0.90, optimal sensitivity/ specificity cutoff P. falciparum and 86% of children with anemia of inflammation would have avoided iron. Conclusions: In African children, hepcidin ascertains iron status, distinguishes iron deficiency anemia from anemia of inflammation, and hence could guide iron supplementation toward groups in whom it will likely be beneficial and safe.

Background: Serum transferrin receptor concentrations indicate both erythropoietic activity and the deficit of functional iron in the erythron. In contrast with serum ferritin concentrations, serum transferrin receptor concentrations are not or are only marginally influenced by the inflammatory response to infection. Objective: We assessed iron status and examined the relation between serum transferrin receptor concentrations and malaria in children aged 2-36 mo who were asymptomatic for malaria. Design: This was a community-based cluster survey (n = 318). Results: Prevalences of malaria, anemia (hemoglobin concentration

Background: In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria. Histidine-rich protein 2 (HRP2) is produced by Plasmodium falciparum, and its plasma concentration reflects the total body parasite burden. We aimed to define the malaria-attributable fraction of severe febrile illness, using the distributions of plasma P. falciparum HRP2 (PfHRP2) concentrations from parasitemic children with different clinical presentations. Methods: Plasma samples were collected from and peripheral blood slides prepared for 1435 children aged 6−60 months in communities and a nearby hospital in northeastern Tanzania. The study population included children with severe or uncomplicated malaria, asymptomatic carriers, and healthy control subjects who had negative results of rapid diagnostic tests. The distributions of plasma PfHRP2 concentrations among the different groups were used to model severe malaria-attributable disease. Results:The plasma PfHRP2 concentration showed a close correlation with the severity of infection. PfHRP2 concentrations of >1000 ng/mL denoted a malaria-attributable fraction of severe disease of 99% (95% credible interval [CI], 96%–100%), with a sensitivity of 74% (95% CI, 72%–77%), whereas a concentration of 10% (95% CI, 3%–27%) of patients. Bacteremia was more common among patients in the lowest and highest PfHRP2 concentration quintiles. Conclusions: The plasma PfHRP2 concentration defines malaria-attributable disease and distinguishes severe malaria from coincidental parasitemia in African children in a moderate-to-high transmission setting.

This abstract is submitted as part of the round-table discussion sponsored by Sight and Life. A recent trial reinforced earlier concerns that iron supplementation can increase malaria rates. The World Health Organization subsequently restricted its recommendations in malaria-endemic areas from universal supplementation to targeted supplementation of iron-deficient children, but continues to advocate universal supplementation in pregnancy. Resurgent interest in iron has led to further studies to assess its safety, particularly in pregnant women; to identify markers for rapid, low-cost screening for deficiency; and to develop safe but efficacious iron interventions. The hepcidin-axis recently emerged as a newly discovered arm of the innate immune system. Hepcidin is now known to regulate iron absorption and metabolism, but also to mediate impaired recycling and absorption of iron in infections. Current evidence suggests that plasma hepcidin concentration may predict haematological and infectious responses to iron, at least in the short term, and that deliberately altering hepcidin concentrations may result in new strategies to control infections by Plasmodium and other iron-requiring pathogens. Folic acid supplementation continues to be recommended around conception and during pregnancy, and international agencies have recommended additional measures to increase the intake of folic acid. Plasmodium parasites can utilise exogenous folate, however, and several trials suggest that folic acid supplementation can reduce the efficacy of antifolate drugs used for malaria control. A better understanding is required of the controversies of interventions to increase folate status and the safety of interventions to improve folate status in malaria-endemic countries.

