Childhood anaemia is perhaps one of the most widespread public health problems in sub-Saharan Africa. Anaemia is defined as a deficiency of red blood cells that can lead to lack of oxygen-carrying ability. The deficiency occurs either through reduced production or an increased loss of red blood cells. Symptoms of anaemia are usually not specific and include tiredness, shortness of breath, dizziness, and palpitations (awareness of heartbeat). Diagnosis is by examining the level of haemoglobin (the protein in the red blood cells responsible for carrying oxygen); values below 11 g/dL are generally accepted as defining anaemia (WHO 2001).
Though the burden of anaemia worldwide is difficult to quantify, community prevalence figures in a single study in Kenya in children less than 15 years showed that up to 80% of the children had anaemia by 11 months of age (Bloland 1999). Iron deficiency and malaria are major contributors to anaemia, especially in preschool children in malaria-endemic areas (Greenwood 1997; Schellenberg 1999).
Iron as a nutrient
Iron deficiency is a common nutrient deficiency that affects approximately two billion people worldwide resulting in over 500 million cases of anaemia (WHO 2004). In sub-Saharan Africa, the prevalence of iron-deficiency anaemia is estimated around 60% (WHO 2004), with 40% to 50% of children under five years in developing countries being iron deficient (UNICEF 1998). Iron-deficiency anaemia is characterized by pallor, fatigue, and weakness; loss of appetite, strange food cravings (pica) like eating dirt, hair loss, and light-headedness among others can also occur. Because iron-deficiency anaemia tends to develop slowly, adaptation occurs and the disease can go unrecognized for some time resulting in consequences of chronic iron-deficiency anaemia. These include impaired cognitive and motor development (Pollitt 1993; Grantham 2001), growth (Lawless 1994), immune function (Oppenheimer 2001), and physical work capacity (Haas 2001). The diagnosis of iron-deficiency anaemia will be suggested by these features and by such blood tests as low haemoglobin, low ferritin, and low iron level. Treatment includes iron supplementation and dietary changes such as increasing the amount of iron-rich foods.
Iron is an important dietary mineral that the body needs to produce haemoglobin, which is essential for transport of oxygen throughout the body. A relatively large amount of iron is required for red blood cell production (erythropoiesis) in the first few months after birth. This is usually provided by the iron stored in the last months of pregnancy. However, by the age of four months to six months of life iron stores are marginal or depleted. Without intervention, a child whose diet does not provide them with enough iron will eventually develop iron-deficiency anaemia. Infants with a low total body iron as a consequence of prematurity, low birthweight, or maternal iron deficiency are particularly prone to iron deficiency, which is estimated to cause 591,000 perinatal deaths globally (FAO/WHO 2005; WHO 2004). Anaemia during this period and early introduction of cereal-based weaning foods from which iron absorption can be as low as 5% may exacerbate the situation further (FAO/WHO 2005). Iron demand may be further increased by chronic blood loss from the intestine as a result of intestinal parasitic infections (Stoltzfus 1997).
Iron is also a component of many enzymes essential for proper cell development and cell growth of the brain, muscle, and the immune system (Beard 2001). While iron is a critical component of the peroxidase and nitrous oxide-generating enzymes required by humans for mounting an effective immune response to infections, it is also required by many pathogens for their survival and pathogenesis (killing ability) (Beard 2001). Iron is likely involved in the regulation of the production and mechanism of action of cytokines (mediators of immune functioning released during early stages of infection). This results in a reduction of the size of free iron pool in the cell available to pathogens through increased production of ferritin (storage form of iron). This removal of iron required by pathogen seems to be an important part of the host (human) response to infection (Beard 2001). Thus a theory that iron deficiency may be an important defence mechanism led to the term "nutritional immunity" being coined to highlight the importance of the low blood iron levels in preventing bacterial growth (Kochan 1973), with protection from mild clinical malaria was observed in cross-sectional surveys (Nyakeriga 2004). However, experimental and clinical data now suggest that there is an increased risk of infection during iron deficiency as almost every effector of the immune system response is limited in number or action (Beard 2001). Although a small number of studies may indicate otherwise, many of these studies did not address the confounding issues of poverty, generalized malnutrition, and micronutrient deficiencies often present in the study populations (Beard 2001).
Malaria and anaemia
Malaria is a leading cause of morbidity and mortality in children, particularly in sub-Saharan Africa where extrinsic factors such as climate (mainly rainfall) and economic conditions (poverty), and intrinsic factors such as host (human) immunity, parasite species, anopheline longevity, and the avidity for humans have the greatest impact on the malaria burden (Breman 2001). Most infections are caused by the most virulent species, Plasmodium falciparum, which is predominantly transmitted to humans by the bite of infected female anopheles mosquitoes. Trends and general patterns of malaria transmission vary greatly geographically, and children are vulnerable to malaria from the age of approximately three months or earlier when immunity acquired from the mother starts waning.
