Zinc Supplementation for Promoting Growth in Children Under 5 years of age in Low- and Middle-income Countries: A Systematic Review.

OBJECTIVE: To study the effect of zinc supplementation in children under 5 years of age rom low- and middle-income countries (LMICs) on anthropometry and prevalence of malnutrition. Design: Systematic review of randomized controlled trials and cluster randomized trials. SETTING: Low- and middle-income countries. PARTICIPANTS: 63 trials with zinc supplementation, incorporating data on 27372 children. Trials conducted exclusively in specifically diseased participants and in children with severe acute malnutrition were excluded. Intervention: Zinc supplementation, provided either as medicinal supplementation or through food fortification. OUTCOME MEASURES: (i) Anthropometry: weight, height, weight-for-height, mid-arm circumference, head circumference; (ii) Prevalence of malnutrition. RESULTS: There was no evidence of effect on height-for-age Z score at the end of supplementation period (25 trials; 9165 participants; MD= 0.00 Z; 95% CI -0.07, 0.07; P=0.98; moderate quality evidence) with significant heterogeneity (I² = 57%; P<0.001) related to dose and duration of zinc between trials. There was little or no effect on change in height-for-age Z score (13 trials; 8852 participants; MD= 0.11 Z; 95% CI -0.00, 0.21; P=0.05), but the heterogeneity was considerable (I²=94%; P<0.001). There was no evidence of effect on length (6303 participants; MD= 1.18 cm; 95% CI -0.63, 2.99 cm, P=0.20; moderate quality evidence; considerable heterogeneity, I²=99%) but a little positive effect on change in length (19 trials; 10783 participants; MD= 0.43 cm; 95% CI 0.16, 0.70, P=0.002; moderate quality evidence; considerable heterogeneity, I²=93%). There was no evidence of effect on weight-for-age Z score or change in weight-for-age Z score but a little positive effect on weight (19 trials; 8851 study participants; MD= 0.23 kg; 95% CI 0.03, 0.42; P=0.02; considerable heterogeneity, I²=91%) and change in weight (kg) (23 trials; 10143 study participants; MD= 0.11 kg; 95% CI 0.05, 0.17, P<0.001, substantial heterogeneity, I²=80%). There was no evidence of effect on weight-for-height Z score, and mid upper arm circumference at the end of supplementation period, but there was a little positive effect on change in MUAC from baseline (8 trials; 1724 participants; MD = 0.09 cm; 95% CI 0.01, 0.16; P=0.03; no heterogeneity, I²=0%). Head circumference in zinc supplemented group was marginally higher compared to control (2966 study participants; MD= 0.39 cm; 95% CI 0.03, 0.75; P=0.03; substantial heterogeneity, I²=67%). There was no evidence of benefit in stunting (10 trials; 11838 study participants; RR= 1.0; 95% CI 0.95, 1.06; P=0.89; Moderate Quality Evidence; no significant heterogeneity, I²=11%), wasting (7 trials; 8988 study participants; RR= 0.94; 95% CI 0.82, 1.06; P=0.31; Moderate Quality Evidence; no significant heterogeneity, I²=13%) or underweight (7 trials; 8677 study participants; RR= 1.08; 95% CI 0.96, 1.21; P=0.19; Moderate Quality Evidence; substantial heterogeneity, I²=73%). CONCLUSION: Available evidence suggests that zinc supplementation probably leads to little or no improvement in anthropometric indices and malnutrition (stunting, underweight and wasting) in children under five years of age in LMICs. Advocating zinc supplementation as a public health measure to improve growth, therefore appears unjustified in these settings with scarce resources.

Lipid based nutrient supplements (LNS) for treatment of children (6 months to 59 months) with moderate acute malnutrition (MAM): A systematic review.

