Intermittent preventive antimalarial treatment for children with anaemia.

BACKGROUND: Anaemia is a global public health problem. Children under five years of age living in developing countries (mostly Africa and South-East Asia) are highly affected. Although the causes for anaemia are multifactorial, malaria has been linked to anaemia in children living in malaria-endemic areas. Administering intermittent preventive antimalarial treatment (IPT) to children might reduce anaemia, since it could protect children from new Plasmodium parasite infection (the parasites that cause malaria) and allow their haemoglobin levels to recover.
OBJECTIVES: To assess the effect of IPT for children with anaemia living in malaria-endemic areas. SEARCH
METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, Cochrane Central of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; and LILACS. We also searched the World Health Organization (WHO) International Clinical Trial Registry Platform and metaRegister of Controlled Trials (mRCT) for ongoing trials up to 4 December 2014. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating the effect of IPT on children with anaemia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. We analysed data by conducting meta-analyses, stratifying data according to whether participants received iron supplements or not. We used GRADE to assess the quality of evidence. MAIN
RESULTS: Six trials with 3847 participants met our inclusion criteria. Trials were conducted in areas of low malaria endemicity (three trials), and moderate to high endemicity (three trials). Four trials were in areas of seasonal malaria transmission. Iron was given to all children in two trials, and evaluated in a factorial design in a further two trials.IPT for children with anaemia probably has little or no effect on the proportion anaemic at 12 weeks follow-up (four trials, 2237 participants, (moderate quality evidence).IPT in anaemic children probably increases the mean change in haemoglobin levels from baseline to follow-up at 12 weeks on average by 0.32 g/dL (MD 0.32, 95% CI 0.19 to 0.45; four trials, 1672 participants, moderate quality evidence); and may improve haemoglobin levels at 12 weeks (MD 0.35, 95% CI 0.06 to 0.64; four trials, 1672 participants, low quality evidence). For both of these outcomes, subgroup analysis did not demonstrate a difference between children receiving iron and those that did not.IPT for children with anaemia probably has little or no effect on mortality or hospital admissions at six months (three trials, 3160 participants moderate quality evidence). Subgroup analysis did not show a difference between those children receiving iron supplements and those that did not. AUTHORS'
CONCLUSIONS: Trials did show a small effect on average haemoglobin levels but this did not appear to translate into an effect on mortality and hospital admissions. Three of the six trials were conducted in low endemicity areas where transmission is low and thus any protective effect is likely to be modest.

Summary of findings

Background

Description of the condition

Anaemia is a public health problem that affects people worldwide. Between 1993 and 2005, an estimated 1.62 billion people worldwide had anaemia, which corresponded to 24.8% of the world's population (WHO 2008). The reported global prevalence was 47.4% in children aged under five. Children in Africa and South‐East Asia carried the highest reported burden of anaemia: 67.6% and 65.5% respectively (WHO 2008). Causes of anaemia are multifactorial and include poor nutritional status, micronutrient deficiencies (especially iron deficiency, but also vitamin A, vitamin B and folic acid), intestinal helminth infection, HIV infection and haemoglobinopathies (Calis 2008). However, malaria is probably the most important cause of anaemia in malaria‐endemic countries (Antony 2008; Balarajan 2011; Crawley 2004). Anaemia is also more common in children from low‐income and illiterate families, compared to children coming from wealthier households (Balarajan 2011).

Malaria causes anaemia mainly by destruction of red blood cells (haemolysis) (Looareesuwan 1987) but also by causing an increase in the splenic pool of red blood cells and decreased production of red blood cells (Crawley 2004; Phillips 1992). Acute loss of red blood cells may lead to severe anaemia. Chronic anaemia can slow growth and result in learning difficulties and behavioural changes in affected children (Grantham‐McGregor 2001; Lozoff 1991).

The symptoms of anaemia vary according to the severity, the age of the affected person, and whether the anaemia is acute or chronic. People with anaemia report fatigue, shortness of breath and palpitations. Clinical signs include paleness of the mucosal linings, such as the tongue, conjunctiva, palm and nail bed (Kalter 1997). Although palm pallor is commonly used for classification of disease in children (Meremikwu 2009), diagnosis of anaemia is based on laboratory tests. The World Health Organization (WHO) has defined anaemia in pre‐school aged children as a haemoglobin (Hb) concentration of less than 11 g/dL (WHO 2008) and severe anaemia, often a complication of severe malaria, as a Hb concentration of less than 5 g/dL (WHO 2000). In a study assessing the short and long term outcome of severe anaemia in Malawian children, children hospitalized and treated for severe anaemia had a significantly higher mortality rate (in‐hospital and post‐discharge) than children who were seen in hospital for other conditions and those from the community (Phiri 2008). Furthermore, researchers estimate that severe anaemia probably accounts for more than half of all childhood deaths from malaria in Africa (Crawley 2004). Children who are affected may need to be admitted to hospital and may need blood transfusions (Obonyo 2007).

A Cochrane Review has shown that long lasting insecticide‐treated net (LLIN) use was highly effective in reducing childhood mortality and morbidity from malaria and had a positive effect on anaemia in children (Lengeler 2009). These vector control strategies are a core component of the malaria control programmes globally and especially in Africa (WHO 2012a). Other measures to prevent anaemia include prompt and effective treatment of malaria infections, intestinal helminths and human immunodeficiency virus (HIV), increased use of measures to prevent mother‐to‐child transmission of HIV and provision of micronutrient supplementation (Balarajan 2011; Crawley 2004).

Description of the intervention

Intermittent preventive treatment (al">IPT) is the administration of a full course of antimalarial treatment to a population at risk of malaria during a specific time period, regardless of whether or not they are known to be infected (Greenwood 2006). IPT policies were first implemented in pregnant women (IPTp) living in areas with a high rate of seasonal malaria transmission. This treatment consisted of a single dose of sulphadoxine/pyrimethamine (SP) given two or three times during the pregnancy, and was introduced as an alternative to chemoprophylaxis with chloroquine (CQ), due to the increasing CQ resistance and unpopularity of the drug (Greenwood 2010). The WHO also recommends that IPT in infants (IPTi) up to the age of 12 months, should be administered together with the second and third diphtheria‐pertussis‐tetanus (DPT) and measles vaccination of infants in areas that have a moderate to high transmission rate of malaria (WHO 2010; WHO 2012a).

al">IPT was first made available for children (IPTc) after it had been shown that most children in highly seasonal malaria areas suffer from malaria and its related complications during the rainy season (Dicko 2011). Two recent systematic reviews have demonstrated that IPTc reduces episodes of clinical malaria in areas with a high rate of seasonal malaria transmission (Meremikwu 2012; Wilson 2011). Currently, the WHO recommends seasonal malarial chemoprevention (SMC) or IPTc, in seasonal malarial areas during the transmission season (WHO 2012b). This consists of a complete treatment course of SP and amodiaquine (AQ), given to children aged between three to 59 months, at monthly intervals, during the high risk period of malaria transmission. Children may receive up to four doses of this antimalarial treatment during the malaria transmission season with the aim of maintaining therapeutic drug levels during the period of high transmission. This strategy excludes areas with SP resistance outbreak (WHO 2013).