Malaria causes anaemia through destruction of red blood cells (haemolysis) and increased clearance of infected and uninfected red blood cells by the spleen and cytokine-induced dyserythropoiesis (abnormal formation of red blood cells) (Menendez 2000; Ekvall 2003). A single overwhelming episode of malaria or repeated episodes due to reinfection or failure to adequately clear parasitaemia as a result of antimalarial drug resistance or poor compliance may result in life-threatening anaemia, and, if untreated, death (Crawley 2004). Hospital studies show that in areas of intense transmission, most cases of severe malarial anaemia, blood transfusion, and death occurred in infants (Slutsker 1994; Schellenberg 1999; Kahigwa 2002) and in children less than five years of age (Newton 1997; Biemba 2000) with case-fatality rate in hospitals between 8% and 18% (Slutsker 1994; Biemba 2000). Iron-deficiency anaemia can be implicated at any point in this spectrum.
Iron supplementation guidelines
Guidelines on iron supplementation for preventing and treating anaemia are in place. In areas where anaemia prevalence is 40% or more in children aged six months to 24 months, International Nutrition Anaemia Consultative Group (INACG) guidelines recommend that children of normal birthweight should receive oral iron (12.5 mg, based on 2 mg/kg/day of elemental iron) daily between the ages of six months and 24 months, and children with low birthweight should receive the same amount of iron between the ages two months and 24 months (Stoltzfus 1998). The current World Health Organization (WHO) recommendations for iron supplementation of young children living in malarial areas are based on the known physiology of iron metabolism as well as clinical practices. They apply to otherwise healthy children and those who are anaemic and at risk of iron deficiency (WHO 2001). Iron-deficiency anaemia is treated with iron supplement either continuously (daily) or intermittently (at intervals) with an oral preparation of elemental iron (3 mg/kg/day). The duration of iron supplementation required to prevent the development of iron-deficiency anaemia in children in developing countries is not clear. Despite these guidelines, iron supplementation is not common practice in most developing countries where iron is administered only for the treatment of anaemia (WHO 2003). This may be linked to difficulties with delivery of supplements, low coverage, poor tolerance, and maintenance of compliance for prolonged periods (WHO 2003).
Iron supplementation and infectious diseases
Although the benefits of iron supplementation have generally been considered to outweigh the putative risks, there is conflicting evidence on iron supplementation and malaria infection. Some randomized controlled trials found that supplementation with iron could increase susceptibility to malaria (Murray 1978; Oppenheimer 1986; Smith 1989), brucellosis, and tuberculosis (Murray 1978), even though haematological and iron measurements improved significantly. Recently, a large community-based randomized controlled trial evaluating the effect of iron and folate supplements in a malaria-intense area of Zanzibar was terminated prematurely due to high rates of malaria, meningitis, sepsis, pneumonia, measles, and pertussis with high risk of adverse events, hospital admissions, and death in the treatment group (Sazawal 2006). Other randomized controlled trials also found significant improvement in haematological and iron status but no association or marginal non-significant protection (Harvey 1989; Menendez 1997; Berger 2000; Desai 2004; Mebrahtu 2004; Tielsch 2006). Also, it is not clear if malaria infection contributes to iron deficiency. The observation of an increased haematologic recovery when iron has been administered after a malaria episode (van Hensbroek 1995; Bojang 1997) tends to support the idea of a role of malaria infection in iron deficiency. However, bone marrow studies in Gambian children with acute attacks of malaria showed adequate stores of iron (Abdalla 1990).
There have been three attempts to summarize trial data on the effects of iron supplementation on infectious disease morbidity and mortality. A systematic review on iron supplementation trials found that iron supplementation had no apparent harmful effect on the overall incidence of infectious illnesses in children, though it slightly increased the risk of developing diarrhoea (Gera 2002). A separate review concluded that iron supplementation increased episodes of clinical malaria, respiratory infections, and diarrhoea (Oppenheimer 2001). Also a review by INACG 1999 recorded that iron supplementation was associated with a small non-statistically significant increase in the risk of a clinical malaria attack with an increased odds of being slide positive for P. falciparum at the end of the iron-supplementation period. These three studies did not separate the assessments of studies from various malaria-endemic areas (as described in Appendix 1), studies in different age groups, nor the relationship between malaria outcomes with iron supplementation as related to age, iron levels, anaemia, or change in haemoglobin level. Also, the study authors did not differentiate between studies in which iron was given as therapy for anaemia nor for prevention of iron deficiency. Is it then possible that these excess risks or results that have been observed in these studies are associated with iron supplementation of children who are already iron replete resulting in excess iron which may even favour pathogens and therefore be harmful to the host (WHO 2004). These areas will be explored in this systematic review in addition to comparing (where possible) the children who were anaemic at baseline with those who were not.