BACKGROUND: Moderate acute malnutrition is a major public health problem affecting children from low- and middle-income countries. Lipid nutrient supplements have been proposed as a nutritional intervention for its treatment. OBJECTIVES: To evaluate the effectiveness and safety of LNS for the treatment of MAM in infants and children 6 to 59 months of age. STUDY DESIGN: Systematic review of randomized-controlled trials and controlled before-after studies. RESULTS: Data from nine trials showed that use of LNS, in comparison to specially formulated foods, improved the recovery rate (RR 1.08; 95% CI 1.02-1.14, 8 RCTs, 8934 participants, low quality evidence); decreased the chances of no recovery (RR 0.70; 95% CI 0.58-0.85, 7 RCTs, 8364 participants, low quality evidence) and the risk of deterioration into severe acute malnutrition (RR 0.87; 95% CI 0.73-1.03, 6 RCTs, 6788 participants, low quality evidence). There was little impact on mortality (RR 0.94, 95% CI 0.54-1.52, 8 RCTs, 8364 participants, very-low- quality evidence) or default rate (RR 1.32; 95% CI 0.73-2.4, 7 studies, 7570 participants, low quality evidence). There was improvement in weight gain, weight-for-height z-scores, height-for-age z-scores and mid-upper arm circumference. Subset analyses suggested higher recovery rates with greater amount of calories provided and with ready-to-use therapeutic foods, in comparison to ready-to-use supplementary foods. One study comparing LNS with nutritional counselling (very low quality evidence) showed higher chance of recovery, lower risk of deteriorating into severe acute malnutrition and lower default rate, with no impact on mortality, and no recovery. CONCLUSIONS: Evidence restricted to the African regions suggests that LNS may be slightly more effective than specially formulated fortified foods or nutritional counselling in recovery from MAM, lowering the risk of deterioration into SAM, and improving weight gain with little impact on mortality or default rate.

Integrated management of childhood illness (IMCI) strategy for children under five.

BACKGROUND: More than 7.5 million children younger than age five living in low- and middle-income countries die every year. The World Health Organization (WHO) developed the integrated management of childhood illness (IMCI) strategy to reduce mortality and morbidity and to improve quality of care by improving the delivery of a variety of curative and preventive medical and behavioral interventions at health facilities, at home, and in the community. OBJECTIVES: To evaluate the effects of programs that implement the IMCI strategy in terms of death, nutritional status, quality of care, coverage with IMCI deliverables, and satisfaction of beneficiaries. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register; MEDLINE; EMBASE, Ovid; the Cumulative Index to Nursing and Allied Health Literature (CINAHL), EbscoHost; the Latin American Caribbean Health Sciences Literature (LILACS), Virtual Health Library (VHL); the WHO Library & Information Networks for Knowledge Database (WHOLIS); the Science Citation Index and Social Sciences Citation Index, Institute for Scientific Information (ISI) Web of Science; Population Information Online (POPLINE); the WHO International Clinical Trials Registry Platform (WHO ICTRP); and the Global Health, Ovid and Health Management, ProQuest database. We performed searches until 30 June 2015 and supplemented these by searching revised bibliographies and by contacting experts to identify ongoing and unpublished studies. SELECTION CRITERIA: We sought to include randomised controlled trials (RCTs) and controlled before-after (CBA) studies with at least two intervention and two control sites evaluating the generic IMCI strategy or its adaptation in children younger than age five, and including at minimum efforts to improve health care worker skills for case management. We excluded studies in which IMCI was accompanied by other interventions including conditional cash transfers, food supplementation, and employment. The comparison group received usual health services without provision of IMCI. DATA COLLECTION AND ANALYSIS: Two review authors independently screened searches, selected trials, and extracted, analysed and tabulated data. We used inverse variance for cluster trials and an intracluster co-efficient of 0.01 