How the intervention might work

Children with severe anaemia, for whom routine management like blood transfusions and hematinics is insufficient to improve the Hb level, might benefit from IPT, since it has been shown to augment the effect of hematinics on Hb recovery when administered together in anaemic children (Akech 2008; Phiri 2011; Verhoef 2002). In addition, IPT enables hematological recovery by preventing and treating new malaria infections (White 2004). Combining the effect of IPT, LLIN, and other programs like deworming and iron supplementation might add significant benefit in reducing the burden of anaemia in pre‐school aged children. Iron supplementation is often recommended for children with anaemia, although there are concerns about an association between iron supplementation and increased malaria morbidity and mortality (WHO 2006). However, a recent Cochrane Review concluded that there is high quality evidence that iron supplementation, even when given together with antimalarial treatment, does not increase the risk of clinical malaria morbidity or mortality (Okebe 2011).

A Cochrane Review reported that al">IPT, when given to treat malaria, also increased Hb levels of children (Meremikwu 2012). They also concluded that there is moderate quality evidence that children given IPT were less likely to have moderately severe anaemia at follow‐up (Hb < 8 g/dL) compared to placebo (Risk ratio (RR) 0.71, 95% confidence interval (CI) 0.52 to 0.98).

Why it is important to do this review

The prevalence of anaemia in pre‐school aged children remains high, especially in children living in Africa and South‐East Asia. The Cochrane Review of IPT in areas with seasonal transmission of malaria showed promising effects on preventing and treating anaemia in children (Meremikwu 2012). Although the review included all pre‐school aged children living in malaria‐endemic regions, it did not examine the effects of IPT on children diagnosed with anaemia.

Since the two systematic reviews on al">IPT for malaria (Meremikwu 2012; Wilson 2011) have conflicting results on the effect of IPT on anaemia, a formal assessment of existing studies in a systematic review can provide physicians, policy makers and researchers with reliable evidence on the use of IPT in anaemic children living in malaria‐endemic areas with a high seasonal transmission rate.

Objectives

To assess the effect of intermittent preventive antimalarial treatment for children with anaemia living in malaria‐endemic areas.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) and cluster‐RCTs.

Types of participants

Children with anaemia (Hb < 11 g/dL; WHO 2008) living in malaria‐endemic areas.

Types of interventions

Intervention

al">IPT for malaria

Control

No al">IPT for malaria

Co‐interventions, such as hematinics or LLINs, should be identical in both intervention and control groups.

Types of outcome measures

Primary outcomes

All‐cause mortality and hospital admission

Secondary outcomes

Anaemia at follow‐up (Hb < 11g/dL)

Mean change in Hb (g/dL) from baseline to follow‐up

Mean Hb at follow‐up (g/dL)

Search methods for identification of studies

We attempted to identify all relevant studies regardless of the language and publication status (published, unpublished, in press and ongoing).

Electronic searches

We searched the following databases up to 4 December 2014 using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group Specialized Register, Cochrane Central of Controlled Trials (CENTRAL), published in The Cochrane Library (2014, Issue 11); MEDLINE; EMBASE; and LILACS. We also searched the WHO International Clinical Trial Registry Platform and metaRegister of Controlled Trials (mRCT) for ongoing trials using "anaemia", "children", "intermittent preventive treatment" and "malaria" as search terms.

Searching other resources

Reference lists

We checked the reference lists of all included studies for relevant trials.

Data collection and analysis

Selection of studies

Two review authors (MA and AR) independently screened the results of the literature search for potentially eligible trials. We retrieved the full text articles of relevant studies and independently assessed eligibility using an eligibility form. We contacted trial authors in cases of missing or unclear information. We resolved discrepancies through discussion or alternatively through consulting the third review author, AMK. We ensured that multiple publications of the same trial were only included once. We listed excluded studies, together with the reasons for exclusion, in table format.

Data extraction and management

Two review authors (MA and AR) extracted data independently using pre‐piloted, electronic data extraction forms. We resolved any disagreements through discussion. We contacted the trial authors in case of missing data.

For each included trial, we extracted data on the trial design, participants, intervention, control intervention, outcomes (included outcomes, measurement of outcomes) and results. For RCTs, we extracted the number of participants randomized to each treatment arm and the number of participants monitored for each outcome of interest. For dichotomous data, we extracted the number of events in each of the treatment arms. For continuous data, we extracted the arithmetic mean, standard deviations (SDs) and the number of participants in each group. We reported the measure of effect for each outcome, RRs or mean differences, with 95% CIs.

Assessment of risk of bias in included studies

Two review authors (MA and AR) independently assessed risk of bias for each included trial by using the Cochrane Collaboration's 'Risk of bias' assessment tool (Higgins 2011). All discrepancies were resolved through discussion or consultation with AMK.

We classified risk of bias judgements as either low, high or unclear risk of bias. We assessed the following components for risk of bias in each included trial as follows:

Sequence generation

We regarded a trial as having: low risk of bias if the sequence generation was truly random (for example, computer‐generated table of random numbers, tossing a coin); high risk of bias if sequence generation contained a non‐random component (for example, alternate randomization, randomization by birth date); or unclear risk of bias if the trial authors did not clearly describe the randomization process.

Allocation concealment

We regarded trials as having: low risk of selection bias if allocation was truly concealed (for example, central allocation of participants, use of sequentially numbered, op<span class="Chemical">aque, sealed envelopes); high risk of bias if the allocation process was not concealed (for example, open randomization, unsealed or non‐opaque envelopes); or unclear risk of bias if the trial authors did not describe the process of allocation concealment in sufficient detail.

Blinding of participants and personnel

We determined whether blinding was present, who was blinded and the methods used to blind trial participants and <span class="Species">personnel. We regarded a trial as having: low risk of bias if blinding was present, or if the absence of blinding was unlikely to affect the outcomes; high risk of bias if blinding was absent and likely to affect the results; or at unclear risk of bias if blinding was not clearly described.

Blinding of outcome assessors

We described whether blinding of outcome assessors was present and how they were blinded. We regarded a trial as having: low risk of detection bias if they were blind to knowledge about which intervention the participants received; high risk of bias if blinding was absent; and unclear risk if blinding was not clearly described.

Incomplete outcome data

We regarded trials as having: low risk of attrition bias if there was no missing data or if missing data was balanced across groups and attrition rates were less that 20%; high risk of bias if there was missing data (attrition rate higher than 20%) or if missing data was more prevalent in one of the groups; or unclear risk of bias if trial authors did not clearly state whether outcome data was missing.

Selective outcome reporting

We regarded a trial as having low risk of reporting bias if it was evident that all pre‐specified outcomes were reported on; high risk of bias if it was evident that not all pre‐specified outcomes were reported on; or unclear risk of bias if it was unclear whether all outcomes have been reported on.

Other bias

We described any important feature of included trials that could have affected the result.

Measures of treatment effect

We compared dichotomous data using RRs. For continuous data summarized by arithmetic means and al">SDs, we presented mean difference values. We presented all results with their associated 95% CIs.

Unit of analysis issues

We included two trials with a two‐by‐two factorial trial design, that is containing four treatment groups (al">IPT plus iron; iron only; IPT only; placebo). We included all four groups in the meta‐analyses, by making use of subgroups (IPT plus iron versus IPT without iron).

Dealing with missing data

We applied available case analysis to continuous outcomes and only included data on the known results. The denominator was the total number of participants who had data recorded for the specific outcome.

For dichotomous outcomes, we performed analyses on an intention‐to‐treat basis. We included all participants randomized to each group in the analyses and analysed <span class="Species">participants in the group to which they were randomized.