A Cochrane Review of randomized controlled trials evaluating iron supplementation in children with iron-deficiency anaemia demonstrated a lack of clear evidence of a beneficial effect of iron therapy on psychomotor development (Martins 2001). While evidence from other systematic reviews of randomized controlled trials evaluating iron supplementation in children demonstrated that iron supplementation improved mental development and intelligent scores (Ramakrishnan 2004; Sachdev 2005). The uncertainties about the potential benefits and harms of giving iron supplements routinely to all young children living in malarial areas make it necessary to review available evidence on this intervention strategy.
To evaluate the effects of iron supplementation in children living in malaria-endemic areas.
Criteria for considering studies for this review
Types of studies
Randomized controlled trials that randomize individuals or clusters.
Types of participants
Children less than 15 years living in a malaria-endemic area regardless of presence of any other medical condition or disease.
Types of interventions
Orally administered iron supplements irrespective of dose, duration, and interval of administration.
Excluded: interventions not limited to micronutrient supplementation only (eg fortification).
Placebo (including other supplements not containing iron), or different dose or treatment duration of the iron supplement (where data analysed separately).
Trials that simultaneously administer other micronutrients (eg folic acid, zinc, vitamin A) and/or antimalarial drugs or anthelminthic drugs to both groups will be eligible.
Types of outcome measures
- Haemoglobin response (change in haemoglobin levels).
- Clinical malaria (defined by symptoms and laboratory diagnosis with no evidence of vital organ dysfunction) or severe malaria (malaria with evidence of vital organ dysfunction).
- Death from any cause.
- Hospitalizations from any cause.
- Morbid episodes caused by other infections than malaria (including diarrhoea, pneumonia, sepsis, meningitis, measles, pertussis).
- Malaria parasite prevalence and density.
- Iron levels (eg serum iron, ferritin levels, total iron binding capacity, zinc protoporphyrin concentration, zinc level).
- Adherence (proportion of days supplement taken).
- Serious adverse events (defined as life-threatening or requiring iron supplement to be discontinued, eg deaths, anaphylaxis, rashes).
- Other adverse events (eg constipation, diarrhoea, nausea, vomiting, dark stools, and abdominal pains).
Search methods for identification of studies
We will attempt to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
The search specialist at the editorial base will search the following databases using the search terms and strategy described in Appendix 2: Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; and LILACS. We will also search the metaRegister of Controlled Trials (mRCT) using 'iron' and 'malaria' as search terms.
Researchers, organizations, and pharmaceutical companies
We will contact individual researchers working in the field for clarifications and further information, if required. We will also contact organizations (eg Iron Deficiency Project Advisory Service; www.micronutrient.org/idpas/) and manufacturers of iron supplements (Pfizer, Sandoz, GlaxoSmithKline) for information regarding unpublished trials or complementary information on their own trials.
We will search the proceedings of the Fourth Multilateral Initiative on Malaria Pan-African Conference, 13 to 18 November 2005, Cameroon for relevant abstracts.
We will scan the bibliographies of all included trials and pertinent reviews for additional references.
Data collection and analysis
Selection of studies
The search specialist at the editorial base will perform the search, and both authors will inspect the abstract of each reference identified and obtain the full text of relevant articles. Both authors will independently review the articles and apply the inclusion criteria. If a potentially relevant trial is eligible for the review but information is unclear, we will attempt to contact the trial authors. Areas of disagreement will be resolved by discussion and/or with help from a Cochrane Infectious Disease Group (CIDG) editor. Each trial will be scrutinized for multiple publications from the same data set. We will document justification for excluding trial from the review.
Data extraction and management
Two authors will independently extract data into pre-piloted data extraction form. Differences in the data extracted will be resolved by referring to the trial report or discussion or involving the CIDG editor. We will attempt to contact the trial authors if the available data are unclear or data are missing or data are reported in a format that is different to the format that we require. J Ojukwu will enter the data into Review Manager 5 using double data entry.
Individually randomized trials
For dichotomous outcome measures, we will record the number of participants experiencing the event and the number analysed in each treatment group. For count data, we will record the number of events and the number of person years of follow up in each group, along with other relevant information. If the number of person years is not available, the product of the duration of follow up and the sample sizes available at the beginning and at the end of the study will be extracted to estimate this figure. For continuous data, we will extract means (arithmetic or geometric) and a measure of variance (standard deviation, standard error, or confidence interval) together with the numbers analysed in each group. If medians have been used we will also extract ranges.
