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Intermittent preventive treatment for malaria in children living in areas with seasonal transmission

  1. Martin M Meremikwu1,*,
  2. Sarah Donegan2,
  3. David Sinclair2,
  4. Ekpereonne Esu3,
  5. Chioma Oringanje4

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 15 FEB 2012

Assessed as up-to-date: 16 JUN 2011

DOI: 10.1002/14651858.CD003756.pub4


How to Cite

Meremikwu MM, Donegan S, Sinclair D, Esu E, Oringanje C. Intermittent preventive treatment for malaria in children living in areas with seasonal transmission. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD003756. DOI: 10.1002/14651858.CD003756.pub4.

Author Information

  1. 1

    University of Calabar Teaching Hospital, Department of Paediatrics, Calabar, Cross River State, Nigeria

  2. 2

    Liverpool School of Tropical Medicine, International Health Group, Liverpool, Merseyside, UK

  3. 3

    University of Calabar Teaching Hospital, Effective Health Care Research Programme - Nigeria, Calabar, Nigeria

  4. 4

    University of Calabar Teaching Hospital, Institute of Tropical Disease Research and Prevention, Calabar, Cross River, Nigeria

*Martin M Meremikwu, Department of Paediatrics, University of Calabar Teaching Hospital, PMB 1115, Calabar, Cross River State, Nigeria. mmeremiku@yahoo.co.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 15 FEB 2012

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 
Summary of findings for the main comparison.

IPTc compared with placebo for reducing malaria morbidity and all cause mortality

Patient or population: Children aged less than 5 years

Settings: Areas with seasonal transmission

Intervention: Intermittent Preventive Treatment of malaria

Comparison: Placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboIPTc

Clinical malaria2.5 episodes per child per year30.7 episodes per child per year (0.4 to 1.0)Rate Ratio 0.26 (0.17 to 0.38)9321
(6 studies)
⊕⊕⊕⊕
high1,2

Severe malaria35 episodes per 1000 children per year49 episodes per 1000 children per year
(4 to 27)
Rate Ratio 0.27 (0.1 to 0.76)5964
(2 studies)
⊕⊕⊕⊕
high2

Death from any cause3 per 1000 per year2 per 1,000 per year

(1 to 5)
Risk Ratio 0.66 (0.31 to 1.39)9533
(6 studies)
⊕⊕⊕⊝
moderate5

Moderately severe anaemia67 per 1000 per year47 per 1000 per year
(35 to 65)
Risk Ratio 0.71 (0.52 to 0.98)8805
(5 studies)
⊕⊕⊕⊝
moderate6

Serious drug related adverse events---9533
(6 studies)
⊕⊕⊕⊝
moderate7

Non-serious adverse events---9533
(6 studies)
⊕⊕⊕⊝
moderate8

*The assumed risk is taken from the sum of events and participants in the control groups in the trials unless stated otherwise in the footnotes.

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;

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 The included trials were conducted in children aged < 5 years in Ghana, Mali (2), The Gambia, Senegal and Burkina Faso. Three studies administered monthly AQ+SP, two studies used SP every two months, and one study used monthly SP + AS. Two studies which also distributed ITNs showed that these benefits remain even where usage of bednets is over 90%.
2 There was no reason to downgrade for study limitations, inconsistency, indirectness or imprecision.
3 The incidence of malaria in the control groups was 2.25 episodes per child per year in Senegal, 2.4 in Mali, and 2.88 in Burkina Faso.
4 The incidence of severe malaria in the control groups was 37 per 1,000 children per year in Mali, and 32 per 1,000 children per year in Burkina Faso
5 Downgraded by one for imprecision: There were very few deaths in these trials, and none of the trials were adequately powered to detect an effect on mortality. Larger trials are necessary to have full confidence in this effect. However, a reduction in death would be consistent with the high quality evidence of a reduction in severe malaria.
6 There was substantial heterogeneity between these five trials and the trials from Ghana and the Gambia did not show an effect. Downgraded by one for inconsistency. There was no reason to downgrade for study limitations, directness or precision.
7 No drug-related serious adverse events are reported. Downgraded by one under precision as trials of this size are underpowered to fully detect or exclude rare serious adverse events.
8 Downgraded by one under study limitations. All seven trials commented on observed adverse events. However, the thoroughness of the methods used to collect these data are incomplete in some of these trials. The only adverse event found to be statistically more common with IPTc was vomiting after AQ+SP

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Malaria

Malaria, a disease common in both the tropics and subtropics, is caused by Plasmodium parasites transmitted to humans through the bite of infected female anopheline mosquitoes. People who live in or visit areas where malaria commonly occurs (endemic areas) are at risk of malaria infection. Infected people may show no sign of illness (asymptomatic malaria) or may develop fever, chills, malaise, and headache (symptomatic malaria). The severity of malaria infection varies from mild (uncomplicated) to life-threatening (severe). Among the five species of malaria parasites that infect humans, Plasmodium falciparum is the main parasite species responsible for causing severe malaria and is most frequently encountered in sub-Saharan Africa. People with severe malaria become very ill, may develop severe anaemia, convulsions, or become unconscious, and, in some cases, die.

Severe malaria is more likely to occur in people who possess low or no immunity to malaria (Gilles 2000). Children living in malaria endemic areas acquire natural immunity to malaria by the age of seven to 10 years old (Branch 1998; Warrell 2001). However, preschool children living in malaria endemic areas have inadequate immunity to malaria. This explains why the majority of the one million malaria deaths that occur each year in endemic areas of sub-Saharan Africa occur in this age group (WHO 2009).

 

Malaria control strategy

Malaria control aims to reduce illness and death from malaria infection. The World Health Organization's (WHO's) global malaria control strategy recommends a multi-pronged control approach that combines multiple preventive interventions with prompt diagnosis and treatment of symptomatic persons with efficacious antimalarial drugs (WHO 2000; WHO 2005). Artemisinin-based combination therapy (ACT) regimens have replaced chloroquine in most malaria-endemic countries as the first-line treatment for uncomplicated P. falciparum malaria, due to the widespread development of parasite resistance to chloroquine. The effectiveness of ACTs has been proven by several randomized controlled trials, but access to prompt ACT treatment has remained low in most parts of sub-Saharan Africa due to limited resources for health care (WHO 2005). Recent reports indicate that less than one-third of African children aged under five years who are sick with malaria receive prompt treatment with ACTs (UNICEF 2007).

Vector control is also another important part of the global malaria control strategy. The effectiveness of insecticide treated nets (ITNs) in reducing malaria morbidity and mortality in preschool children (Lengeler 2004) and pregnant women (Gamble 2006) has been confirmed, but coverage of this intervention in most sub-Saharan African countries lags far behind global targets. By 2009, less than one-third of the endemic countries in this region had attained 30% coverage for children under five years, far below the Roll Back Malaria (RBM) targets of 60% and 80% for 2005 and 2010 respectively (WHO 2009). Indoor residual spraying (IRS) is another vector control measure recommended by the WHO for community protection. However, it is expensive and requires high coverage to be effective (WHO 2006). Such high levels of coverage would be difficult to attain in many endemic areas, especially those with high perennial transmission.

 

Malaria prevention using drugs

Prophylaxis and IPT are two drug-based methods for preventing malaria. Prophylaxis refers to "the administration of a drug in such a way that its blood concentration is maintained above the level that inhibits parasite growth, at the pre-erythrocytic or erythrocytic stage of the parasite's life-cycle, for the duration of the period at risk" (Greenwood 2006). Drugs used for malaria prophylaxis are usually given in daily or weekly doses.