when adjustment had not been made in the primary study. We used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) approach to assess the certainty of evidence. MAIN RESULTS: Two cluster-randomised trials (India and Bangladesh) and two controlled before-after studies (Tanzania and India) met our inclusion criteria. Strategies included training of health care staff, management strengthening of health care systems (all four studies), and home visiting (two studies). The two studies from India included care packages targeting the neonatal period.One trial in Bangladesh estimated that child mortality may be 13% lower with IMCI, but the confidence interval (CI) included no effect (risk ratio (RR) 0.87, 95% CI 0.68 to 1.10; 5090 participants; low-certainty evidence). One CBA study in Tanzania gave almost identical estimates (RR 0.87, 95% CI 0.72 to 1.05; 1932 participants).One trial in India examined infant and neonatal mortality by implementing the integrated management of neonatal and childhood illness (IMNCI) strategy including post-natal home visits. Neonatal and infant mortality may be lower in the IMNCI group compared with the control group (infant mortality hazard ratio (HR) 0.85, 95% CI 0.77 to 0.94; neonatal mortality HR 0.91, 95% CI 0.80 to 1.03; one trial, 60,480 participants; low-certainty evidence).We estimated the effect of IMCI on any mortality measured by combining infant and child mortality in the one IMCI and the one IMNCI trial. Mortality may be reduced by IMCI (RR 0.85, 95% CI 0.78 to 0.93; two trials, 65,570 participants; low-certainty evidence).Two trials (India, Bangladesh) evaluated nutritional status and noted that there may be little or no effect on stunting (RR 0.94, 95% CI 0.84 to 1.06; 5242 participants, two trials; low-certainty evidence) and there is probably little or no effect on wasting (RR 1.04, 95% CI 0.87 to 1.25; two trials, 4288 participants; moderate-certainty evidence).The Tanzania CBA study showed similar results.Investigators measured quality of care by observing prescribing for common illnesses at health facilities (727 observations, two studies; very low-certainty evidence) and by observing prescribing by lay health care workers (1051 observations, three studies; very low-certainty evidence). We could not confirm a consistent effect on prescribing at health facilities or by lay health care workers, as certainty of the evidence was very low.For coverage of IMCI deliverables, we examined vaccine and vitamin A coverage, appropriate care seeking, and exclusive breast feeding. Two trials (India, Bangladesh) estimated vaccine coverage for measles and reported that there is probably little or no effect on measles vaccine coverage (RR 0.92, 95% CI 0.80 to 1.05; two trials, 4895 participants; moderate-certainty evidence), with similar effects seen in the Tanzania CBA study. Two studies measured the third dose of diphtheria, pertussis, and tetanus vaccine; and two measured vitamin A coverage, all providing little or no evidence of increased coverage with IMCI.Four studies (2 from India, and 1 each from Tanzania and Bangladesh) reported appropriate care seeking and derived information from careful questioning of mothers about recent illness. Some studies on effects of IMCI may report better care seeking behavior, but others do not report this.All four studies recorded maternal responses on exclusive breast feeding. They provided mixed results and very low-certainty evidence. Therefore, we do not know whether IMCI impacts exclusive breast feeding.No studies reported on the satisfaction of mothers and service users. AUTHORS' CONCLUSIONS: The mix of interventions examined in research studies evaluating the IMCI strategy varies, and some studies include specific inputs to improve neonatal health. Most studies were conducted in South Asia. Implementing the integrated management of childhood illness strategy may reduce child mortality, and packages that include interventions for the neonatal period may reduce infant mortality. IMCI may have little or no effect on nutritional status and probably has little or no effect on vaccine coverage. Maternal care seeking behavior may be more appropriate with IMCI, but study results have been mixed, providing evidence of very low certainty about whether IMCI has effects on adherence to exclusive breast feeding.