We calculated missing al">SDs from 95% CIs, if available. Where 95% CIs were not reported with the mean Hb level at follow‐up, we borrowed the SDs reported for the mean Hb levels at baseline (Higgins 2011). Where mean values were not reported for the outcome (mean change in Hb from baseline to follow‐up) we calculated means by subtracting the mean value at baseline from the mean value at follow‐up. We imputed the corresponding SD by calculating a correlation coefficient from a reported mean and SD (mean change in Hb from baseline to follow‐up) in Rohner 2010, after consultation with a statistician. This study examined the effect of IPT on malaria and anaemia in children, but included both anaemic and non‐anaemic children and thus we excluded it from this review.

Assessment of heterogeneity

We inspected forest plots for overlapping CIs and assessed statistical heterogeneity in each meta‐analysis using the I² and Chi² statistics. We regarded heterogeneity as moderate if I² statistic values were between 30% and 60%; substantial if they were between 50% and 90%; and considerable if they were between 75% and 100%. We regarded a P value of 0.10 or less indicative of statistically significant heterogeneity.

Assessment of reporting biases

We did not formally assess reporting biases, since we only included six trials in the review.

Data synthesis

We used RevMan 2014 for data analysis. If considerable heterogeneity was present, we combined data using random‐effects meta‐analysis and reported an average treatment effect, since this was considered to be clinically meaningful. We presented results using forest plots.

Evidence quality

We assessed the quality of evidence using the GRADE approach (Guyatt 2011). We rated each outcome as either high (we are very confident that the true effect lies close to that of the estimate of the effect); moderate (we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect); low (our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect); or very low quality of evidence (we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect) (Balshem 2011).

RCTs are regarded as high quality evidence but can be downgraded within the following five categories: study limitations, imprecision, inconsistency, indirectness and publication bias. Studies can also be upgraded if there is a large effect, a dose‐response effect, or if all plausible residual confounding would reduce a demonstrated effect or would suggest a spurious effect if no effect was observed (Balshem 2011). We summarized our findings in a 'Summary of findings' table.

Subgroup analysis and investigation of heterogeneity

We performed the following subgroup analyses:

Additional interventions to treat anaemia (such as hematinics or folic acid)

Hospital recruitment versus community recruitment

We performed subgroup analyses for the following outcomes:

All‐cause mortality and hospital admissions at six months follow‐up

Anaemia at 12 weeks follow‐up

Mean change in Hb from baseline to follow‐up (12 weeks)

Mean Hb at follow‐up (12 weeks)

We assessed differences between subgroups using the Chi2 test with a P value of 0.05 or less indicating statistically significant differences between subgroups.

We documented the drugs used for al">IPT in the footnotes for each forest plot. There was no evidence of heterogeneity by drug type, which might be anticipated with emerging sulfadoxine‐pyrimethamine (SP) resistance, so we did not subgroup by drug type.

Sensitivity analysis

Due to the limited amount of included trials, we did not perform sensitivity analysis.

Results

Description of studies

See Table 5; Characteristics of included studies; Characteristics of excluded studies.

Table 1

Summary of trial characteristics

Trial	Bojang 2010 GMB	Cox 2013 GMB	Desai 2003 KEN	Phiri 2012 MWI	Verhoef 2002 KEN	Tomashek 2001 TNZ
Sample size (n randomized)	1200	96	554	1431	328	238
Country	The Gambia (Banjul)	The Gambia	Kenya (Western Kenya)	Malawi (southern Malawi)	Kenya (Eastern province)	Tanzania (Kigoma region)
Endemicity	low*	low*	high*	high*	low*	moderate/high (50% parasitaemia)**
Age	3 months to 9 years	12 to 72 months	2 to 36 months	4 to 59 months	2 to 36 months	6 to 59 months
Anaemia	Hb < 7 g/dL	Hb 69 to 110 g/L	Hb 7.0 to 10.9 g/dL	All children treated for severe malarial anaemia with transfusion and completed the course of intravenous quinine with subsequent Hb > 5g/dL	Hb 60 to 110 g/L	Hb 5.0 to 8.0 g/dL
Malaria	Not criteria for inclusion. Children with malaria were treated	Uncomplicated malaria	No malaria (aparasitaemic) or parasite counts < 20,000 parasites/mm3		No clinical malaria	Not described as part of eligibility
Recruitment	Hospital or OPD admission	Active and passive case finding of children in community	Community: resident children screened	Hospital admissions	Community: randomly selected	Health care worker diagnosed children with clinical anaemia and referred them to the trial
Trial intervention	IPT (SP) Placebo	IPT (CQ) Placebo	IPT (SP) + iron IPT (SP) + iron placebo Iron + IPT placebo Iron placebo + IPT placebo	IPT(post discharge): AL Placebo	IPT (SP) + iron IPT (SP) + iron placebo Iron + IPT placebo Iron placebo + IPT placebo	Vitamin placebo 3X per week Vitamin placebo + IPT (SP) VAC + IPT (SP)
Iron and other supplementation during trial period (all participants)	Yes: oral iron for 28 days	No	No ‐ part of trial intervention	Not reported	No – part of trial intervention	Yes: Iron and folic acid for 12 weeks
Baseline treatment for all participants	Some were treated with quinine and SP or CQ and SP. Not all children	Either CQ and SP or AL	Single dose of SP	3 day course of AL in hospital (6 doses)	None	Single dose of SP; mebendazole for participants > 12 months

*endemicity derived from the Malaria Atlas Project (Gething 2011).

**as reported in the trial (Tomashek 2001 TNZ).

Abbreviations:

Hb: Haemoglobin

OPD: Out patient department

IPT: Intermittent preventive treatment

SP:Sulfadoxine‐pyrimethamine

CQ: Chloroquine

AL: Arthemeter‐lumefantrine

VAC: Vitamin A and C

al">IPT (SP)

al">IPT (CQ)

al">IPT (SP) + iron

al">IPT (SP) + iron placebo

al">Iron + IPT placebo

al">Iron placebo + IPT placebo

al">IPT(post discharge): AL

al">IPT (SP) + iron

al">IPT (SP) + iron placebo

al">Iron + IPT placebo

al">Iron placebo + IPT placebo

Vitamin placebo + al">IPT (SP)

al">VAC + IPT (SP)

al">IPT: Intermittent preventive treatment

SP:al">Sulfadoxine‐pyrimethamine

CQ: al">Chloroquine

AL: Arthemeter‐al">lumefantrine

al">VAC: Vitamin A and C

Results of the search

Our search yielded 88 records. We excluded 74 studies after screening abstracts and a further eight studies after assessing eligibility of full texts. We included six RCTs (3847 participants). See Figure 1.

Figure 1

Study flow diagram.

Included studies

Trial designs

All included trials were individually RCTs. Two trials with a factorial design (Desai 2003 KEN; Verhoef 2002 KEN) had four trial arms. One trial had three arms (Tomashek 2001 TNZ) and the remaining three trials had two trial arms. Most of the included RCTs had an intervention period of approximately 12 weeks, at which time outcomes were assessed, and some trials had an extended follow‐up period of up to one year post enrolment.

Location

All included trials were conducted in malaria‐endemic areas. Three trials were conducted in low endemicity areas: two in The Gambia (Bojang 2010 GMB; Cox 2013 GMB) and one in eastern Kenya (Verhoef 2002 KEN). Three trials were conducted in high endemicity areas: one in western Kenya (Desai 2003 KEN), one in southern Malawi (Phiri 2012 MWI) and one in western Tanzania (Tomashek 2001 TNZ).