Intermittent treatment, also known as 'intermittent preventive treatment' or 'intermittent presumptive treatment' (IPT), is an alternative strategy and is defined as "the administration of a full therapeutic course of an antimalarial or antimalarial combination to a selected, target population at specified times without determining whether or not the subject is infected."(Greenwood 2010). While some experts believe that IPT is of benefit through some mechanism that is qualitatively different to prophylaxis, others suggest it is basically the same mechanism (White 2005).

Some scientists are concerned that prophylaxis in children may impair the acquisition of natural immunity to malaria and therefore make them more vulnerable to severe malaria when they grow older (WHO 1993). Previous research has shown that young African children who received malaria prophylaxis over an extended period of time had lower levels of malaria antibodies than their counterparts, although there is less robust evidence that this increased the risk of death from malaria later in life (Otoo 1988b; Greenwood 2004). Also, there are concerns that the widespread use of antimalarial drugs for prophylaxis in young children could increase the resistance of the malaria parasites to these drugs (WHO 1990; WHO 1993; Alexander 2007). However, the design of a randomized controlled trial will not detect this.

One of the assumed advantages of IPTc over prophylaxis, especially when used during a defined malaria transmission season, is the belief that short and intermittent use of antimalarial drugs for preventive purposes are unlikely to result in as much compromise of natural immunity as continuous prophylaxis (Greenwood 2010). Researchers have defined an area as having marked seasonality in malaria transmission if 75% or more of all malaria episodes occur within six months or less of the year (Roca-Feltrer 2009). IPTc is also likely to have fewer adverse events than prophylaxis because it is taken less often, and be easier to deliver through clinics (Aponte 2009).

IPT is now a recommended strategy for preventing the complications of malaria in pregnant women and infants living in endemic settings (WHO 2005; WHO 2010). IPT in these population groups is not included in this review but has been evaluated elsewhere (Garner 2006; Aponte 2009).

An earlier version of this systematic review addressed the broader question of the effectiveness of chemoprevention (including prophylaxis and IPT) against malaria in preschool children resident in endemic communities. Continuous prophylaxis is no longer included in this review, as attention has turned towards intermittent treatment strategies, but the details of prophylaxis trials are well documented in the previous versions of this review available from the archives of The Cochrane Collaboration (Meremikwu 2002, Meremikwu 2005, Meremikwu 2008).

 

Why it is important to do this review

IPTc has the potential to provide significant health benefits for pre-school age children, especially in areas of seasonal transmission. In order to provide reliable evidence to inform public health guidance and policy on this issue the need for a systematic review on this subject has become pertinent.

A further change in terminology has occurred recently, and the WHO now refer to IPTc targeted at areas of seasonal transmission as 'Seasonal Malaria Chemoprevention'.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To evaluate the effects of Intermittent Preventive Treatment (IPTc) to prevent malaria in preschool children living in endemic areas with seasonal transmission.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized controlled trials. The randomization unit may be the individual participant or a cluster, such as a household.

 

Types of participants

Children aged below six years living in an area where malaria is endemic with seasonal transmission. Children with unknown infection status (ie unknown whether each child was infected or uninfected) or known infection status, were eligible.

Trials that included only infants (age < 12 months) and trials that included only anaemic participants were excluded from this review.

 

Types of interventions

 

Intervention

  • IPTc, defined as a full curative dose of an antimalarial alone or in combination given to children monthly or every two months during the malaria transmission season.

 

Control

  • Placebo or no treatment.

Trials that allocated an additional intervention to both the intervention and control group were also included providing the additional intervention was the same for each group.

 

Types of outcome measures

 

Primary

  • Clinical malaria (clinical feature of malaria with asexual peripheral parasitaemia of any density).

 

Secondary

  • Severe malaria (as defined by WHO, (WHO 2000)).
  • Parasitaemia.
  • Death from any cause.
  • Hospital admission for any reason.
  • Severe anaemia (ie haemoglobin < 5 g/dL).
  • Moderately severe anaemia (ie haemoglobin < 8 g/dL or haematocrit < 25%).
  • Any anaemia (ie haemoglobin < 11 g/dL).
  • Haemoglobin (or haematocrit).

 

Adverse events

  • Serious adverse events (ie any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage).
  • Non-serious adverse events (ie any adverse change in health or side effect that occurs in a person within the follow-up time of the trial, but is not a serious adverse event).

 

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).

 

Databases

We searched the following databases using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group Specialized Register (July 2011); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2011, Issue 6 ); MEDLINE (1966 to July 2011); EMBASE (1974 to July 2011); and LILACS (1982 to July 2011). We also searched the metaRegister of Controlled Trials (mRCT) using 'malaria', 'child*', 'intermittent', 'prevent*' and 'IPT' as search terms (July 2011).

 

Researchers

We contacted researchers working in the field for unpublished and ongoing trials.

 

Reference lists

We also checked the reference lists of all studies identified by the above methods.

 

Data collection and analysis

 

Selection of studies

Two authors (EE, CO) independently screened the results of the literature search for potentially relevant trials and obtained the full reports of the potentially relevant trials. Two authors (EE, CO) independently assessed their eligibility using a form based on the inclusion criteria. Each trial report was scrutinized to ensure that multiple publications from the same trial were included only once. The trial's investigators were contacted for clarification if eligibility was unclear. We resolved disagreements through discussion, and when necessary, by consulting a member of The Cochrane Infectious Diseases Group editorial team. We listed the excluded studies and the reasons for their exclusion.

 

Data extraction and management

Two authors (MM, EE) independently extracted data from the included trials using a data extraction form. We resolved disagreements through discussion by all four reviewers and, when necessary, by consulting a member of the Cochrane Infectious Diseases Group editorial team. We contacted the corresponding publication author in the case of unclear information or missing data.

For each outcome, we extracted the number of patients randomized and the number analysed in each treatment group for each trial.

For dichotomous outcomes from trials that randomized individual patients, we recorded the number of participants experiencing the event and the number analysed in each treatment group. For continuous outcomes, we extracted arithmetic means and standard deviations, along with the number of patients analysed, for each treatment group. For each count outcome, we extracted a rate ratio with its standard error, however, when this information was not given we extracted the number of episodes and the number of person-years for each treatment group.

For trials that randomized clusters, we recorded the number of clusters in the trial, the average size of clusters, and the randomization unit (eg household or institution). The statistical methods used to analyse the trial were 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 were recorded. When the trials' analyses had adjusted for clustering, we extracted the treatment effect and a corresponding measure of variability. Where the analyses were not adjusted for clustering, we extracted the same data as for the trials that randomized individual patients.

 

Assessment of risk of bias in included studies

Two authors (MM, CO) independently assessed the risk of bias of each trial using a risk of bias form. We attempted to contact the authors if this information was not specified or if it was unclear. We resolved any disagreements by discussion between review authors.

For trials that randomized individuals, six components were assessed: generation of the randomization sequence, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other biases (such as the trial stopped early). For trials that randomized clusters, additional components were assessed, that is, recruitment bias, baseline imbalances, loss of clusters, incorrect analysis and comparability with trials that randomized individuals.

Judgements of 'yes', 'no' and 'unclear' were made to indicate a low, high or unclear risk of bias. We presented the results of the assessment in a risk of bias graph, risk of bias tables and a risk of bias summary.

 

Measures of treatment effect

The risk ratio was used to summarise dichotomous outcomes, the mean difference was reported for continuous outcomes, and the rate ratio was used for count outcomes. All measures of effect were presented with 95% CI.

 

Unit of analysis issues

If the original trial analyses had not adjusted for clustering, we planned to adjust the results for clustering, by multiplying the standard errors of the treatment effect by the square root of the design effect. The design effect is calculated as 1+(m-1)*ICC where m is the average cluster size and ICC is the intra-cluster correlation coefficient.  We planned to estimate the ICC from other trials included in the review or by contacting trial investigators.