If outcomes are reported using survival analysis, we will extract estimates of the hazards ratio and standard error of the log hazards ratio. If these estimates are not available, then we aim to obtain survival probabilities or, ideally, the numbers at risk from Kaplan-Meier curves and life tables (Parmar 1998).
Cluster randomized trials
We will record the number of clusters in the trial, the average size of clusters, and the unit of randomization (eg household or institution). The statistical methods used to analyse the trial will be documented along with details describing whether these methods adjusted for clustering or other covariates. When reported, estimates of the intra-cluster correlation (ICC) coefficient for each outcome will be recorded. Trial authors will be contacted to request missing information.
Where results have been adjusted for clustering, we will extract the point estimate and the standard deviation or confidence interval. If the results are not adjusted for clustering, we will extract the same data as for the individually randomized trials and use these data in a sensitivity analysis.
Assessment of risk of bias in included studies
Both authors will independently assess methodological quality. We will grade the generation of the allocation sequence and allocation concealment as adequate, unclear, inadequate, or not described according to Jüni 2001. We will contact the authors if this information is missing. We will consider the percentage of randomized participants available for analysis as adequate if it is 85% or more, inadequate if less than 85%, or unclear. We will assess blinding by recording whether the participants, investigators, or outcome assessors were aware of the treatment group allocation. We will present a summary of the quality assessment in a table and detail the actual methods in the 'Characteristics of included studies'.
We will use Review Manager 5 for data analysis and present all the results with 95% confidence intervals. We will aim to perform an intention-to-treat analysis where the trial authors accounted for all randomized participants; otherwise we will perform a complete-case analysis.
We will stratify the analyses for studies using iron for prevention and treatment of iron-deficiency anaemia, unit of randomization, and type of intervention and control.
Individually randomized trials
We will calculate risk ratios for dichotomous data. If continuous data are summarized by arithmetic means and standard deviations data, then we will calculate the mean difference. There is an assumption that data are normally distributed when arithmetic means and standard deviations are used to summarize continuous data. If arithmetic means are reported and the scale is naturally bound at zero (ie measurements of the outcome can not be negative numbers), we will check the normality of the data by calculating the ratio of the mean over the standard deviation. If the ratio (mean/standard deviation) is less than two, then it is likely that the data are skewed and we will therefore not combine them in a meta-analysis. We will pool the rate ratios using the generic inverse variance approach by inserting the log (rate ratio) and corresponding standard error. When continuous data are summarized using geometric means or when hazards ratios are available we will combine them on the log scale using the generic inverse variance method and report them on the natural scale; medians and ranges will be reported in a table. We will present adverse event data in a table or use a narrative summary as appropriate.
Cluster randomized trials
When the results have been adjusted for clustering, we will combine the adjusted measures of effect in the analysis using the generic inverse variance approach. If the trial's results have not been cluster-adjusted, we will use the same methods as for individually randomized trials and present the results in a table. Alternatively, for dichotomous or continuous outcomes attempts can be made to adjust the results for clustering by multiplying the standard errors of the estimates by the square root of the design effect where the design effect is calculated as DEff=1+(m-1)*ICC. This requires information to be reported such as the average cluster size (m) and the intra-cluster correlation coefficient (ICC).
Subgroup analysis and investigation of heterogeneity
Heterogeneity in the results of the trials will be assessed by visually examining the forest plot to detect overlapping confidence intervals using the chi-squared test of heterogeneity (P < 0.1 indicating statistical significance) and the I
Assessment of bias will be performed through sensitivity analyses for allocation concealment and visually examining a funnel plot for the primary outcome measure.
Dr Juliana U Ojukwu was awarded a Reviews for Africa Programme Fellowship (www.mrc.ac.za/cochrane/rap.htm), funded by a grant from the Nuffield Commonwealth Programme, through The Nuffield Foundation. The editorial base for the Cochrane Infectious Diseases Group is funded by the UK Department for International Development (DFID) for the benefit of developing countries.
Appendix 1. Description and location of malaria-endemic areas
Appendix 2. Search methods: detailed search strategies
Protocol first published: Issue 3, 2007
Contributions of authors
Dr Juliana Ojukwu and Dr Joseph Okebe wrote the protocol.
Declarations of interest
Sources of support
- Ebonyi State University, Abakaliki, Nigeria.
- Nuffield Commonwealth Foundation, UK.
- Department for International Development (DFID), UK.
- Cochrane Health Promotion and Public Health Field, Australia.