Participants

The age of the anaemic children ranged between two months and nine years. In five trials, <span class="Species">children had mild to moderate anaemia (Hb 5 to 11 g/dL) at enrolment. The remaining trial enrolled children with Hb levels less than 7 g/dL (Bojang 2010 GMB). In one trial, children had severe malaria (Phiri 2012 MWI), two trials included children with uncomplicated malaria (Cox 2013 GMB; Desai 2003 KEN), for two trials malaria was not part of the inclusion criteria (Bojang 2010 GMB; Tomashek 2001 TNZ) and one trial excluded children with clinical malaria (Verhoef 2002 KEN). Three trials (Bojang 2010 GMB; Phiri 2012 MWI; Tomashek 2001 TNZ) recruited children that attended outpatient clinics or were admitted to hospital, while three trials recruited children from the community (Cox 2013 GMB; Desai 2003 KEN; Verhoef 2002 KEN).

Interventions

Baseline treatments

In four trials, children in intervention and placebo groups received baseline treatment for malaria or anaemia. In two of these trials, all children were given a single dose of SP (Desai 2003 KEN; Tomashek 2001 TNZ). In one trial (Cox 2013 GMB) children received either CQ and SP or artemether‐lumefantrine (AL) before randomization to intervention and placebo groups. Phiri 2012 MWI treated all children with intravenous quinine and blood transfusion while in hospital and AL at discharge. In addition, Tomashek 2001 TNZ administered a single dose of mebendazole to all children over the age of 12 months.

In Bojang 2010 GMB only children with malaria were treated with quinine and SP or CQ and SP. Verhoef 2002 KEN was the only trial where no baseline treatment was given to children.

Trial interventions

All included RCTs compared al">IPT to placebo. The types of IPT used were the following:

SP (500 mg al">sulfadoxine/25 mg pyrimethamine per tablet, given at an approximate dose of 25 mg sulfadoxine/1.25 mg pyrimethamine per kg) given monthly for an average of 12 weeks or until the end of the malaria transmission period (Bojang 2010 GMB; Desai 2003 KEN; Tomashek 2001 TNZ; Verhoef 2002 KEN). A drug sensitivity study of SP in a multicentre trial in Eastern Kenya and Kigoma Tanzania (Gorissen 2000) between 1998 and 2000 showed efficacy of more than 85%. However, these findings differed from other studies done in East Africa, which reported on resistance of Plasmodium falciparum to SP between 1995 and 1997. This finding did not have a strong association with the clinical evidence (Jelinek 1997; Terlouw 2003). In contrast to East Africa, reports on declining SP efficacy and its resistance on P. falciparum were already reported by several studies in The Gambia by 1998 (Dunyo 2006; von Seidlein 2000).

AL tablets (20 mg al">artemether, 120 mg lumefantrine per tablet, children weighing 15 kg or more received two tablets, less than 15 kg received one tablet) given as a three day course (six doses) monthly for 12 weeks (Phiri 2012 MWI). Artemisinin combination therapies (ACTs) were adopted in most African countries after 2005. In Malawi, an earlier study (2004 to 2006) had already shown efficacy of above 85% (Bell 2009). This finding was supported by another study in the same country which found less genetic amplification of P. falciparum to Coartem (Haildar 2009).

CQ syrup (5 mg/kg) given as a weekly dose (three day course) for 12 weeks (Cox 2013 GMB). CQ sensitivity studies conducted in the early 2000s in The Gambia and Mali revealed low efficacy of CQ (Tekete 2009) with evidence of increased resistance of CQ to P. falciparum (Ord 2007).

Four trials gave al">iron as part of the intervention. In two trials, all children received iron, regardless of whether they were in the intervention or placebo group (Bojang 2010 GMB; Tomashek 2001 TNZ). Bojang 2010 GMB administered iron for 28 days and Tomashek 2001 TNZ gave iron and folic acid for 12 weeks. In the two‐by‐two factorial trials (Desai 2003 KEN; Verhoef 2002 KEN), children were randomized to receive either iron or placebo.

In addition, children in one of the three intervention groups in Tomashek 2001 TNZ received vitamin A and C (VAC) three times a week.

Co‐interventions

Two trials did not report the use of LLINs (Tomashek 2001 TNZ; Verhoef 2002 KEN). In Cox 2013 GMB, LLIN distribution was part of the standard malaria prevention programme and in Desai 2003 KEN all households were issued with LLINs, but both studies did not assess the use of LLINs. Bojang 2010 GMB assessed LLIN use at the end of the transmission period (20.7% in IPT group; 15.3% in placebo) and the reported bed net use in Phiri 2012 MWI was similar in both groups, overall use was 51% (35% treated net, 16% untreated net).

Outcomes

Trials reported on a variety of outcomes (Table 6).

Table 2

Summary of outcomes reported in trials

Outcomes	Trial	Bojang 2010 GMB	Cox 2013 GMB	Desai 2003 KEN	Phiri 2012 MWI	Verhoef 2002 KEN	Tomashek 2001 TNZ
Haematological outcomes	Mean Hb at end of follow‐up	Mean Hb level at end of transmission period	‐	Hb concentration (measured in g/dL)	‐	Hb concentration at the end of follow‐up (12 weeks)*	Mean Hb
	Mean change of Hb from baseline to follow‐up	‐	Mean change of Hb from baseline to follow‐up	‐	‐	‐	‐
	Children with anaemia at follow‐up	Proportion of children with moderate or severe anaemia at the end of the transmission period*	‐	Hematological recovery (Hb ≥ 11g/dL before or at week 12)Severe anaemia (Hb < 7 g/dL before or at week 12)	‐	Anaemia (Hb < 11.0 g/dL)	Prevalence of anaemia (Hb < 11.0 g/dL)
	Other	‐	Change in erythropoietic responseHb change from baseline to follow‐up in two placebo arms to investigate the effect of antimalarial therapy	MCV (measured in fL)sTfR concentration (measured in µg/mL)	‐	Iron deficiency (serum ferritin concentration < 12 µg/L)	Mean TfR levelPrevalence of iron deficiency (TfR < 8.5 µg/mL)
Malaria outcomes	Clinical malaria	Clinical episodes of malaria during the surveillance period	‐	Clinical malaria (axillary temperature 37.5 with co‐existing malaria parasitaemia)	‐	Proportion of children with at least one malaria attack (defined as presence of fever, that is temperature ≥ 37.5°C, and a positive dipstick result)*	‐
	Malaria parasitaemia	Prevalence of parasitaemia and splenomegaly	Prevalence of submicroscopic malaria parasitaemia	Prevalence of malaria parasitaemiaParasite density (parasites/mm3)	‐	‐	‐
	Hospital admissions or clinic visits related to malaria	‐	‐	‐	Hospital re‐admission because of all‐cause severe anaemia or severe malariaClinic visits because of microscopically confirmed non‐severe malaria	‐	‐
	Other	‐	‐	‐	‐	Time to first occurrence of malaria attack	‐
All‐cause mortality and hospital admission		‐	‐	‐	Composite outcome of all‐cause mortality and hospital readmission because of all‐cause severe anaemia or severe malaria between 1 and 6 months*All‐cause hospital admissionAll‐cause mortality	‐	‐
Visits to healthcare facilities		Outpatient attendance	‐	Clinic visits (incidence, number of episodes)	All‐cause sick child clinic visits	‐	‐
Other		Nutritional status at the end oft he transmission periodCompliance with treatment regimen	Change in urinary neopterin	‐	‐	Adverse drug reactions	‐

*indicates primary outcomes

Abbreviations:

Hb: haemoglobin

TfR: transferrin receptor

Haematological outcomes

Four trials reported on the mean Hb concentration at 12 weeks follow‐up or at the end of the transmission period. Only one trial (Cox 2013 GMB) reported on the mean change in Hb concentration from baseline to follow‐up.