 

Dealing with missing data

We aimed to carry out the analysis according to the intention-to-treat principle. However, when there was loss to follow up, a complete-case analysis was employed, such that, patients for whom no outcome was reported were excluded from the analysis. This analysis assumes that the patients for whom an outcome is available are representative of the original randomized patients.

 

Assessment of heterogeneity

We inspected the forest plots to detect overlapping CIs, applied the Chi2 test and a P value of 0.10 was used as the cut-off value to determine statistical significance. We also estimated the I2 statistic with values of 30 to 59%, 60 to 89% , and 90 to 100%  used to denote moderate, substantial and considerable levels of heterogeneity respectively.

 

Assessment of reporting biases

We planned to explore publication biases by constructing a funnel plot providing sufficient studies contributed to the treatment comparison.

 

Data synthesis

We used Review Manager (RevMan) 5 for data analysis.

We stratified the analyses by whether the outcome was measured during intervention or postintervention.

We combined cluster randomized trials that adjusted for clustering with trials that randomized individual patients using generic inverse variance meta-analysis. We tabulated the results from cluster randomized trials that did not adjusted for clustering.

In the first instance, we applied a fixed-effect meta-analysis. However, if we detected a degree of heterogeneity but still considered it appropriate to combine the trials, we used a random-effects approach.

 

Subgroup analysis and investigation of heterogeneity

If heterogeneity was detected, we explored possible causes using subgroup analyses. Subgroups used were: type of antimalarial drug and additional interventions (no additional intervention versus ITN versus other).

 

Sensitivity analysis

We conducted a sensitivity analysis to investigate the robustness of the results to the risk of bias components by including only trials that concealed the allocation and had low incomplete outcome data (i.e. <10%).

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

 

Results of the search

We assessed the search results and included seven trials (see 'Characteristics of included studies'), and excluded 95 studies (see 'Characteristics of excluded studies').

 

Included studies

 

Location

All seven trials (12,589 participants) were conducted in West Africa: one in each of Burkina Faso, Gambia and Senegal; two in Ghana and Mali respectively.

 

Malaria endemicity

The pattern of malaria transmission was seasonal in all trial sites. Five trials reported entomological inoculation rates (infective bites per person per year): 173 bites (Konate 2011); from 1 to 177 bites (Sesay 2011), 65 bites (Kweku 2008), from 6 to 37 bites (Dicko 2011) and 10 bites (Cissé 2006). Two trials did not report entomological inoculation rates but described malaria endemicity as hyperendemic in the study areas (Dicko 2008, Tagbor 2011).

 

Trial design

Six of the trials randomized individuals, while one randomized clusters (communities) (Tagbor 2011). This trial adjusted for clustering in its analysis by analysing the data at the community level. The length of follow-up for the included trials varied from six months to two years; with one year being most common.

 

Interventions

All seven trials comprehensively used IPTc for the primary prevention of anaemia and malaria in healthy preschool children during malaria transmission seasons from three to six months.

The trial regimens consisted of:

  • Standard treatment doses of sulfadoxine-pyrimethamine given monthly or every two months during the malaria transmission season (Dicko 2008; Kweku 2008),
  • A combination of standard treatment doses of sulphadoxine-pyrimethamine and amodiaquine monthly for three consecutive courses during the peak malaria transmission season (Dicko 2011; Konate 2011;Sesay 2011),
  • A combination of artesunate (4 mg/kg) plus amodiaquine (10 mg/kg) monthly or every two months (Kweku 2008; Tagbor 2011),
  • A combination of the standard dose of sulfadoxine-pyrimethamine plus one dose of artesunate (4 mg/kg body weight) once monthly for three consecutive months (Cissé 2006).

 

Co-interventions

Two trials (Sesay 2011, Tagbor 2011) studied the effect of IPTc in areas where access to antimalarials was also being improved through home-based management of malaria (HMM).

Two trials (Dicko 2011, Konate 2011) administered IPTc alongside ITN distribution and promotion.

 

Outcomes

Clinical malaria: Six trials reported on incidence of clinical malaria, while one reported incidence of fever episodes without parasitological confirmation (Tagbor 2011). Trialists reported clinical malaria defined by different parasite density cut-off points and defined by any parasitaemia but we extracted data on clinical malaria with any parasitaemia. Two trials provided adequate information on severe malaria for meta-analysis. Clinical malaria and severe malaria were reported as incidence rates.

Anaemia: All included trials provided some data on anaemia but only five provided adequate information for inclusion in meta-analysis. (Cissé 2006; Dicko 2008; Dicko 2011; Konate 2011; Kweku 2008). All five trials reported data on moderately severe anaemia (haemoglobin < 8 g/dL or packed cell volume < 25%) but only two (Dicko 2011, Konate 2011) provided information on severe anaemia (haemoglobin < 5 g/dL). Three trials (Dicko 2011; Konate 2011; Tagbor 2011) provided data on mild anaemia (haemoglobin < 11 g/dL). Tagbor 2011 was a cluster-randomized trial and provided adequate information for calculation of design effect; anaemia data from this trial was therefore included in meta-analysis following adjustment for cluster design effect.

Other outcomes: Other relevant outcomes reported were death (six trials included in meta-analysis), hospital admission (three trials) and parasitaemia (six trials).

Adverse events: All trials reported on adverse events; information on adverse events are summarized in a table. Data on reported adverse events were included in meta-analysis if they helped to provide additional information to explain any remarkable differences observed between treatment and control groups.

Post-intervention (rebound) events: Data on post-intervention assessment of trial outcomes were included in meta-analysis if they were adequate; only a few trials provided adequate post-intervention data for meta-analysis. Three trials provided adequate information on incidence of clinical malaria post-intervention (Cissé 2006; Dicko 2008; Kweku 2008).

 

Excluded studies

The excluded studies and the reason for their exclusion are shown in the 'Characteristics of excluded studies' table.

 

Risk of bias in included studies

See Figure 1 and Figure 2 for a summary of the risk of bias assessments.

 FigureFigure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

 

Allocation

Six trials used suitable methods to generate the allocation sequence and were classified as low risk of bias. Four used a computer; one trial was randomized in permuted blocks of 10 by a statistician (Konate 2011), while another (Kweku 2008) used simple balloting with tokens. One trial did not describe the procedure used (Tagbor 2011) and was of unclear risk.

Allocation was adequately concealed in six trials that used identical and centrally-coded drugs and placebo or sealed, opaque envelopes. Allocation concealment was unclear in one trial (Tagbor 2011.

 

Blinding

Five trials blinded participants and care providers/assessors. Blinding was unclear in one trial (Tagbor 2011), and not used in another described as open-label (Dicko 2008).

 

Incomplete outcome data

Four trials included more than 90% of randomized participants in the analysis and were classified as low risk of bias.

Three trials (Dicko 2008; Sesay 2011; Tagbor 2011) had greater than 10% attrition and were classified as high risk of bias.

 

Selective reporting

All seven trials were judged to be at low risk of selective reporting.

 

Other potential sources of bias

The six trials that randomized individuals (Cissé 2006; Dicko 2008; Dicko 2011; Konate 2011; Kweku 2008; Sesay 2011) were judged to be free of other sources of bias and thus low risk of bias.

The cluster randomized trial (Tagbor 2011) adjusted for clustering in the analysis (low risk of bias), had reasonably comparable treatment groups at baseline (low risk of bias); did not appear to be biased in terms of the recruited patients (low risk of bias); and showed no obvious differences with the trials that randomized individuals (low risk of bias).