Fortification of staple foods with zinc for improving zinc status and other health outcomes in the general population.

BACKGROUND: Zinc deficiency is a global nutritional problem, particularly in children and women residing in settings where diets are cereal based and monotonous. It has several negative health consequences. Fortification of staple foods with zinc may be an effective strategy for preventing zinc deficiency and improving zinc-related health outcomes. OBJECTIVES: To evaluate the beneficial and adverse effects of fortification of staple foods with zinc on health-related outcomes and biomarkers of zinc status in the general population. SEARCH METHODS: We searched the following databases in April 2015: Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3 of 12, 2015, the Cochrane Library), MEDLINE & MEDLINE In Process (OVID) (1950 to 8 April 2015), EMBASE (OVID) (1974 to 8 April 2015), CINAHL (1982 to April 2015), Web of Science (1900 to 9 April 2015), BIOSIS (1969 to 9 April 2015), POPLINE (1970 to April 2015), AGRICOLA, OpenGrey, BiblioMap, and Trials Register of Promoting Health Interventions (TRoPHI), besides regional databases (April 2015) and theses. We also searched clinical trial registries (17 March 2015) and contacted relevant organisations (May 2014) in order to identify ongoing and unpublished studies. SELECTION CRITERIA: We included randomised controlled trials, randomised either at the level of the individual or cluster. We also included non-randomised trials at the level of the individual if there was a concurrent comparison group. We included non-randomised cluster trials and controlled before-after studies only if there were at least two intervention sites and two control sites. Interventions included fortification (central/industrial) of staple foods (cereal flours, edible fats, sugar, condiments, seasonings, milk and beverages) with zinc for a minimum period of two weeks. Participants were members of the general population who were over two years of age (including pregnant and lactating women) from any country. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of studies for inclusion, extracted data from included studies, and assessed the risk of bias of the included studies. MAIN RESULTS: We included eight trials (709 participants); seven were from middle-income countries of Asia, Africa, Europe, and Latin America where zinc deficiency is likely to be a public health problem. Four trials compared the effect of zinc-fortified staple foods with unfortified foods (comparison 1), and four compared zinc-fortified staple foods in combination with other nutrients/factors with the same foods containing other nutrients or factors without zinc (comparison 2). The interventions lasted between one and nine months. We categorised most trials as having unclear or high risk of bias for randomisation, but low risk of bias for blinding and attrition. None of the studies in comparison 1 reported data on zinc deficiency.Foods fortified with zinc increased the serum or plasma zinc levels in comparison to foods without added zinc (mean difference (MD) 2.12 µmol/L, 95% confidence interval (CI) 1.25 to 3.00 µmol/L; 3 studies; 158 participants; low-quality evidence). Participants consuming foods fortified with zinc versus participants consuming the same food without zinc had similar risk of underweight (average risk ratio 3.10, 95% CI 0.52 to 18.38; 2 studies; 397 participants; low-quality evidence) and stunting (risk ratio (RR) 0.88, 95% CI 0.36 to 2.13; 2 studies; 397 participants; low-quality evidence). A single trial of addition of zinc to iron in wheat flour did not find a reduction in proportion of zinc deficiency (RR 0.17, 95% CI 0.01 to 3.94; very low-quality evidence). We did not find a difference in serum or plasma zinc levels in participants consuming foods fortified with zinc plus other micronutrients when compared with participants consuming the same foods with micronutrients but no added zinc (MD 0.03 µmol/L, 95% CI -0.67 to 0.72 µmol/L; 4 studies; 250 participants; low-quality evidence). No trial in comparison 2 provided information about underweight or stunting.There was no reported adverse effect of fortification of foods with zinc on indicators of iron or copper status. AUTHORS' CONCLUSIONS: Fortification of foods with zinc may improve the serum zinc status of populations if zinc is the only micronutrient used for fortification. If zinc is added to food in combination with other micronutrients, it may make little or no difference to the serum zinc status. Effects of fortification of foods with zinc on other outcomes including zinc deficiency, children's growth, cognition, work capacity of adults, or on haematological indicators are unknown. Given the small number of trials and participants in each trial, further investigation of these outcomes is required.

Promoting appropriate management of diarrhea: a systematic review of literature for advocacy and action: UNICEF-PHFI series on newborn and child health, India.

BACKGROUND: Scaling up of evidence-based management and prevention of childhood diarrhea is a public health priority in India, and necessitates robust literature review, for advocacy and action. OBJECTIVE: To identify, synthesize and summarize current evidence to guide scaling up of management of diarrhea among under-five children in India, and identify existing knowledge gaps. METHODS: A set of questions pertaining to the management (prevention, treatment, and control) of childhood diarrhea was identified through a consultative process. A modified systematic review process developed a priori was used to identify, synthesize and summarize, research evidence and operational information, pertaining to the problem in India. Areas with limited or no evidence were identified as knowledge gaps. RESULTS: Childhood diarrhea is a significant public health problem in India; the point (two weeks) prevalence is 9 to 20%. Diarrhea accounts for 14% of the total deaths in under-five children in India. Infants aged 6 to 24 months are at the highest risk of diarrhea. There is a lack of robust nation-wide data on etiology; rotavirus and diarrheogenic E.coli are the most common organisms identified. The current National Guidelines are sufficient for case-management of childhood diarrhea. Exclusive breastfeeding, handwashing and point of use water treatment are effective strategies for prevention of all-cause diarrhea; rotavirus vaccines are efficacious to prevent rotavirus specific diarrhea. ORS and zinc are the mainstay of management during an episode of childhood diarrhea but have low coverage in India due to policy and programmatic barriers, whereas indiscriminate use of antibiotics and other drugs is common. Zinc therapy given during diarrhea can be upscaled through existing infrastructure is introducing the training component and information, education and communication activities. CONCLUSION: This systematic review summarizes current evidence on childhood diarrhea and provides evidence to inform child health programs in India.

Effect of iron-fortified foods on hematologic and biological outcomes: systematic review of randomized controlled trials.