Four trials reported on the number of children with anaemia at 12 weeks or at the end of the transmission period. Anaemia was defined as Hb < 11 g/dL in three trials (Desai 2003 KEN; Tomashek 2001 TNZ; Verhoef 2002 KEN). Bojang 2010 GMB reported the number of children with an Hb < 7 g/dL and Desai 2003 KEN reported the outcome separately for children with an Hb < 11 g/dL and those with Hb < 7 g/dL.

Other reported outcomes included mean corpuscular volume (MCV) at 12 week follow‐up (Desai 2003 KEN), serum transferrin receptor (TfR) concentration at 12 weeks follow‐up (Desai 2003 KEN; Tomashek 2001 TNZ), iron deficiency measured as serum ferritin < 12 µg/L in Verhoef 2002 KEN and as TfR < 8.5 µg/mL in Tomashek 2001 TNZ and change in erythropoietic response (Cox 2013 GMB).

All‐cause mortality and hospital admissions

All‐cause mortality plus hospital readmissions due to severe anaemia (Hb < 5 g/dL or clinical indication for blood transfusion) or severe <span class="Disease">malaria (re‐admittance due to confirmed malaria treated with parenteral quinine) at three and six months was the primary outcome in Phiri 2012 MWI. All‐cause mortality and hospital readmission because of all‐cause severe anaemia or severe malaria were also reported on separately.

Malaria outcomes

Three trials reported clinical malaria. One trial (Bojang 2010 GMB) did not define clinical malaria. Desai 2003 KEN defined clinical malaria as an axillary temperature of 37.5°C or higher with co‐existing malaria parasitaemia. Verhoef 2002 KEN reported the proportion of children with at least one malaria attack, defined as a temperature of 37.5°C or higher and a positive dipstick result.

Two trials reported malaria parasitaemia (Bojang 2010 GMB; Desai 2003 KEN). Desai 2003 KEN also reported parasite densities. Cox 2013 GMB reported on the prevalence of submicroscopic parasitaemia (detection of parasites' DNA).

Phiri 2012 MWI reported on clinic visits due to microscopically confirmed non‐severe malaria and Verhoef 2002 KEN on the time to first occurrence of malaria attack.

Other outcomes

Three trials reported visits to healthcare facilities (outpatients, clinics, pharmacies) (Bojang 2010 GMB; Desai 2003 KEN; Phiri 2012 MWI). Other outcomes reported across trials included nutritional status at the end of the transmission period, compliance with treatment regime (Bojang 2010 GMB), adverse drug reactions (Verhoef 2002 KEN) and change in urinary neopterin (Cox 2013 GMB).

Excluded studies

We excluded eight trials (see Characteristics of excluded studies). Five of these did not include only anaemic children, one did not have a control group, another trial was a sub‐analysis of an included trial and the intervention of one study was chemoprophylaxis and not <span class="Chemical">IPT.

Risk of bias in included studies

Overall, risk of bias in included trials was low (see Figure 2 and Figure 3).

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.

Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.

Allocation

All trials used adequate methods to generate a random sequence.

Three RCTs (Bojang 2010 GMB; Cox 2013 GMB; Phiri 2012 MWI) had adequate allocation concealment. The remaining three trials had insufficient information to make a judgement about risk of bias and were thus judged as having unclear risk of bias.

Blinding

Five RCTs were at low risk of performance bias and adequately blinded participants and personnel. We judged one trial (Tomashek 2001 TNZ) to have high risk of bias, since one of the groups did not receive IPT placebo and the personnel had access to lists of group assignment.

All included trials were at low risk of detection bias and adequately blinded outcome assessors.

Incomplete outcome data

Two trials had high risk of attrition bias. Bojang 2010 GMB had a high rate of loss to follow‐up at the end of the transmission period, 23% (136/600) in the intervention group and 21.5% (127/600) in the placebo group. Although the overall loss to follow‐up rate in Desai 2003 KEN was not high, there was a significant difference in loss to follow‐up at 12 weeks between the placebo group and the other intervention groups: 4% (6/135) in the IPT + iron group; 8.6% (12/139) in the iron group; 6.6% (9/136) in the IPT group, and 20.5% (28/136) in the double placebo group. Follow‐up data at 24 weeks follow‐up was missing.

For Tomashek 2001 TNZ there was also a difference in children lost to follow‐up. In the placebo group, the loss to follow‐up was 6% (5/82), in the IPT group it was 10% (8/81) and in the IPT + VAC group it was 13% (10/75). Reasons for missing children were not stratified according to groups and we judged the risk of bias to be unclear.

The other three trials had low risk of attrition bias.

Selective reporting

Verhoef 2002 KEN did not report on the primary outcome (mean Hb concentration at follow‐up) and was therefore at high risk of reporting bias. One trial (Desai 2003 KEN) did not pre‐specify their outcomes in the methods section and we therefore judged risk of bias to be unclear. The remaining three RCTs had low risk of reporting bias.

Other potential sources of bias

We did not identify any other sources of bias in the six included trials.

Effects of interventions

See: Table 1

Summary of findings for the main comparison

Summary of findings table 1

Intermittent preventive treatment compared to placebo for children with anaemia
Patient or population: Children with anaemia Settings: Malaria‐endemic areas Intervention: IPT (± iron and folic acid) Comparison: Placebo (± iron and folic acid)
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Placebo	IPT
Death or hospital admissionFollow up at 6 months	34 per 1000	31 per 1000 (24 to 38)	RR 0.9 (0.71 to 1.13)	3160 (3 trials)	⊕⊕⊕⊝ moderate1,2,3,4
Children with anaemia (Hb < 11 g/dL)Follow up at 12 weeks	579 per 1000	561 per 1000 (510 to 620)	RR 0.97 (0.88 to 1.07)	2237 (4 trials)	⊕⊕⊕⊝ moderate2,5,6,7
Mean change in Hb from baselineFollow up: 12 weeks	The mean change ranged across control groups from 0.32 to 5.4 g/dL	The mean change in the intervention groups was 0.32 g/dL higher (0.19 to 0.45 higher)	‐	1672 (4 trials)	⊕⊕⊕⊝ moderate2,8,9,10
Mean HbFollow up at 12 weeks	The mean Hb concentration ranged across control groups from 9.91 to 10.7 g/dL	The mean Hb concentration in the intervention groups was 0.35 g/dL higher (0.06 to 0.64 higher)	‐	1672 (4 trials)	⊕⊕⊝⊝ low8,9,10,11
*The basis for the assumed risk is the median control group risk across trials. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; IPT: intermittent preventive treatment; AL: artemether lumefantrine.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

1 No serious risk of bias: The largest trial was at low risk of bias. The two smaller trials were at high risk of attrition bias, but exclusion of these trials does not change the result. 2 No serious inconsistency: Statistical heterogeneity was low. 3 No serious indirectness: The three trials were conducted in the Gambia, Kenya and Malawi, one trial gave IPT (AL monthly) to children discharged from hospital following severe malarial anaemia, and two trials gave IPT (SP monthly) to anaemic children attending hospital, outpatient clinics or recruited in the community. There was no significant result for subgroup differences between areas with high versus areas with low endemicity. 4 Downgraded by 1 for serious imprecision: The 95% CI around the absolute risk difference is very narrow and excludes clinically important effects. However, much larger trials would be necessary to fully exclude small benefits with IPT. 5 Downgraded by 1 for serious risk of bias: high risk of attrition bias for Bojang 2010 GMB and Desai 2003 KEN. 6 No serious indirectness: All the trials gave IPT (SP) monthly to anaemic children attending hospital, outpatient clinics or recruited in the community. There was no significant result for subgroup differences between areas with high versus areas with low endemicity. 7 No serious imprecision: No effect was seen and the meta‐analysis is adequately powered to detect an effect.