 

Effects of interventions

See:  Summary of findings for the main comparison

Three trials compared IPTc versus placebo (Cissé 2006; Dicko 2008; Kweku 2008).Two trials compared IPTc plus distribution and promotion of ITNs versus ITNs alone (Dicko 2011; Konate 2011); and two trials compared IPTc plus Home-based Manaegement of malaria (HMM) versus HMM alone (Tagbor 2011; Sesay 2011). The cluster randomized trial (Tagbor 2011) adjusted for clustering.

 

Clinical malaria

Overall, IPTc prevented around three-quarters of clinical malaria episodes during the intervention period (rate ratio 0.26, 95% CI 0.17 to 0.38; 9321 participants, six trials;  Analysis 1.1). The size of this effect varied from a 45% reduction in Mali (Dicko 2008) to an 86% reduction in Senegal (Cissé 2006). This variation could be explained by differences in efficacy between the antimalarial regimen used, by variation in local transmission or resistance patterns, or other factors related to the conduct of the trials. However there were insufficient trials to make meaningful conclusions from subgroup analyses exploring the effects of these factors ( Analysis 2.1;  Analysis 3.1).

Three studies continued to monitor children for a full transmission season after IPTc was stopped. There was no observed rebound increase in malaria in children who had received the intervention compared to controls (2299 participants, three trials;  Analysis 1.1).

 

Severe malaria

IPTc also prevented around three-quarters of severe malaria episodes (rate ratio 0.27, 95% CI 0.10 to 0.76; 5964 participants, two trials;  Analysis 1.2). Two other trials [Cissé 2006, Dicko 2008] reported on severe malaria but did not provide suitable information for inclusion in the meta-analysis: Dicko 2008 reported that five cases of severe malaria occurred during the first 12 months of the follow-up, all in the control group incidence rate of 0.048 episodes per 1000 persons-days at risk. One child in the control group of Cissé 2006 died from severe malaria.

 

Parasitaemia

The prevalence of parasitaemia was also reduced by IPTc compared to controls (risk ratio 0.35, 95% CI 0.25 to 0.50; 8781 participants, six trials;  Analysis 1.3). Again, although all trials favoured IPTc, there was substantial heterogeneity regarding the size of the effect but too few trials to explain this heterogeneity using subgroup analyses ( Analysis 2.2;  Analysis 3.2).

In the post-intervention transmission season, none there was no statistically significant difference in the prevalence of parasitaemia between IPTc and controls (1627 participants, two trials;  Analysis 1.3).

 

Death from any cause

The number of deaths observed in these trials was very low. Although fewer deaths were seen in the children who received IPTc the difference was not statistically significant (9533 participants, six trials;  Analysis 1.4).

The difference in deaths was also not statistically significant in the transmission season after IPTc was stopped (1,207 participants, one trial;  Analysis 1.4).

 

Hospital admission for any reason

No significant difference in risk of hospitalization was found between IPTc and control groups, during the intervention (7171 participants, three trials;  Analysis 1.5); or post-intervention (1207 participants, one trial;  Analysis 1.5).

 

Severe anaemia (haemoglobin < 5 g/dL)

Although the number of cases of severe anaemia reported in these trials was very low, there was a statistically significant reduction in the risk of severe anaemia with IPTc (risk ratio 0.24, 95% CI 0.06 to 0.94; 5964 participants, two trials;  Analysis 1.6).

 

Moderately severe anaemia (haemoglobin < 8 g/dL or haematocrit < 25%)

During the intervention, there was a reduction in the risk of moderately severe anaemia in children given IPTc (risk ratio 0.71, 95% CI 0.52 to 0.98; 8805 participants, five trials;  Analysis 1.7). There was substantial heterogeneity between trials, with three trials suggesting benefit and two showing almost no difference ( Analysis 1.7). The cause of this heterogeneity is unclear. The trials showing greatest benefit were Dicko 2011 and Konate 2011 which both administered IPTc as amodiaquine plus sulfadoxine-pyrimethamine ( Analysis 2.3;  Analysis 3.3).

One cluster-randomized trial of IPTc plus HMM versus HMM (Tagbor 2011), which was not included in the meta-analysis, reported that the prevalence of severe anaemia (defined by trial authors as haemoglobin < 7 g/dL) during the intervention was 0.44% in the IPTc arm compared to 1.75% in the control arm.

Post-intervention, no difference between IPTc and control was found (768 participants, one trial;  Analysis 1.7).

 

Any anaemia (haemoglobin < 11 g/dL)

During the intervention, the risk of mild anaemia did not significantly differ between IPTc and control groups (6786 participants, three trials;  Analysis 1.8).There was heterogeneity regarding the size of the effect but again, all of the trials favoured IPTc or showed almost no difference ( Analysis 1.8).

One cluster-randomized trial of IPTc plus HMM versus HMM (Tagbor 2011), which was not included in the meta-analysis, reported that the prevalence of mild anaemia (defined by trial authors as haemoglobin < 11 g/dL) during the intervention was 46.4% in the IPTc arm compared to 47.2% in the control arm.

 

Haemoglobin

During the intervention, three trials found no significant difference in mean haemoglobin concentration between IPTc and control arms (2266 participants, three trials;  Analysis 1.9). Post-intervention, no difference between IPTc and control was found (1207 participants, one trial;  Analysis 1.9).

 

IPTc plus co-interventions

Two trials distributed and promoted the use of ITNs to both the intervention and control groups (Dicko 2011 and Konate 2011). Despite ITN use being reported as >90% in both treatment arms, IPTc had high protective efficacy against both clinical malaria (rate ratio 0.22, 95% CI 0.13 to 0.38; 5964 participants, two trials;  Analysis 2.1) and severe malaria (rate ratio 0.27, 95% CI 0.10 to 0.76; 5964 participants, two trials;  Analysis 1.2).

Two trials were conducted in the context of a program of home-based management of malaria (HMM) which was provided to both the intervention and control groups (Sesay 2011; Tagbor 2011). Only Sesay 2011 reported data on clinical malaria or anaemia, and failed to show a statistically significant effect (146 participants, one trial  Analysis 2.1,  Analysis 2.3;  Analysis 2.4). Neither trial demonstrated a statistically significant reduction in parasitaemia follwing IPTc in the presence of HMM ( Analysis 2.2).

 

Adverse events

 
Serious adverse events during the intervention

All seven trials reported that there were no cases of drug-related serious adverse events.

 
Non-serious adverse events during the intervention

 Analysis 4.1 displays adverse events reported by the three trials (Dicko 2011; Konate 2011; and Sesay 2011) that compared sulfadoxine-pyrimethamine plus amodiaquine versus a control. Children given IPTc were more likely to vomit than those in the control group (risk ratio 2.78, 95% CI 2.31 to 3.35; 3544 patients, two trials). When comparing the IPTc versus control groups, no difference in risk of diarrhoea (3951 patients, two trials), loss of appetite (3950 patients, two trials), jaundice (1353 patients, one trial), skin rash (5227 patients, three trials), itching (3949 patients, two trials), fever (3951 patients, two trials), drowsiness (2951 patients, two trials), or coughing (3913 patients, two trials), was detected.

 Analysis 5.1 displays adverse events reported by Cissé 2006 that compared sulfadoxine-pyrimethamine plus artesunate versus a control. When comparing the IPTc versus control groups, there was no difference in risk of severe skin or neurological reaction (941 patients, one trial), convulsions (942 patients, one trial), minor skin rash (945 patients, one trial), dizziness (946 patients, one trial), diarrhoea (947 patients, one trial), or vomiting after first dose (948 patients, one trial). A difference between IPTc and control was detected in terms of the risk of nervousness (risk ratio 1.39, 95% CI 1.13 to 1.70; 943 patients, one trial) and pruritus (risk ratio 3.74, 95% CI 1.06 to 13.18, 944 patients, one trial). Cissé 2006 also found that children given IPTc were more likely to vomit than those in the control group after the second (risk ratio 7.26, 95% CI 2.58 to 20.39; 949 patients, one trial) and third dose (risk ratio 13.11, 95% CI 1.73 to 99.27; 950 patients, one trial).