BACKGROUND: The utility of iron fortification of food to improve iron deficiency, anemia, and biological outcomes is not proven unequivocally. OBJECTIVES: The objectives were to evaluate 1) the effect of iron fortification on hemoglobin and serum ferritin and the prevalence of iron deficiency and anemia, 2) the possible predictors of a positive hemoglobin response, 3) the effect of iron fortification on zinc and iron status, and 4) the effect of iron-fortified foods on mental and motor development, anthropometric measures, and infections. DESIGN: Randomized and pseudorandomized controlled trials that included food fortification or biofortification with iron were included. RESULTS: Data from 60 trials showed that iron fortification of foods resulted in a significant increase in hemoglobin (0.42 g/dL; 95% CI: 0.28, 0.56; P < 0.001) and serum ferritin (1.36 µg/L; 95% CI: 1.23, 1.52; P < 0.001), a reduced risk of anemia (RR: 0.59; 95% CI: 0.48, 0.71; P < 0.001) and iron deficiency (RR: 0.48; 95% CI: 0.38, 0.62; P < 0.001), improvement in other indicators of iron nutriture, and no effect on serum zinc concentrations, infections, physical growth, and mental and motor development. Significant heterogeneity was observed for most of the evaluated outcomes. Sensitivity analyses and meta-regression for hemoglobin suggested a higher response with lower trial quality (suboptimal allocation concealment and blinding), use of condiments, and sodium iron edetate and a lower response when adults were included. CONCLUSION: Consumption of iron-fortified foods results in an improvement in hemoglobin, serum ferritin, and iron nutriture and a reduced risk of remaining anemic and iron deficient.

Acute respiratory infection and pneumonia in India: a systematic review of literature for advocacy and action: UNICEF-PHFI series on newborn and child health, India.

BACKGROUND: Scaling up of evidence based management of childhood acute respiratory infection/pneumonia, is a public health priority in India, and necessitates robust literature review, for advocacy and action. OBJECTIVE: To identify, synthesize and summarize current evidence to guide scaling up of management of childhood acute respiratory infection/pneumonia in India, and identify existing knowledge gaps. METHODS: A set of ten questions pertaining to the management (prevention, treatment, and control) of childhood ARI/pneumonia was identified through a consultative process. A modified systematic review process developed a priori was used to identify, synthesize and summarize, research evidence and operational information, pertaining to the problem in India. Areas with limited or no evidence were identified as knowledge gaps. RESULTS: Childhood ARI/pneumonia is a significant public health problem in India, although robust epidemiological data is not available on its incidence. Mortality due to pneumonia accounts for approximately one-fourth of the total deaths in under five children, in India. Pneumonia affects children irrespective of socioeconomic status; with higher risk among young infants, malnourished children, non-exclusively breastfed children and those with exposure to solid fuel use. There is lack of robust nation-wide data on etiology; bacteria (including Pneumococcus, H. influenzae, S. aureus and Gram negative bacilli), viruses (especially RSV) and Mycoplasma, are the common organisms identified. In-vitro resistance to cotrimoxazole is high. Wheezing is commonly associated with ARI/pneumonia in children, but difficult to appreciate without auscultation. The current WHO guidelines as modified by IndiaCLEN Task force on Penumonia (2010), are sufficient for case-management of childhood pneumonia. Other important interventions to prevent mortality are oxygen therapy for those with severe or very severe pneumonia and measles vaccination for all infants. There is insufficient evidence for protective or curative effect of vitamin A; zinc supplementation could be beneficial to prevent pneumonia, although it has no therapeutic benefit. There is insufficient evidence on potential effectiveness and cost-effectiveness of Hib and Pneumococcal vaccines on reduction of ARI specific mortality. Case-finding and community-based management are effective management strategies, but have low coverage in India due to policy and programmatic barriers. There is a significant gap in the utilization of existing services, provider practices as well as family practices in seeking care. CONCLUSION: The systematic review summarizes current evidence on childhood ARI and pneumonia management and provides evidence to inform child health programs in India.

Efficacy and safety of therapeutic nutrition products for home based therapeutic nutrition for severe acute malnutrition a systematic review.