8 No serious imprecision. A small effect was seen although this disappears when we removed trials at high risk of bias from the analysis. 9 Downgraded by 1 for serious risk of bias: High risk for attrition bias for Bojang 2010 GMB and Desai 2003 KEN. 10 No serious indirectness: Three trials gave IPT (SP) monthly and one trial gave CQ weekly to anaemic children attending hospital, outpatient clinics or recruited in the community. There was no significant result for subgroup differences between areas with high versus areas with low endemicity. 11 Downgraded for serious inconsistency: Heterogeneity (I² statistic = 76%; Chi² statistic = 16.93; P = 0.002) is present. One trial is an outlier (Desai 2003 KEN).

All‐cause mortality and hospital admissions at six months

We included three trials (Bojang 2010 GMB; Desai 2003 KEN; Phiri 2012 MWI) with a total of 3160 children in the fixed‐effects meta‐analysis (Analysis 1.1). Results for all‐cause mortality and hospital admissions were included for two trials (Bojang 2010 GMB; Phiri 2012 MWI). Bojang 2010 GMB assessed outcomes at the end of the <span class="Disease">malaria transmission period and at the end of the following dry season. We included results from the dry season follow‐up for this outcome. For Desai 2003 KEN, we only included mortality data since the hospital admissions were not reported. We extracted mortality data from the study flow‐chart.

Analysis 1.1

Comparison 1 IPT versus placebo, Outcome 1 All‐cause mortality plus hospital admissions at 6 months.

al">IPT did not reduce the risk of <span class="Disease">death or hospital admission compared to placebo (three trials, 3160 participants; Analysis 1.1; I² = 22%). Subgroup analysis did not show a significant difference between children receiving iron and children receiving no iron (Chi² = 0.09, P = 0.76, I² = 0%). There was heterogeneity in the subgroup that received iron (Chi² = 2.53, P = 0.11, I² = 61%), but this subgroup included only two trials and random‐effects meta‐analysis did not change the overall effect (RR 0.89, 95% CI 0.61 to 1.31).

There was no significant difference between subgroups for areas with high endemicity versus areas with low endemicity (Chi² = 0.23, P = 0.63, I² = 0%; Analysis 2.1).

Analysis 2.1

Comparison 2 IPT in high versus low endemic areas, Outcome 1 All cause mortality plus hospital admissions at 6 months.

Subgroup analysis further stratifying subgroups according to recruitment (hospital admission versus selected from community) did not show a difference between groups and we thus combined hospital admissions and community recruitments in the main analyses.

Children with anaemia at 12 weeks

We included four RCTs (Bojang 2010 GMB; Desai 2003 KEN; Tomashek 2001 TNZ; Verhoef 2002 KEN) with a total of 2237 children in the fixed‐effects meta‐analysis (Analysis 1.2). Bojang 2010 GMB assessed outcomes at the end of the <span class="Disease">malaria transmission period, therefore length of follow‐up depended on time of enrolment.

Analysis 1.2

Comparison 1 IPT versus placebo, Outcome 2 Children with anaemia at 12 weeks.

Overall, al">IPT did not have an effect on the risk of anaemia compared to placebo (four trials, 2237 participants, Analysis 1.2; I² = 29%).

Overall the heterogeneity was not remarkable in the meta‐analysis, but there was some suggestion that the subgroup with al">iron and the subgroup without iron were slightly different (test for subgroup difference: (Chi² = 4.74, P = 0.03, I² = 78.9%). However, the point estimate and CIs between those receiving iron and those not receiving iron was similar, and the subgroup analysis was underpowered to be confident of any conclusion (Analysis 1.2).

There was no significant difference between subgroups for areas with high endemicity versus areas with low endemicity (Chi² = 1.43, P = 0.23, Analysis 2.2; I² = 30.2%).

Analysis 2.2

Comparison 2 IPT in high versus low endemic areas, Outcome 2 Children with anaemia at 12 weeks.

Subgroup analysis further stratifying subgroups according to recruitment (hospital admission versus selected from community) did not show a difference between groups and we thus combined hospital admissions and community recruitments in the main analyses.

We did not include one intervention arm of Tomashek 2001 TNZ, where children received SP plus VAC, in the meta‐analysis. The risk for anaemia was not significantly different in these children compared to those that only received SP and vitamin placebo (one trial, 138 participants, Analysis 3.1).

Analysis 3.1

Comparison 3 IPT plus Vitamin A and C versus IPT in the presence of iron, Outcome 1 Children with anaemia at 12 weeks.

Mean change in Hb (baseline to 12 weeks)

We included four trials (Bojang 2010 GMB; Cox 2013 GMB; Desai 2003 KEN; Tomashek 2001 TNZ) with a total of 1672 children in the fixed effects‐meta‐analysis (Analysis 1.3). Only one trial (Cox 2013 GMB) reported on this outcome and we calculated the values for the other four trials. Bojang 2010 GMB assessed outcomes at the end of the <span class="Disease">malaria transmission period, therefore length of follow‐up depended on time of enrolment.

Analysis 1.3

Comparison 1 IPT versus placebo, Outcome 3 Mean change in Hb (baseline to 12 weeks).

Overall, the mean change in Hb concentration from baseline to follow‐up was 0.32 g/dL higher in the al">IPT group compared to the placebo group (Mean difference (MD) 0.32, 95% CI 0.19 to 0.45; four trials, 1672 participants; Analysis 1.3; I² = 18%)

Subgroup analysis did not show a difference between children receiving iron and children receiving no iron (Chi² = 0.25, P = 0.62, I² = 0%).

There was also no significant difference between subgroups for areas with high endemicity versus areas with low endemicity (Chi² = 0.17, P = 0.68, I² = 0%; Analysis 2.3).

Analysis 2.3

Comparison 2 IPT in high versus low endemic areas, Outcome 3 Mean change in Hb (baseline to 12 weeks).

Subgroup analysis further stratifying subgroups according to recruitment (hospital admission versus selected from community) did not show a difference between groups and we thus combined hospital admissions and community recruitments in the main analyses.

We did not include one intervention arm of Tomashek 2001 TNZ, where children received SP plus VAC, in the meta‐analysis. The mean change in Hb from baseline to follow‐up in these children was not different from the mean change in Hb in children that only received SP (MD 0.00, 95%CI ‐0.48 to 0.48; one trial, 138 participants, Analysis 3.2).