Data reported by Tagbor 2011, that compared sulfadoxine-pyrimethamine plus amodiaquine versus control, is presented in  Table 1 but does not adjust for clustering.

Dicko 2008, that compared sulfadoxine-pyrimethamine versus control, simply reported that 'No subject was withdrawn because of allergy to sulfadoxine-pyrimethamine.'

Kweku 2008, that compared sulfadoxine-pyrimethamine plus artesunate versus control, reported that 'Adverse events were reported slightly less frequently in each of the three IPTc groups compared to the placebo group throughout the intervention period (5.6 % vs 5.9%). Diarrhoea, vomiting, drowsiness and abdominal pains were the most frequently reported symptoms in both IPTc and placebo groups. The number of children who reported at least one adverse event or any specific adverse event did not differ significantly between the study groups.' Kweku 2008 also reported that 'The incidence of mild adverse events such as fever, general weakness, vomiting, diarrhoea, abdominal pain and cough were similar in the placebo and IPTc groups'.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

See  Summary of findings for the main comparison.

IPTc given to children in areas with seasonal malaria transmission can prevent approximately three quarters of clinical malaria episodes (high quality evidence), and a similar proportion of severe malaria episodes (high quality evidence; Appendix 2). These effects remain present even where insecticide treated net (ITN) usage is high (high quality evidence; Appendix 3).

IPTc probably also produces a small reduction in all-cause mortality, but the trials were underpowered to reach statistical significance (moderate quality evidence).

The effect on anaemia varied between studies but the risk of moderately severe anaemia is probably reduced by IPTc (moderate quality evidence).

Serious drug-related adverse events, if they occur, are probably rare, with none reported in the six trials (moderate quality evidence). Amodiaquine plus sulphadoxine-pyrimethamine is the most studied drug combination for seasonal chemoprevention. Although effective, it does cause increased vomiting in this age-group (high quality evidence; Appendix 5).

When antimalarial IPTc was stopped, no rebound increase in malaria was observed in the three trials which continued follow-up for one season after IPTc (Appendix 6).

 

Overall completeness and applicability of evidence

All seven trials included in the review were conducted in areas of West Africa where P. falciparum is the predominant cause of malaria and transmission is highly seasonal, and the results can reasonably be applied to other areas with similar conditions. Most studies included healthy children aged between 3 and 59 months.

Several different IPTc regimens have been proposed and evaluated and all appear effective. Amodiaquine plus sulphadoxine-pyrimethamine is the most studied with more than 50% of all trial participants, but has not been directly compared with alternative regimens.

The reduction in clinical malaria episodes was large in all the trials but with some variation in the size of this effect. The reasons for this variation are unclear, but could be due to differences in the drug regimen, or differences in the local malaria transmission or resistance patterns. The trials were too few in number to perform meaningful subgroup analyses.

The results of trials included in this review demonstrated that IPTc given to preschool children over a short period (during malaria transmission season) is unlikely to result in a rebound effect on malaria morbidity or mortality, once IPTc is stopped. While the trials that reported detailed post-intervention data are few, these results are consistent across trials and appear to support the hypothesis that IPTc, allows longer periods in between treatments for children to acquire protective malarial immunity and are therefore less likely to cause rebound morbidity and mortality than continuous prophylaxis.

 

Quality of the evidence

The quality of evidence has been assessed using the GRADE methodology.

The GRADE system considers ‘quality’ to be a judgment of the extent to which we can be confident that the estimates of effect are correct. The level of ‘quality’ is judged on a 4-point scale. Evidence from randomized controlled studies is initially graded as high and downgraded by one, two or three levels after full consideration of: any limitations in the design of the studies, the directness (or applicability) of the evidence, the consistency and precision of the results, and the possibility of publication bias.

The evidence that IPTc reduces clinical malaria episodes and severe malaria episodes is considered to be of 'High quality', which implies that we are confident in these estimates of effect and further research addressing these aspects is not necessary (see  Summary of findings for the main comparison).

The full GRADE profiles with reasons for the downgrading of evidence quality are available as Appendices addressing 5 questions:

  • Does IPTc reduce all-cause mortality and malaria morbidity in children aged < 5 years?
  • Is there a rebound increase in all-cause mortality or malaria morbidity once IPTc is stopped?
  • Is IPTc still effective when ITN usage is high?
  • Is IPTc still effective where home-based management of malaria is practiced?
  • Is amodiaquine plus sulfadoxine-pyrimethamine an effective and safe option for IPTc?

 

Agreements and disagreements with other studies or reviews

The findings of this review agree broadly with a similar systematic review published in 2011 (Wilson 2011), but there are some differences in the conclusions regarding an effect on mortality.

Wilson 2011 concludes that IPTc 'appears to have a substantial protective effect against all-cause mortality'. We have excluded data from some uncontrolled observational trials included by Wilson 2011, and consequently our estimates do not reach statistical significance. However, we agree that a reduction in mortality with IPTc is likely and would be consistent with the high quality evidence of a reduction in severe malaria. However, the magnitude of this reduction, appears to be around 1 averted death per 1,000 children receiving IPTc.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

Giving antimalarial drugs to preschool children (age < six years) as IPTc during the malaria transmission season reduces the incidence of clinical malaria, and severe malaria. Several antimalarial drug combination options have been evaluated and show good levels of effectiveness, even in the presence of high levels of ITN use.

 
Implications for research

The evidence for benefit in areas with seasonal transmission is of high quality and further assessment of these antimalarials in these settings is unnecessary.

The effectiveness of IPT for pre-school age children living in settings with perennial transmission remains unclear, and may be an area for further research. However, concerns about the practicality, adverse effects, or costs of IPT in these settings may limit the usefulness of the intervention.

Concern remains about the potential for IPT to increase the development of antimalarial resistance, and resistance monitoring should be integrated into appropriate pharmaco-epidemiological studies and surveillance programmes.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Paul Garner, the Co-ordinating Editor of the Cochrane Infectious Diseases Group, supervised this update, read and commented on several versions of the draft. Aika Omari and Paul Garner co-authored the first version of this review with Martin Meremikwu (Meremikwu 2005). The protocol for this review (Meremikwu 2002) was developed during the Fellowship Programme organized by the Cochrane Infectious Diseases Group in November 2001. The UK Department for International Development (DFID) supports this Programme through the Effective Health Care Alliance Programme at the Liverpool School of Tropical Medicine.