CONTEXT: Severe acute malnutrition (SAM) in children is a significant public health problem in India with associated increased morbidity and mortality. The current WHO recommendations on management of SAM are based on facility based treatment. Given the large number of children with SAM in India and the involved costs to the care-provider as well as the care-seeker, incorporation of alternative strategies like home based management of uncomplicated SAM is important. The present review assesses (a) the efficacy and safety of home based management of SAM using therapeutic nutrition products or ready to use therapeutic foods (RUTF); and (b) efficacy of these products in comparison with F-100 and home-based diet. EVIDENCE ACQUISITION: Electronic database (Pubmed and Cochrane Controlled Trials Register) were scanned using keywords severe malnutrition, therapy, diet, ready to use foods and RUTF. Bibliographics of identified articles, reviews and books were scanned. The information was extracted from the identified papers and graded according to the CEBM guidelines. RESULTS: Eighteen published papers (2 systematic reviews, 7 controlled trials, 7 observational trials and 2 consensus statements) were identified. Systematic reviews and RCTs showed RUTF to be at least as efficacious as F-100 in increasing weight (WMD=3.0 g/kg/day; 95% CI -1.70, 7.70) and more effective in comparison to home based dietary therapies. Locally made RUTFs were as effective as imported RUTFs (WMD=0.07 g/kg/d; 95% CI=-0.15, 0.29). Data from observational studies showed the energy intake with RUTF to be comparable to F-100. The pooled recovery rate, mortality and default in treatment with RUTF was 88.3%, 0.7% and 3.6%, respectively with a mean weight gain of 3.2 g/kg/day. The two consensus statements supported the use of RUTF for home based management of uncomplicated SAM. CONCLUSIONS: The use of therapeutic nutrition products like RUTF for home based management of uncomplicated SAM appears to be safe and efficacious. However, most of the evidence on this promising strategy has emerged from observational studies conducted in emergency settings in Africa. There is need to generate more robust evidence, design similar products locally and establish their efficacy and cost-effectiveness in a non-emergency setting, particularly in the Indian context.

Multiple micronutrient supplementation for improving cognitive performance in children: systematic review of randomized controlled trials.

BACKGROUND: Although multiple micronutrient interventions have been shown to benefit children's intellectual development, a thorough evaluation of the totality of evidence is currently lacking to direct public health policy. OBJECTIVE: This study aimed to systematically review the present literature and to quantify the effect of multiple micronutrients on cognitive performance in schoolchildren. METHODS: The Institute for Scientific Information Web of Knowledge and local medical databases were searched for trials published from 1970 to 2008. Randomized controlled trials that investigated the effect of > or =3 micronutrients compared with placebo on cognition in healthy children aged 0-18 y were included following protocol. Data were extracted by 2 independent researchers. The cognitive tests used in the trials were grouped into several cognitive domains (eg, fluid and crystallized intelligence), and pooled effect size estimates were calculated per domain. Heterogeneity was explored through sensitivity and meta-regression techniques. RESULTS: Three trials were retrieved in children aged <5 y, and 17 trials were retrieved in children aged 5-16 y. For the older children, pooled random-effect estimates for intervention were 0.14 SD (95% CI: -0.02, 0.29; P = 0.083) for fluid intelligence and -0.03 SD (95% CI: -0.21, 0.15; P = 0.74) for crystallized intelligence, both of which were based on 12 trials. Four trials yielded an overall effect of 0.30 SD (95% CI: 0.01, 0.58; P = 0.044) for academic performance. For other cognitive domains, no significant effects were found. CONCLUSIONS: Multiple micronutrient supplementation may be associated with a marginal increase in fluid intelligence and academic performance in healthy schoolchildren but not with crystallized intelligence. More research is required, however, before public health recommendations can be given.

Effect of combining multiple micronutrients with iron supplementation on Hb response in children: systematic review of randomized controlled trials.

OBJECTIVES: To study the effect of combining multiple (two or more) micronutrients with Fe supplementation on Hb response, when compared with placebo and with Fe supplementation, in children. DATA SOURCES: Electronic databases, personal files, hand search of reviews, bibliographies of books, and abstracts and proceedings of international conferences. REVIEW METHODS: Randomized controlled trials evaluating change in Hb levels with interventions that included Fe and multiple-micronutrient supplementation in comparison to placebo alone or Fe alone were analysed in two systematic reviews. RESULTS: Twenty-five trials were included in the review comparing Fe and micronutrient supplementation with placebo. The pooled estimate (random effects model) for change in Hb with Fe and micronutrient supplementation (weighted mean difference) was 0.65 g/dl (95 % CI 0.50, 0.80, P < 0.001). Lower baseline Hb, lower height-for-age Z score, non-intake of 'other micronutrients' and malarial non-hyperendemic region were significant predictors of greater Hb response and heterogeneity. Thirteen trials were included in the review comparing Fe and micronutrient supplementation with Fe alone. The pooled estimate for change in Hb with Fe and micronutrient supplementation (weighted mean difference) was 0.14 g/dl (95 % CI 0.00, 0.28, P = 0.04). None of the variables were found to be significant predictors of Hb response. CONCLUSIONS: Synthesized evidence indicates that addition of multiple micronutrients to Fe supplementation may only marginally improve Hb response compared with Fe supplementation alone. However, addition of 'other micronutrients' may have a negative effect. Routine addition of unselected multiple micronutrients to Fe therefore appears unjustified for nutritional anaemia control programmes.