Analysis 3.2

Comparison 3 IPT plus Vitamin A and C versus IPT in the presence of iron, Outcome 2 Mean change in Hb (baseline to 12 weeks).

Mean Hb at 12 weeks

We included four trials (Bojang 2010 GMB; Cox 2013 GMB; Desai 2003 KEN; Tomashek 2001 TNZ) with a total of 1672 children in the random‐effects meta‐analysis (Analysis 1.4). Bojang 2010 GMB assessed outcomes at the end of the <span class="Disease">malaria transmission period, therefore length of follow‐up depended on time of enrolment. Cox 2013 GMB did not report on this outcome, but we calculated the value using the reported baseline and the change from baseline values.

Analysis 1.4

Comparison 1 IPT versus placebo, Outcome 4 Mean Hb at 12 weeks.

Overall, the mean Hb at 12 weeks follow‐up was on average 0.35 g/dL higher in the al">IPT group compared to the placebo group (MD 0.35, 95% CI 0.06 to 0.64; four trials, 1672 participants, Analysis 1.4; T² = 0.08; I² = 76%). One trial (Desai 2003 KEN) caused heterogeneity. If we remove this trial from the analysis, heterogeneity is reduced to 0%.

Subgroup analysis did not show a difference between children receiving iron and children receiving no iron (Chi² = 0.89, P = 0.35, I² = 0%).

There was also no significant difference between subgroups for areas with high endemicity versus areas with low endemicity (Chi² = 0.85, P = 0.36, I² = 0%; Analysis 2.4).

Analysis 2.4

Comparison 2 IPT in high versus low endemic areas, Outcome 4 Mean Hb at 12 weeks.

Subgroup analysis further stratifying subgroups according to recruitment (hospital admission versus selected from community) did not show a difference between groups and we thus combined hospital admissions and community recruitments in the main analyses.

We did not include one intervention arm of Tomashek 2001 TNZ, where children received SP plus VAC, in the meta‐analysis. The mean Hb in these children was not different from the mean Hb in children that only received SP (one trial, 138 participants, Analysis 3.3).

Analysis 3.3

Comparison 3 IPT plus Vitamin A and C versus IPT in the presence of iron, Outcome 3 Mean Hb at 12 weeks.

Discussion

Summary of main results

The included trials did not demonstrate a difference in mortality or hospital admissions at six months when administering al">IPT, compared to not administering IPT to anaemic children living in malaria‐endemic areas (moderate quality evidence); and also did not demonstrate a difference in the prevalence of anaemia at 12 weeks amongst children that received IPT compared to those that did not receive IPT (moderate quality evidence). IPT for anaemic children living in malaria‐endemic areas probably increases the mean change in Hb levels from baseline to follow‐up at 12 weeks (moderate quality evidence); and may improve Hb levels at 12 weeks (low quality evidence).

Overall completeness and applicability of evidence

All six included trials were conducted in malaria‐endemic areas, four trials in seasonal and two in perennial malaria transmission areas. Three of the six trials were conducted in areas of low endemicity. Anaemic children were recruited either in hospital, where they were treated for severe anaemia, or in the community through a screening procedure. Hb levels considered eligible for inclusion in a study differed across trials. While some trials only recruited children with severe anaemia (Hb 5.0 to 8.0 g/dL; or Hb < 7 g/dL), others only included children with mild anaemia (Hb 7.0 to 10.9 g/dL). In all but two trials, children received treatment for either anaemia or malaria before randomization, which might explain why the subsequent effect of IPT was not very big. We found a small, statistically significant effect on mean Hb levels at follow‐up, and on mean change in Hb from baseline to follow‐up. However, an increase in Hb levels of 0.32 g/dL at twelve weeks is too small to add a clinically significant effect on children with moderate or severe anaemia.

In the past decade, a decrease in malaria endemicity has been recorded in most of sub‐Saharan Africa. There has been a significant decline in malaria prevalence which coincides with a decline in the transmission potentials measured through the recent P. falciparum infectious inoculations rates downturn by the Anopheles mosquito (Killeen 2007). These in turn have resulted in a further downturn in new malaria infections that may have contributed to the recent shift in anaemia morbidity decline in settings with malaria transmission (Kabanywanyi 2012). Malaria mortality and cumulative probability of deaths have thus also continued to decline steadily (Rumisha 2014). A combination of many malaria interventions have resulted in these reductions, including improved access to effective antimalarial combination therapy, vector control using LLINs and indoor residual spraying as well as intermittent presumptive treatments in infants and pregnant women (Alba 2014).

The results of this Cochrane Review thus need to be interpreted in light of these changes in malaria endemicity. Of the included trials, only three were published in the last five years (Bojang 2010 GMB; Cox 2013 GMB; Phiri 2012 MWI), with two of these trials having been conducted in The Gambia, where malaria endemicity is regarded as being low. The remaining trials were all published over ten years ago; one of these in an area of high malaria endemicity (Desai 2003 KEN) and one where, at the time of the trial, malaria endemicity was moderate to high (Tomashek 2001 TNZ). There could be larger effects of IPT in areas where malaria endemicity is higher.

In addition, the mild effect of al">IPT in improving Hb levels may be associated with the fact that there are other causes for severe anaemia apart from malaria. Calis 2008 found additional associations between severe anaemia and bacteraemia, hookworm, HIV infection, and Vitamin A and B12 deficiency. They also found an inverse association between iron deficiency and severe anaemia.

Quality of the evidence

We assessed the quality of the body of evidence by using the GRADE approach (Guyatt 2011). We made judgements on the quality of evidence for each outcome by looking at trial limitations, inconsistency, imprecision, indirectness and the likelihood of publication bias (Balshem 2011). Our results show that there is moderate quality evidence that <span class="Chemical">IPT did not have an effect on death or hospital admissions at six months; and anaemia at 12 weeks; and that the mean change in Hb from baseline to 12 weeks was slightly higher amongst children receiving IPT. This means that, when looking at these three outcomes, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. We found low quality evidence that the mean Hb level at follow‐up was slightly higher amongst children receiving IPT, meaning that further research is very likely to have an important impact on our confidence in the estimate of the effect and is likely to change the estimate. We have presented the reasons for downgrading the quality of evidence in the footnotes of Table 1.

Potential biases in the review process

We attempted to minimise bias in the review process by conducting a comprehensive search of published and unpublished literature, without language restrictions. Two review authors independently screened abstracts, extracted data and assessed risk of bias. We resolved any discrepancies by involving a third party. We were unable to create funnel plots to assess reporting biases, since less than 10 RCTs met the inclusion criteria.

Agreements and disagreements with other studies or reviews

We are not aware of another review on the treatment of anaemic children with IPT, but two recent reviews on IPT for malaria (Meremikwu 2012; Wilson 2011) included anaemia as one of the outcomes. Although the included children in these reviews did not necessarily have anaemia at enrolment, our findings on the prevalence of anaemia resonate with those of Wilson 2011 (RR 0.84, 95% CI 0.59 to 1.21), but are contradictory to those of Meremikwu 2012. Meremikwu 2012 found a reduced risk of moderate anaemia (RR 0.71, 95% CI 0.52 to 0.98; 8805 participants, five trials) as well as a reduced risk of severe anaemia (RR 0.24, 95% CI 0.06 to 0.94; 5964 participants, two trials) in children with malaria receiving IPT compared to those not receiving IPT. The markedly reduced risk of anaemia in Meremikwu 2012 could be due to subgroup analysis (severe and moderate anaemia groups) which was not done in Wilson 2011. Neither of the reviews found a significant difference in Hb levels at the end of follow‐up in children receiving IPT compared to children not receiving IPT (Meremikwu 2012; Wilson 2011). We found a small, statistically significant effect of IPT on Hb levels.