This document is an output from a project funded by DFID for the benefit of developing countries. The views expressed are not necessarily those of DFID. The update was partly funded by a grant from the World Health Organization.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. IPTc versus placebo or no IPTc

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical malaria6Rate Ratio (Random, 95% CI)Subtotals only

    1.1 During intervention
69321Rate Ratio (Random, 95% CI)0.26 [0.17, 0.38]

    1.2 Post-intervention
32299Rate Ratio (Random, 95% CI)0.98 [0.82, 1.17]

 2 Severe malaria2Rate Ratio (Fixed, 95% CI)Subtotals only

    2.1 During intervention
25964Rate Ratio (Fixed, 95% CI)0.27 [0.10, 0.76]

   2.2 Post-intervention
00Rate Ratio (Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Parasitaemia5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 During intervention
58781Risk Ratio (M-H, Random, 95% CI)0.35 [0.25, 0.50]

    3.2 Post-intervention
21627Risk Ratio (M-H, Random, 95% CI)1.01 [0.89, 1.16]

 4 Death from any cause6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 During intervention
69533Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.31, 1.39]

    4.2 Post-intervention
11207Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.39, 2.73]

 5 Hospital admission for any reason3Rate Ratio (Fixed, 95% CI)Subtotals only

    5.1 During intervention
37171Rate Ratio (Fixed, 95% CI)0.66 [0.41, 1.05]

    5.2 Post-intervention
11207Rate Ratio (Fixed, 95% CI)1.13 [0.00, 770.22]

 6 Severe anaemia2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 During intervention
25964Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.06, 0.94]

 7 Moderately severe anaemia5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 During intervention
58805Risk Ratio (M-H, Random, 95% CI)0.71 [0.52, 0.98]

    7.2 Post-intervention
1768Risk Ratio (M-H, Random, 95% CI)0.80 [0.53, 1.20]

 8 Any anaemia3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    8.1 During intervention
36786Risk Ratio (M-H, Random, 95% CI)0.82 [0.65, 1.04]

 9 Haemoglobin3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    9.1 During intervention
32266Mean Difference (IV, Fixed, 95% CI)0.03 [-0.08, 0.14]

    9.2 Post-intervention
11207Mean Difference (IV, Fixed, 95% CI)0.03 [-0.24, 0.30]

 
Comparison 2. IPTc versus placebo or no IPTc (subgroup analysis: additional interventions)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical malaria6Rate Ratio (Random, 95% CI)Subtotals only

    1.1 During intervention (no additional)
32311Rate Ratio (Random, 95% CI)0.28 [0.12, 0.63]

    1.2 During intervention (ITN)
25964Rate Ratio (Random, 95% CI)0.22 [0.13, 0.38]

    1.3 During intervention (HMM)
11046Rate Ratio (Random, 95% CI)0.34 [0.04, 3.05]

 2 Parasitaemia6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 During intervention (no additional)
22041Risk Ratio (M-H, Random, 95% CI)0.31 [0.20, 0.47]

    2.2 During intervention (ITN)
25694Risk Ratio (M-H, Random, 95% CI)0.38 [0.20, 0.75]

    2.3 During intervention (HMM)
21059Risk Ratio (M-H, Random, 95% CI)0.70 [0.25, 1.90]

 3 Moderately severe anaemia5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 During intervention (no additional)
22019Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.66, 1.11]

    3.2 During intervention (ITN)
25740Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.36, 0.63]

    3.3 During intervention (HMM)
11046Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.68, 1.51]

 4 Any anaemia3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 During intervention (ITN)
25740Risk Ratio (M-H, Random, 95% CI)0.77 [0.59, 1.00]

    4.2 During intervention (HMM)
11046Risk Ratio (M-H, Random, 95% CI)1.02 [0.75, 1.39]

 
Comparison 3. IPTc versus placebo or no IPTc (subgroup analysis: type of antimalarial drug)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical malaria6Rate Ratio (Random, 95% CI)Subtotals only

    1.1 During intervention (SP)
21407Rate Ratio (Random, 95% CI)0.61 [0.50, 0.74]

    1.2 During intervention (SP+AQ)
37010Rate Ratio (Random, 95% CI)0.23 [0.14, 0.37]

    1.3 During intervention (SP+AS)
1872Rate Ratio (Random, 95% CI)0.14 [0.10, 0.20]

    1.4 During intervention (AQ+AS)
11207Rate Ratio (Random, 95% CI)0.26 [0.19, 0.37]

 2 Parasitaemia6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 During intervention (SP)
11121Risk Ratio (M-H, Random, 95% CI)0.83 [0.65, 1.07]

    2.2 During intervention (SP+AQ)
36740Risk Ratio (M-H, Random, 95% CI)0.41 [0.22, 0.75]

    2.3 During intervention (SP+AS)
1886Risk Ratio (M-H, Random, 95% CI)0.37 [0.28, 0.48]

    2.4 During intervention (AQ+AS)
21168Risk Ratio (M-H, Random, 95% CI)0.35 [0.12, 1.05]

 3 Moderately severe anaemia4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 During intervention (SP)
11140Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.88, 1.70]

    3.2 During intervention (SP+AQ)
25740Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.36, 0.63]

    3.3 During intervention (SP+AS)
1872Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.54, 1.17]

    3.4 During intervention (AQ+AS)
11147Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.64, 1.30]

 
Comparison 4. IPTc (SP +AQ) versus placebo or no IPTc

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Non-serious adverse events (during intervention)3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Vomiting
23544Risk Ratio (M-H, Fixed, 95% CI)2.78 [2.31, 3.35]

    1.2 Diarrhoea
23951Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.90, 1.43]

    1.3 Loss of appetite
23950Risk Ratio (M-H, Fixed, 95% CI)2.17 [0.95, 4.96]

    1.4 Jaundice
11353Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.94]

    1.5 Skin rash
35227Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.50, 1.52]

    1.6 Itching
23949Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.65, 1.63]

    1.7 Fever
23951Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.79, 1.09]

    1.8 Drowsiness
22951Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.15, 4.67]

    1.9 Coughing
23913Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.81, 1.32]

 
Comparison 5. IPTc (AS+SP) versus placebo or no IPTc

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Non-serious adverse events (during intervention)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Severe skin or neurological reaction
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Convulsions
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Nervousness
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.4 Pruritus
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.5 Minor skin rash
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.6 Dizziness
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.7 Diarrhoea
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.8 Vomiting after first dose
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.9 Vomiting after second dose
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.10 Vomiting after third dose
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Search methods: detailed search strategies


Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSb

1malariamalariaMALARIAMALARIAmalaria

2prophylaxisprophylaxismalariamalariaprophylaxis

3intermittent treatmentintermittent treatment1 or 21 or 2prevention

4presumptive treatmentprophylaxisprophylaxis2 or 3

52 or 3 or 4chemoprophylaxischemoprophylaxis1 and 4

61 and 5preventionprevention

7intermittent treatmentintermittent treatment

8presumptive treatmentpresumptive treatment

94 or 5 or 6 or 7 or 84 or 5 or 6 or 7 or 8

103 and 93 and 9



aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.

 

Appendix 2. GRADE profile 1

Question: Does IPTc reduce all-cause mortality and malaria morbidity in children aged < 5 years?

Setting: Areas with marked seasonal malaria transmission


Quality assessmentNo of events/patientsEffectQualityImportance



No of studiesDesignRisk of biasInconsistencyIndirectnessImprecisionOther considerationsIPTcControlRelative
(95% CI)
Absolute

Clinical malaria

6randomized trialsno serious risk of bias1no serious inconsistency2no serious indirectness3no serious imprecision4none0.7 episodes per child per year2.5 episodes per child per year 5Rate Ratio 0.26 (0.17 to 0.38)1.8 fewer episodes per child per year (from 1.6 fewer to 2.1 fewer)⊕⊕⊕⊕
HIGH
Critical

Severe malaria

2randomized trialsno serious risk of bias6no serious inconsistencyno serious indirectness7no serious imprecision4none9 episodes per 1000 children per year35 episodes per 1000 children per year8Rate Ratio 0.27 (0.1 to 0.76)26 fewer episodes per 1000 children per year (from 8 fewer to 31 fewer)⊕⊕⊕⊕
HIGH
Critical

Death from any cause

6randomized trialsno serious risk of bias1no serious inconsistencyno serious indirectness3serious9none10/4751
(0.21%)
16/4782
(0.33%)10
RR 0.66 (0.31 to 1.39)1 fewer per 1000 (from 2 fewer to 1 more)⊕⊕⊕
MODERATE
Important

Moderately severe anaemia

5randomised trialsno serious risk of biasserious11no serious indirectnessno serious imprecisionnone203/4373
(4.6%)
296/4432
(6.7%)10
RR 0.71 (0.52 to 0.98)19 fewer per 1000 (from 1 fewer to 32 fewer)⊕⊕⊕
MODERATE
Important