Effect of iron supplementation on haemoglobin response in children: systematic review of randomised controlled trials.

OBJECTIVE: To evaluate the effect of iron supplementation on haemoglobin (Hb) in children through a systematic review of randomised controlled trials. MATERIALS AND METHODS: Electronic databases, personal files, hand search of reviews, bibliographies of books, and abstracts and proceedings of international conferences were reviewed. Randomised controlled trials evaluating change in Hb levels with interventions that included oral or parenteral iron supplementation or iron-fortified formula milk or cereals were analysed. RESULTS: A total of 55 trials (56 cohorts) provided relevant information. Publication bias was evident (P < 0.001). The pooled estimate (random-effects model) for change in Hb with iron supplementation (weighted mean difference) was 0.74 g/dL (95% CI, 0.61-0.87; P < 0.001; P < 0.001 for heterogeneity). Lower baseline Hb level, oral medicinal iron supplementation, and malarial nonhyperendemic region were significant predictors of greater Hb response and heterogeneity. Projections suggested that, on average, between 37.9% and 62.3% of baseline anaemia (Hb <11 g/dL) was responsive to iron supplementation among children under 6 years of age; the corresponding range for malarial hyperendemic regions was 5.8% to 31.8%. CONCLUSIONS: This systematic review indicates that iron supplementation increases Hb levels in children significantly but modestly. The increase is greater in subjects who are anaemic at the start of the trial and lower in malarial hyperendemic areas and in those consuming iron-fortified food. The projected reductions in prevalence of anaemia with iron supplementation alone highlight the need for additional area-specific interventions, particularly in malaria-prone regions.

Effect of iron supplementation on physical performance in children and adolescents: systematic review of randomized controlled trials.

OBJECTIVE: To evaluate the effect of iron supplementation on physical performance in children (0-18 years) through systematic review of randomised controlled trials (RCTs). DATA SOURCES: Electronic databases, personal files, handsearch of reviews, bibliographies of books, abstracts and proceedings of international conferences. REVIEW METHODS: RCTs with interventions that included oral or parenteral iron supplementation, fortified formula milk, or cereals were evaluated. The physical performance outcomes studied were heart rate, treadmill endurance times, blood lactate, and oxygen consumption. RESULTS: A total of three studies were included, in all of which iron was supplemented in the form of oral medicinal iron. At 5, 6 and 7 miles per hour running speeds, the pooled weighted mean (95% Cl) difference (WMD) in the heart rate (per minute) between the iron and the placebo, following exercise was -7.3 (-19.6, 4.9; p = 0.241), -6.6 (- 19.9, 6.6; p = 0.327), and -8.0 (-19.7, 3.7; p = 0.182), respectively. After excluding the study with nonanemic subjects, the corresponding figures were -13.1 (-23.2, -3.1; p= 0.01), -14.2 (-22.3, -6.1; p = 0.001) and -12.7 (-23.5, 1.9; p = 0.021), respectively. Oxygen consumption, estimated in two studies, showed no significant difference between the treatment groups. Blood lactate levels were estimated in one study only at two different doses of iron, and were significantly lower (p < 0.05) in iron supplemented group in comparison to placebo both before (7.71 and 7.55 mg/dL versus 8.43 mg/dL) and after (14.36 and 14.35 mg/dL versus 16.48 mg/dL) exercise. Treadmill endurance time was significantly better in iron supplemented group when compared with placebo in one study. CONCLUSIONS: Iron supplementation may have a positive effect on the physical performance of children, as evaluated through the post exercise heart rate in anemic subjects, blood lactate levels and treadmill endurance time. In view of the limited data availability, this finding cannot be considered conclusive.

Effect of iron supplementation on physical growth in children: systematic review of randomised controlled trials.