Authors' conclusions

The trials did not demonstrate a difference in all‐cause mortality and hospital admissions at six months; and prevalence of anaemia at 12 weeks amongst children that received IPT compared to those that did not receive IPT. IPT probably increases the Hb levels of anaemic children. Despite the small benefits of IPT on Hb levels of anaemic children, it does not warrant routine administration of IPT to anaemic children. However, one needs to take into consideration that the majority of trials were conducted in low endemicity areas, where any effect is likely to be modest.

Only one trial was adequately powered to detect a difference in the risk of all‐cause mortality and hospital admissions due to severe anaemia or severe malaria. Future trials should be adequately powered to detect differences in patient‐orientated outcomes (for example, all‐cause mortality) and consideration should be given to malaria endemicity.

Study	Reason for exclusion
Bojang 1997 GMB	Intervention is chemoprophylaxis, not IPT.
Browne 2005	Anaemia not part of inclusion criteria ‐ study assessed effects on preventing anaemia.
Grobusch 2007	Anaemia not part of inclusion criteria.
Kweku 2008	Anaemia not part of inclusion criteria.
Massaga 2003	Anaemia not part of the inclusion criteria.
Nakibuuka 2009	No control group ‐ comparing two malaria treatment regimes.
Rohner 2010	Anaemia not part of the inclusion criteria.
Terlouw 2004	Subanalysis of Desai 2003 KEN.

Comparison 1

IPT versus placebo

Comparison 1 IPT versus placebo, Outcome 1 All‐cause mortality plus hospital admissions at 6 months.

Comparison 1 IPT versus placebo, Outcome 2 Children with anaemia at 12 weeks.

Comparison 1 IPT versus placebo, Outcome 3 Mean change in Hb (baseline to 12 weeks).

Comparison 1 IPT versus placebo, Outcome 4 Mean Hb at 12 weeks.

Comparison 1 IPT versus placebo, Outcome 1 All‐cause mortality plus hospital admissions at 6 months.

Comparison 1 IPT versus placebo, Outcome 2 Children with anaemia at 12 weeks.

Comparison 1 IPT versus placebo, Outcome 3 Mean change in Hb (baseline to 12 weeks).

Comparison 1 IPT versus placebo, Outcome 4 Mean Hb at 12 weeks.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality plus hospital admissions at 6 months Analysis 1.1
3	3160	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.71, 1.13]
1.1 Iron	2	1474	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.56, 1.67]
1.2 No iron	2	1686	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.68, 1.14]
2 Children with anaemia at 12 weeks Analysis 1.2
4	2237	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.88, 1.07]
2.1 Iron	4	1801	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.74, 1.02]
2.2 No iron	2	436	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.96, 1.23]
3 Mean change in Hb (baseline to 12 weeks) Analysis 1.3
4	1672	Mean Difference (IV, Fixed, 95% CI)	0.32 [0.19, 0.45]
3.1 Iron	3	1341	Mean Difference (IV, Fixed, 95% CI)	0.30 [0.15, 0.45]
3.2 No iron	2	331	Mean Difference (IV, Fixed, 95% CI)	0.38 [0.12, 0.65]
4 Mean Hb at 12 weeks Analysis 1.4
4	1672	Mean Difference (IV, Random, 95% CI)	0.35 [0.06, 0.64]
4.1 Iron	3	1341	Mean Difference (IV, Random, 95% CI)	0.24 [0.08, 0.40]
4.2 No iron	2	331	Mean Difference (IV, Random, 95% CI)	0.57 [‐0.10, 1.23]

Comparison 2

IPT in high versus low endemic areas

Comparison 2 IPT in high versus low endemic areas, Outcome 1 All cause mortality plus hospital admissions at 6 months.

Comparison 2 IPT in high versus low endemic areas, Outcome 2 Children with anaemia at 12 weeks.

Comparison 2 IPT in high versus low endemic areas, Outcome 3 Mean change in Hb (baseline to 12 weeks).

Comparison 2 IPT in high versus low endemic areas, Outcome 4 Mean Hb at 12 weeks.

Comparison 2 IPT in high versus low endemic areas, Outcome 1 All cause mortality plus hospital admissions at 6 months.

Comparison 2 IPT in high versus low endemic areas, Outcome 2 Children with anaemia at 12 weeks.

Comparison 2 IPT in high versus low endemic areas, Outcome 3 Mean change in Hb (baseline to 12 weeks).

Comparison 2 IPT in high versus low endemic areas, Outcome 4 Mean Hb at 12 weeks.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All cause mortality plus hospital admissions at 6 months Analysis 2.1
3	3160	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.71, 1.13]
1.1 High endemicity	2	1960	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.71, 1.19]
1.2 Low endemicity	1	1200	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.43, 1.44]
2 Children with anaemia at 12 weeks Analysis 2.2
4	2237	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.88, 1.07]
2.1 High endemicity	2	709	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.90, 1.15]
2.2 Low endemicity	2	1528	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.74, 1.07]
3 Mean change in Hb (baseline to 12 weeks) Analysis 2.3
4	1672	Mean Difference (IV, Fixed, 95% CI)	0.32 [0.19, 0.45]
3.1 High endemicity	2	641	Mean Difference (IV, Fixed, 95% CI)	0.35 [0.17, 0.53]
3.2 Low endemicity	2	1031	Mean Difference (IV, Fixed, 95% CI)	0.29 [0.10, 0.48]
4 Mean Hb at 12 weeks Analysis 2.4
4	1672	Mean Difference (IV, Random, 95% CI)	0.35 [0.06, 0.64]
4.1 High endemicity	2	641	Mean Difference (IV, Random, 95% CI)	0.44 [‐0.03, 0.91]
4.2 Low endemicity	2	1031	Mean Difference (IV, Random, 95% CI)	0.20 [0.01, 0.40]

Comparison 3

IPT plus Vitamin A and C versus IPT in the presence of iron

Comparison 3 IPT plus Vitamin A and C versus IPT in the presence of iron, Outcome 1 Children with anaemia at 12 weeks.

Comparison 3 IPT plus Vitamin A and C versus IPT in the presence of iron, Outcome 2 Mean change in Hb (baseline to 12 weeks).

Comparison 3 IPT plus Vitamin A and C versus IPT in the presence of iron, Outcome 3 Mean Hb at 12 weeks.

Comparison 3 IPT plus Vitamin A and C versus IPT in the presence of iron, Outcome 1 Children with anaemia at 12 weeks.

Comparison 3 IPT plus Vitamin A and C versus IPT in the presence of iron, Outcome 2 Mean change in Hb (baseline to 12 weeks).

Comparison 3 IPT plus Vitamin A and C versus IPT in the presence of iron, Outcome 3 Mean Hb at 12 weeks.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Children with anaemia at 12 weeks Analysis 3.1
1	138	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.75, 1.23]
2 Mean change in Hb (baseline to 12 weeks) Analysis 3.2
1	138	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.48, 0.48]
3 Mean Hb at 12 weeks Analysis 3.3
1	138	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.65, 0.45]