Serious drug-related adverse event

6randomized trialsno serious risk of bias1no serious inconsistency12no serious indirectness3serious13none47514782--⊕⊕⊕
MODERATE
Important

Non-serious adverse event

6randomized trialsserious14no serious inconsistencyno serious indirectness3no serious imprecisionnone47514782--⊕⊕⊕
MODERATE
important



1 The studies were well conducted with allocation concealment at low risk of bias in all studies, and 5 out of 6 studies were blinded and used placebos.
2 There was substantial heterogeneity between these 6 trials. All 6 trials showed a statistically significant benefit but the magnitude of this benefit was variable. Not downgraded.
3 The included trials were conducted in Ghana, Mali (2), The Gambia, Senegal and Burkina Faso, in areas described as ‘seasonal malaria transmission’. Most studies were limited to pre-school aged children. Three studies administered monthly AQ+SP, two studies used bimonthly SP, and one study used monthly SP + AS.
4 There was no reason to downgrade for study limitations, inconsistency, indirectness or imprecision.
5 The incidence of malaria in the control groups was 2.25 episodes per child per year in Senegal, 2.4 in Mali, and 2.88 in Burkina Faso.
6 These two trials were well conducted and at low risk of bias.
7 These trials were conducted in areas of seasonal transmission in Mali and Burkina Faso. Both trials compared SP+AQ with placebo in pre-school age children. Of note, LLITN use was high in both the intervention and control groups in both studies.
8 The incidence of severe malaria in the control groups was 37 per 1,000 children per year in Mali, and 32 per 1,000 children per year in Burkina Faso
9 Downgraded by 1 for imprecision: There were very few deaths in these trials, and none of the trials were adequately powered to detect an effect on mortality. Larger trials are necessary to have confidence in this effect. However, a reduction in death would be consistent with the high quality evidence of a reduction in severe malaria.
10 These control group risks are taken from the sum of events and participants in the included trials.
11 There was substantial heterogeneity between these 5 trials and the trials from Ghana and The Gambia did not show an effect. Downgraded by 1 for Inconsistency. There was no reason to downgrade for study limitations, directness or precision.
12 All six trials reported that there was no case of drug-related serious adverse event. One trial reported that four participants were withdrawn from the treatment arm: two cases for non-severe skin rash, one for itching and another for acute respiratory infection. One trial reported skin eruptions with macular hyper-pigmentation which was neither Stevens Johnson syndrome nor any other form of severe skin lesions.
13 Downgraded by 1 under precision. Trials of this size are underpowered to fully detect or exclude rare serious adverse events. Observation should continue once implemented.
14 Downgraded by 1 under study limitations. All seven trials commented on observed adverse events. However, the thoroughness of the methods used to collect these data are incomplete in some of these trials. The only adverse event found to be statistically more common with IPTc was vomiting after AQ+SP (see Appendix 5).

 

Appendix 3. GRADEprofile 2

Question: Is IPTc still effective where ITN coverage is high?

Setting: Areas with marked seasonal transmission


Quality assessmentNo of patientsEffectQualityImportance



No of studiesDesignRisk of biasInconsistencyIndirectnessImprecisionOther considerationsIPTcControlRelative
(95% CI)
Absolute

Clinical malaria - (where bed-nets are also used)

2randomized trialsno serious risk of bias1no serious inconsistencyno serious indirectness2no serious imprecision3none0.6 episodes per child per year2.5 episodes per child per year4Rate Ratio 0.22 (0.13 to 0.38)1.9 fewer per child per year (from 1.6 fewer to 2.2 fewer)⊕⊕⊕⊕
HIGH
Critical

Severe malaria

2randomized trialsno serious risk of bias1no serious inconsistencyno serious indirectness2no serious imprecision3none9 episodes per 1000 children per year35 episodes per 1000 children per year5Rate Ratio 0.25 (0.1 to 0.68)26 fewer episodes per 1000 children per year (from 11 fewer to 32 fewer)⊕⊕⊕⊕
HIGH
Critical



1 These trials were well conducted and considered at low risk of bias.
2 Two trials compared IPTc with placebo where both groups were also given insecticide treated bednets (ITNs). These trials were conducted in Mali and Burkina Faso. ITN usage was over 99% in both groups in Mali, and 92% in both groups in Burkina Faso.
3 There was no reason to downgrade for study limitations, insistency, directness or precision.
4 The incidence of malaria in the control groups was 2.4 in Mali, and 2.88 in Burkina Faso.
5 The incidence of severe malaria in the control groups was 37 per 1,000 children per year in Mali, and 32 per 1,000 children per year in Burkina Faso

 

Appendix 4. GRADEprofile 3

Question: Is IPTc still effective where home-based management of malaria is practiced?

Setting: Areas with marked seasonal transmission


Quality assessmentNo of patientsEffectQualityImportance



No of studiesDesignRisk of biasInconsistencyIndirectnessImprecisionOther considerationsIPTcControlRelative
(95% CI)
Absolute

Clinical malaria - (where home-based management of malaria is used)

1randomized trialsserious1no serious inconsistencyno serious indirectness2serious3none0.2 episodes per child per year0.5 episodes per child per year4Rate Ratio 0.34 (0.04 to 3.05)0.3 fewer episodes per child per year (0.5 fewer to 1.0 more)⊕⊕
LOW
Critical

Severe malaria - Not reported

0----------Critical



1 Downgraded by 1 for risk of bias: This trial did not adequately describe the methodology to make judgements about the risk of bias.
2 One trail conducted in Ghana compared IPTc with no IPTc in the context of an on-going programme of home-based management of malaria.
3 Downgraded by 1 for imprecision: The result is not statistically significant.
4 The incidence of febrile episodes (treated presumptively as malaria) in the control group was lower in this trial than seen elsewhere.

 

Appendix 5. GRADEprofile 4

Question: Is amodiaquine plus sulfadoxine-pyrimethamine an effective and safe option for IPTc?

Setting: Areas with marked seasonal transmission


Quality assessmentNo of patientsEffectQualityImportance



No of studiesDesignRisk of biasInconsistencyIndirectnessImprecisionOther considerationsAQ+SPControlRelative
(95% CI)
Absolute

Clinical malaria

3randomized trialsno serious risk of bias1no serious inconsistency2no serious indirectness3no serious imprecision4none0.6 episodes per child per year2.5 episodes per child per year5Rate Ratio 0.23 (0.14 to 0.37)1.9 episodes fewer per child per year (from 1.6 fewer to 2.2 fewer)⊕⊕⊕⊕
HIGH
Critical

Severe malaria

2randomized trialsno serious risk of bias1no serious inconsistencyno serious indirectness6no serious imprecision7none9 episodes per 1000 children per year35 episodes per 1000 children per year8Rate Ratio 0.27 (0.1 to 0.76)26 fewer episodes per 1000 children per year (from 8 fewer to 31 fewer)⊕⊕⊕⊕
HIGH
Critical

Death from any cause

3randomized trialsno serious risk of bias1no serious inconsistencyno serious indirectness3serious9none6/3498
(0.17%)
10/3512
(0.28%)10
RR 0.62 (0.23 to 1.65)1 fewer per 1000 (from 2 fewer to 2 more)⊕⊕⊕
MODERATE
Important

Moderately severe anaemia

2randomized trialsno serious risk of bias1no serious inconsistencyno serious indirectness6no serious imprecision7none66/2866
(2.3%)
139/2874
(4.8%)10
RR 0.48 (0.36 to 0.63)25 fewer per 1000 (from 18 fewer to 31 fewer)⊕⊕⊕⊕
HIGH
Important