BACKGROUND: The efficacy of preventive zinc supplementation against diarrhea and respiratory illness may depend on simultaneous supplementation with other micronutrients. We aimed to assess the effect of supplementation with zinc and multiple micronutrients on diarrhea and other causes of non-malarial morbidity. METHODS AND FINDINGS: Rural Tanzanian children (n = 612) aged 6-60 months and with height-for-age z-score < -1.5 SD were randomized to daily supplementation with zinc (10 mg) alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Children were followed for an average of 45 weeks. During follow-up, we recorded morbidity episodes. 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 (guardian-reported illness with symptoms involving skin, ears, eyes and abscesses, but excluding trauma or burns). Zinc supplementation reduced the hazard rate of diarrhea by 24% (4%-40%). By contrast, multi-nutrients seemed to increase this rate (HR; 95% CI: 1.19; 0.94-1.50), particularly in children with asymptomatic Giardia infection at baseline (2.03; 1.24-3.32). Zinc also protected against episodes of fever without localizing signs (0.75; 0.57-0.96), but we found no evidence that it reduced the overall number of clinic visits. CONCLUSIONS: We found no evidence that the efficacy of zinc supplements in reducing diarrhea rates is enhanced by concurrent supplementation with other micronutrients. By reducing rates of fever without localizing signs, supplementation with zinc may reduce inappropriate drug use with anti-malarial medications and antibiotics. TRIAL REGISTRATION: ClinicalTrials.gov NCT00623857.

Hans Verhoef and colleagues report findings from a randomized trial conducted among Tanzanian children at high risk for malaria. Children in the trial received either daily oral supplementation with either zinc alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. The investigators did not find evidence from this study that zinc or multi-nutrients protected against malaria episodes., Background It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates. Methods and Findings In a 2×2 factorial trial, 612 rural Tanzanian children aged 6–60 months in an area with intense malaria transmission and with height-for-age z-score≤−1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191–296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93–1.18 and 1.10, 0.97–1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration, Editors' Summary Background Malaria is a serious global public-health problem. Half of the world's population is at risk of this parasitic disease, which kills a million people (mainly children living in sub-Saharan Africa) every year. Malaria is transmitted to people through the bites of infected night-flying mosquitoes. Soon after entering the human body, the parasite begins to replicate in red blood cells, bursting out every 2–3 days and infecting more red blood cells. The presence of the parasite in the blood stream (parasitemia) causes malaria's characteristic recurring fever and can cause life-threatening organ damage and anemia (insufficient quantity of red blood cells). Malaria transmission can be reduced by using insecticide sprays to control the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Effective treatment with antimalarial drugs can also reduce malaria transmission. Why Was This Study Done? One reason why malaria kills so many children in Africa is poverty. Many children in Africa are malnourished, and malnutrition—in particular, insufficient micronutrients in the diet—impairs the immune system, which increases the frequency and severity of many childhood diseases. Micronutrients are vitamins and minerals that everyone needs in small quantities for good health. Zinc is one of the micronutrients that helps to maintain a healthy immune system, but zinc deficiency is very common among African children. Zinc supplementation has been shown to reduce the burden of diarrhea in developing countries, so might it also reduce the burden of malaria? Unfortunately, the existing evidence is confusing—some trials show that zinc supplementation protects against malaria but others show no evidence of protection. One possibility for these conflicting results could be that zinc supplementation alone is not sufficient—supplementation with other micronutrients might be needed for zinc to have an effect. In this randomized trial (a study that compares the effects of different interventions in groups that initially are similar in all characteristics except for intervention), the researchers investigate the effect of supplementation with zinc alone and in combination with other micronutrients on the rate of uncomplicated (mild) malaria among children living in Tanzania. What Did the Researchers Do and Find? The researchers enrolled 612 children aged 6–60 months who were living in a rural area of Tanzania with intense malaria transmission and randomly assigned them to receive daily oral supplements containing zinc alone, multi-nutrients (including iron) without zinc, multi-nutrients with zinc, or a placebo (no micronutrients). Nutritional indicators (including zinc concentrations in blood plasma) were assessed at baseline and 6–10 months after starting the intervention. During the study period, there were 1,572 malaria episodes. The incidence of malaria in all four intervention groups was very similar (about three episodes per child-year), and there was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Moreover, none of the supplements had any effect on malaria rates when compared to the placebo, even though the occurrence of zinc deficiency was strongly reduced by zinc supplementation. In a secondary analysis in which they analyzed their data by iron status at baseline, the researchers found that multi-nutrient supplementation increased the overall number of malaria episodes in children with iron deficiency by 41%, whereas multi-nutrient supplementation had no effect on the number of malaria episodes among children who were iron-replete at baseline. What Do These Findings Mean? In this study, the researchers found no evidence that zinc supplementation protected against malaria among young children living in Tanzania when given alone or in combination with other multi-nutrients. However, the researchers did find some evidence that multi-nutrient supplementation may increase the risk of malaria in children with iron deficiency. Because this finding came out of a secondary analysis of the data, it needs to be confirmed in a trial specifically designed to assess the effect of multi-nutrient supplements on malaria risk in iron-deficient children. Nevertheless, it is a potentially worrying result because, on the basis of evidence from a single study, the World Health Organization currently recommends that regular iron supplements be given to iron-deficient children in settings where there is adequate access to anti-malarial treatment. This recommendation should be reconsidered, suggest the researchers, and the safety of multi-nutrient mixes that contain iron and that are dispensed in countries affected by malaria should also be carefully evaluated. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001125. Information is available from the World Health Organization on malaria (in several languages), on micronutrients, and on zinc deficiency; the 2010 World Malaria Report provides details of the current global malaria situation The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria Information is available from the Roll Back Malaria Partnership on the global control of malaria and on malaria in Africa The Malaria Centre at the UK London School of Hygiene & Tropical Medicine develops tools, techniques, and knowledge about malaria, and has a strong emphasis on teaching, training, and translating research outcomes into practice The Micronutrient Initiative, the Global Alliance for Improved Nutrition, and the Flour Fortification Initiative are not-for-profit organizations dedicated to ensuring that people in developing countries get the minerals and vitamins they need to survive and thrive The International Zinc Nutrition Consultative Group (iZiNCG) is a non-profit organization that aims to promote and assist efforts to reduce zinc deficiency worldwide, through advocacy efforts, education, and technical assistance MedlinePlus provides links to additional information on malaria (in English and Spanish)