OBJECTIVE: To evaluate the effect of iron supplementation on physical growth in children through a systematic review of randomised controlled trials (RCTs). DATA SOURCES: Electronic databases, personal files, and hand search of reviews, bibliographies of books, abstracts and proceedings of international conferences. REVIEW METHODS: RCTs evaluating change in anthropometry with interventions that included oral or parenteral iron supplementation, or iron-fortified formula milk or cereals, were analysed. RESULTS: Twenty-five trials (26 cohorts) had relevant information. There was no evidence of publication bias. The pooled estimates (random effects model) did not document a statistically significant (P>0.05) positive effect of iron supplementation on any anthropometric variable (weight-for-age, weight-for-height, height-for-age, mid upper-arm circumference, skinfold thickness, head circumference). Significant heterogeneity was evident, and its predictors included greater weight-for-age in supplemented children in malaria hyperendemic regions and greater weight-for-height for children above 5 years of age, but a negative effect on linear growth in developed countries and with supplementation for 6 months or longer. CONCLUSIONS: This review did not document a positive effect of iron supplementation on the physical growth of children. The identified predictors of heterogeneity should be considered as exploratory and requiring confirmation, not conclusive.

Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials.

OBJECTIVE: To evaluate the effect of iron supplementation on mental and motor development in children through a systematic review of randomised controlled trials (RCTs). DATA SOURCES: Electronic databases, personal files, hand search of reviews, bibliographies of books, abstracts and proceedings of international conferences. REVIEW METHODS: RCTs with interventions that included oral or parenteral iron supplementation, fortified formula milk or cereals were evaluated. The outcomes studied were mental and motor development scores and various individual development tests employed, including Bayley mental and psychomotor development indices and intelligence quotient. RESULTS: The pooled estimate (random effects model) of mental development score standardised mean difference (SMD) was 0.30 (95% confidence interval (CI) 0.15 to 0.46, P<0.001; P<0.001 for heterogeneity). Initial anaemia and iron-deficiency anaemia were significant explanatory variables for heterogeneity. The pooled estimate of Bayley Mental Development Index (weighted mean difference) in younger children (<27 months old) was 0.95 (95% CI -0.56 to 2.46, P=0.22; P=0.016 for heterogeneity). For intelligence quotient scores (> or =8 years age), the pooled SMD was 0.41 (95% CI 0.20 to 0.62, P<0.001; P=0.07 for heterogeneity). There was no effect of iron supplementation on motor development score (SMD 0.09, 95% CI -0.08 to 0.26, P=0.28; P=0.028 for heterogeneity). CONCLUSIONS: Iron supplementation improves mental development score modestly. This effect is particularly apparent for intelligence tests above 7 years of age and in initially anaemic or iron-deficient anaemic subjects. There is no convincing evidence that iron treatment has an effect on mental development in children below 27 months of age or on motor development.

Effect of iron supplementation on incidence of infectious illness in children: systematic review.

OBJECTIVE: To evaluate the effect of iron supplementation on the incidence of infections in children. DESIGN: Systematic review of randomised controlled trials. DATA SOURCES: 28 randomised controlled trials (six unpublished and 22 published) on 7892 children. INTERVENTIONS: Oral or parenteral iron supplementation or fortified formula milk or cereals. OUTCOMES: Incidence of all recorded infectious illnesses, and individual illnesses, including respiratory tract infection, diarrhoea, malaria, other infections, and prevalence of positive smear results for malaria. RESULTS: The pooled estimate (random effects model) of the incidence rate ratio (iron v placebo) was 1.02 (95% confidence interval 0.96 to 1.08, P=0.54; P<0.0001 for heterogeneity). The incidence rate difference (iron minus placebo) for all recorded illnesses was 0.06 episodes/child year (-0.06 to 0.18, P=0.34; P<0.0001 for heterogeneity). However, there was an increase in the risk of developing diarrhoea (incidence rate ratio 1.11, 1.01 to 1.23, P=0.04), but this would not have an overall important on public health (incidence rate difference 0.05 episodes/child year, -0.03 to 0.13; P=0.21). The occurrence of other illnesses and positive results on malaria smears (adjusted for positive smears at baseline) were not significantly affected by iron administration. On meta-regression, the statistical heterogeneity could not be explained by the variables studied. CONCLUSION: Iron supplementation has no apparent harmful effect on the overall incidence of infectious illnesses in children, though it slightly increases the risk of developing diarrhoea.