Background It is controversial to what degree α+-thalassaemia protects against episodes of uncomplicated malaria and febrile disease due to infections other than Plasmodium. Methods In Tanzania, in children aged 6-60 months and height-for-age z-score < -1.5 SD (n = 612), rates of fevers due to malaria and other causes were compared between those with heterozygous or homozygotes α+-thalassaemia and those with a normal genotype, using Cox regression models that accounted for multiple events per child. Results The overall incidence of malaria was 3.0/child-year (1, 572/526 child-years); no differences were found in malaria rates between genotypes (hazard ratios, 95% CI: 0.93, 0.82-1.06 and 0.91, 0.73-1.14 for heterozygotes and homozygotes respectively, adjusted for baseline factors that were predictive for outcome). However, this association strongly depended on age: among children aged 6-17 months, those with α+-thalassaemia experienced episodes more frequently than those with a normal genotype (1.30, 1.02-1.65 and 1.15, 0.80-1.65 for heterozygotes and homozygotes respectively), whereas among their peers aged 18-60 months, α+-thalassaemia protected against malaria (0.80, 0.68-0.95 and 0.78, 0.60-1.03; p-value for interaction 0.001 and 0.10 for hetero- and homozygotes respectively). No effect was observed on non-malarial febrile episodes. Conclusions In this population, the association between α+-thalassaemia and malaria depends on age. Our data suggest that protection by α+-thalassaemia is conferred by more efficient acquisition of malaria-specific immunity.

BACKGROUND: In hospital-based studies, alpha(+)-thalassemia has been found to protect against severe, life-threatening falciparum malaria. alpha(+)-Thalassemia does not seem to prevent infection or high parasite densities but rather limits progression to severe disease--in particular, severe malarial anemia. We assessed to what extent alpha(+)-thalassemia influences the association between mild, asymptomatic Plasmodium falciparum infection and hemoglobin concentration. METHODS: The study was based on 2 community-based surveys conducted among afebrile children (0.5-8 years old; n=801) in Kenya and Tanzania. RESULTS: Among children without inflammation (whole-blood C-reactive protein concentration

The contribution of various factors to malnutrition, particularly stunting, may differ among areas and communities. This cross-sectional study aimed to estimate the level of malnutrition and identify factors associated with the high level of stunting in breast-fed infants aged 5-11 mo living in Dodota-Sire District, Ethiopia. Infants (n = 305) and their mothers were examined physically, and anthropometric and demographic data were collected. The content of zinc, calcium and copper in breast milk was measured, and data collected on the type, frequency of consumption, and time of introduction of supplementary feeding. Overall, 36% were stunted, 41% underweight and 13% wasted. The highest prevalence of malnutrition was seen in infants aged 9-11 mo. Among mothers, 27% had chronic energy deficiency (body mass index, 3 times/d, consuming > 600 mL/d or consuming cow's milk in addition to cereals and/or legumes had markedly higher length-for-age Z-scores than their peers fed less frequently, consuming less food or not consuming cow's milk [differences: 0.39, 95% confidence interval (Cl): 0.04-0.74; 0.17, 95% Cl: 0.02-0.32; 0.40, 95% Cl: 0.07-0.72, respectively]. Infants of mothers with low concentrations of zinc in their breast milk were more stunted. In conclusion, the quality and quantity of foods consumed by infants is insufficient to prevent stunting. Thus it is necessary to increase the,nutrient supply to infants by increasing intake and nutrient concentration of breast milk and of supplementary foods they consume, and by providing supplements to infants Where appropriate.

textabstractSpectacular progress has been made in the last decades in the global fight against deficiencies of iodine and vitamin A [1]. As a result, the number of people suffering from iodine deficiency has been reduced from about 1.5 billion in 1990 to about 0.5 billion now, almost entirely due to the introduction in many countries of what has been termed ‘universal salt iodization’. In addition, approximately one million child deaths may have been prevented between 1998 and 2000 by vitamin A supplementation [2]. The political and financial commitment that has allowed these achievements has been generated to a large extent by scientific studies that have shown the extent of human suffering caused by these deficiencies, and that have determined the potential health gains of interventions. Progress in eliminating deficiencies of other micronutrients, notably iron, has been much slower. About two billion people, or about one third of the human population, continue to suffer from iron deficiency. Iron supplementation programs have been advocated for infants and preschool children, largely because of concerns of possible adverse effects of iron deficiency on mental and motor development. Similar concerns were instrumental in establishing salt iodization programs. The questions that will be addressed in this chapter concern the extent to which a shortage of iodine and iron during fetal and infant development impairs mental development, and the extent to which this impairment can be redressed by increasing the intake of these micronutrients. First, the stages of brain development in the fetus and infant will be addressed, followed by an assessment of the timing of vulnerable periods when the brain of the fetus and infant is at high risk of exposure to an inadequate supply of iodine or iron. Where possible, the mechanisms involved will be discussed. Then, observational and intervention studies will be reviewed that have examined the effect of deficiencies of iodine or iron on mental development. Approximately half of the world’s population may be at risk of low zinc intake [3]. Given this high prevalence, inconclusive but mounting evidence that zinc deficiency during pregnancy may possibly impair the infant’s neurobehavioral development and immune function should also raise great concern [4–10]. However, because of space limitations, such effects and those of other micronutrients [11] will not be reviewed in the present report.

Summary Background Iron supplementation is recommended for children at high risk of anaemia, but its benefits may not outweigh the associated risk of malaria in areas of seasonal transmission. We investigated the effect on haemoglobin concentrations of intermittent administration of iron supplements and sulfadoxine-pyrimethamine in symptom-free children under intense health surveillance. Methods In a trial of two by two factorial design, 328 anaemic Kenyan children were randomly assigned either iron or placebo and sulfadoxine-pyrimethamine or placebo (82 to each group). Primary outcomes were haemological indicators of iron status and inflammation at the end of the follow-up, and occurrence of malaria attacks. Morbidity surveillance consisted of medical examinations every 4 weeks, continuous passive case detection, and visits twice a week to community health-workers. Analyses were by intention to treat. Findings After 12 weeks, the groups assigned iron plus sulfadoxine-pyrimethamine, iron alone, or sulfadoxine-pyrimethamine alone had higher haemoglobin concentrations than the group assigned placebo (treatment effect adjusted for prognostic factors at baseline: 11·1 g/L [95% CI 7·5 to 14·7]; 10·7 g/L [7·1 to 14·3]; and 3·1 g/L [−0·5 to 6·7]). Administration of iron plus sulfadoxine-pyrimethamine also lowered the proportion with anaemia from 100% at baseline to 36% at 12 weeks, and of iron deficiency from 66% at baseline to 8% at 12 weeks. Survival analysis showed no evidence of substantially increased risk of malaria after iron supplementation. Interpretation Iron supplementation gives substantial health benefits, which may outweigh possible inherent risks caused by malaria. A larger study than ours is needed to assess benefits and risks of intermittent administration of sulfadoxine-pyrimethamine in reducing the incidence of malaria attacks in areas of seasonal malaria transmission.

Selective digestive decontamination (SDD) is the most extensively studied method for the prevention of infection in patients in intensive care units (ICUs). Despite 27 prospective randomized studies and six meta-analyses, routine use of SDD is still controversial. In this review, we summarize the available scientific information on effectiveness of SDD in ICU patients. The effects of SDD have been studied in different combinations of the concept, using different antibiotics. Comparison of the individual studies, therefore, is difficult. In most studies, SDD resulted in significant reductions in the number of diagnoses of ventilator-associated pneumonia. However, incidences of ventilator-associated pneumonia in control groups ranged from 5% to 85%. Moreover, these reductions in incidences of ventilator-associated pneumonia in individual studies were not associated with improved patient survival, reductions of duration of ventilation or ICU stay, or reductions in antibiotic use. The numbers of patients studied are too small to determine effects on patient survival. Although two meta-analyses suggested a 20% mortality reduction when using the full concept of SDD (topical and systemic prophylaxis) these results should be interpreted with caution. Formal cost-benefit analyses of SDD have not been performed. SDD is associated with the selection of microorganisms that are intrinsically resistant to the antibiotics used. However, the studies are too small and too short to investigate whether SDD will lead to development of antibiotic resistance. As long as the benefits of SDD (better patient survival, reduction in antibiotic use or improved cost-effectiveness) have not been firmly established, the routine use of SDD for mechanically ventilated patients is not advised.

Sunil Sazawal and colleagues in their large trial in Pemba Zanzibar found that zinc supplementation led to a less-than-expected reduction of mortality (7%; 95% CI -6 to 19). The study was designed with a 90% probability to detect a 20% reduction in mortality. It is not helpful that Sazawal and colleagues take this power into consideration when interpreting the results. First the results indicate that power calculations were based on assumptions that were not met during trial implementation. A study with an expected upper limit equal to a particular value will have only 50% probability of yielding an upper limit below that value. Thus under the conditions prevailing in the Pemba trial the probability of detecting a mortality reduction of 19% is only 50%. (excerpt)

The aims of this study were to estimate the proportion of asymptomatic Kenyan preschool children using anti-malarial drugs, to identify factors associated with chloroquine use, and to assess the validity of frequency of febrile episodes and drug use reported by mothers or carers. Of 318 children studied, 38% (95% confidence interval [CI] = 30-47%]) tested positive for chloroquine or sulfadoxine. Of chloroquine-positive children, 15% had concentrations exceeding the estimated minimum therapeutically effective values. Among those testing negative for sulfadoxine, chloroquine-positive children were more frequently parasitemic (odds ratio = 2.6, 95% CI = 1.3-5.2), and had lower mean hemoglobin concentrations (6.1 g/L, 95% CI = 2.1-10.1) than chloroquine-negative children. Mothers over-reported the frequency of malaria or fever episodes as usually defined in medical studies, and underreported anti-malarial drug use. We conclude that anti-malarials are frequently given for treatment of malaria or malaria-associated illness, rather than prophylactically or for symptoms unrelated to malaria. Questionnaire surveys cannot replace biochemical markers to obtain information on anti-malarial drug use.