Serious drug-related adverse event

3randomized trialsno serious risk of bias1no serious inconsistency11no serious indirectness3serious12none----⊕⊕⊕
MODERATE
 Important

Non-serious adverse events- vomiting

2randomized trialsno serious risk of bias1no serious inconsistencyno serious indirectness6no serious imprecision7none387/1814
(21.3%)
131/1730
(7.6%)10
RR 2.78 (2.31 to 3.35)135 more per 1000 (from 99 more to 178 more)⊕⊕⊕⊕
HIGH
 Important



1 The studies were well conducted with allocation concealment at low risk of bias in all studies, and all studies were blinded and used placebos.
2 There was substantial heterogeneity between these 3 trials. All 3 trials showed a trend to favour IPTc but the magnitude of this benefit was variable. Not downgraded.
3 Two trials compared IPTc with placebo where both groups were also given insecticide treated bednets (ITNs). These trials were conducted in Mali and Burkina Faso. ITN usage was over 99% in both groups in Mali, and 92% in both groups in Burkina Faso. The third trial was conducted in the Gambia. All were in pre-school age children, and administered monthly SP+AQ.
4 There was no reason to downgrade for study limitations, inconsistency, indirectness or imprecision.
5 The incidence of malaria in the control groups was 2.4 in Mali, and 2.88 in Burkina Faso.
6 These trials were conducted in areas of seasonal transmission in Mali and Burkina Faso.
7 There was no reason to downgrade for study limitations, inconsistency, indirectness or imprecision.
8 The incidence of severe malaria in the control groups was 37 per 1,000 children per year in Mali, and 32 per 1,000 children per year in Burkina Faso
9 Downgraded by 1 for imprecision: There were very few deaths in these trials, and none of the trials were adequately powered to detect an effect on mortality. Larger trials are necessary to have confidence in this effect. However, a reduction in death would be consistent with the high quality evidence of a reduction in severe malaria.
10 These control group risks are taken from the sum of events and participants in the included trials.
11 All three trials reported that there was no case of drug-related serious adverse event. One trial reported that four participants were withdrawn from the treatment arm: two cases for non-severe skin rash, one for itching and another for acute respiratory infection. One trial reported skin eruptions with macular hyper-pigmentation which was neither Stevens Johnson syndrome nor any other form of severe skin lesions.
12 Downgraded by 1 under precision. Trials of this size are underpowered to detect or exclude rare serious adverse events.

 

Appendix 6. GRADEprofile 5

Question: After stopping IPTc is there a rebound increase in all-cause mortality or malaria morbidity during the following malaria transmission season?

Setting: Areas with marked seasonal transmission


Quality assessmentNo of patientsEffectQualityImportance



No of studiesDesignRisk of biasInconsistencyIndirectnessImprecisionOther considerationsIPTcControlRelative
(95% CI)
Absolute

Clinical malaria

3randomized trialsno serious risk of bias1no serious inconsistencyno serious indirectness2no serious imprecision3none2.5 episodes per child per year2.5 episodes per child per year4Rate Ratio 0.98 (0.82 to 1.17)0 fewer episodes per child per year (from 0.5 fewer to 0.4 more)⊕⊕⊕⊕
HIGH
Critical

Severe malaria - not reported

0---------- Critical

Death from any cause

1randomized trialsno serious risk of bias5no serious inconsistencyno serious indirectness6serious7none8/594
(1.3%)
8/613
(1.3%)8
RR 1.03 (0.39 to 2.73)0 more per 1000 (from 8 fewer to 23 more)⊕⊕⊕
MODERATE
Important

Moderately severe anaemia

1randomized trialsno serious risk of bias5no serious inconsistencyserious indirectness9no serious imprecisionnone36/376
(9.6%)
47/392
(12%)8
RR 0.8 (0.53 to 1.2)24 fewer per 1000 (from 56 fewer to 24 more)⊕⊕⊕
MODERATE
Important



1 These trials were well conducted and considered at low risk of bias.
2 Three trials report clinical malaria during the following malaria season when IPTc was not given.  These were conducted in Senegal, Mali, and Ghana.
3 There was no reason to downgrade for study limitations, inconsistency, indirectness or imprecision.
4 The incidence of malaria in the control groups was 2.25 episodes per child per year in Senegal, 2.4 in Mali, and 2.88 in Burkina Faso.
5 This trial was well conducted and considered at low risk of bias.
6 This trial was conducted in Ghana. A large reduction in clinical malaria was seen during the intervention period, following IPTc with either bimonthly sulfadoxine-pyrimethamine or amodiaquine plus artesunate.
7 Downgraded by 1 for imprecision: there were very few deaths in these trials, and none of the trials were adequately powered to detect or exclude an effect on mortality. Larger trials are necessary to have confidence that there is no increase.
8 These control group risks are taken from the sum of events and participants in the included trials.
9 Downgraded by 1 for indirectness: only one trial reports the incidence of moderate anaemia during the following transmission season. This trial found no statistically significant benefit on anaemia during the administration of IPTc.

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 16 June 2011.


DateEventDescription

13 January 2012New citation required but conclusions have not changedSignificant update and changed focus

3 August 2011New search has been performedThe original review has been split into two separate topics: "Intermittent treatment for malaria in children (IPTc) living in areas with seasonal transmission" and "Intermittent preventive treatment in infants". This update addresses a focused question on the potential benefit and harm of giving IPTc to children aged below five years living is areas with seasonal malaria transmission. Trials on continuous prophylaxis have been excluded.



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 3, 2002
Review first published: Issue 4, 2005


DateEventDescription

22 August 2008New search has been performedConverted to new review format with minor editing.

20 February 2008New citation required and conclusions have changed2008, Issue 2: We included four new trials of intermittent treatment (Chandramohan 2005a; Cissé 2006; Macete 2006a; Kobbe 2007a). We removed quasi-randomized controlled trials from the inclusion criteria and excluded two such trials (Bradley-Moore 1985; Oyediran 1993) that were included in the Meremikwu 2005 version of this review. The evidence on benefits regarding reduction of malaria episodes, severe anaemia, and admissions remains strong and consistent with these changes. We also updated the analysis methods to stratify the individual and cluster-randomized trials. S Donegan and E Esu joined the author team, while P Garner and A Omari stepped down.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Martin Meremikwu, Ekpereonne Esu and Chioma Oringanje identified and extracted data from eligible trials for this update. Sarah Donegan, David Sinclair and Martin Meremikwu analysed the data, with Sarah Donegan playing the key role in handling the difficult statistical issues. Martin Meremikwu prepared the first draft, and the other authors read through and made input to all sections of the review. David Sinclair and Martin Meremikwu developed the GRADE profiles and summary of findings tables.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • University of Calabar, Nigeria.
  • Liverpool School of Tropical Medicine, UK.

 

External sources

  • Department for International Development, UK.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

This version of the review differs from the first protocol and previous versions (Meremikwu 2002, Meremikwu 2005, Meremikwu 2008), because it includes only trials that administered short duration (monthly or every two months) antimalarial treatments as IPTc to preschool children living in areas with seasonal malaria transmission. Unlike the earlier versions, it excluded trials on prolonged daily or weekly chemoprophylaxis and those that gave IPT to only, or predominantly, infants.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Cissé 2006 {published data only}
  • Cissé B, Sokhna C, Boulanger D, Milet J, Bâ el H, Richardson K, et al. Seasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial. Lancet 2006;367(9511):659-67.
Dicko 2008 {published data only}
  • Dicko A, Sagara I, Sissoko MS, Guindo O, Diallo AI, Kone M, et al. Impact of intermittent preventive treatment with sulphadoxine-pyrimethamine targeting the transmission season on the incidence of clinical malaria in children in Mali. Malaria Journal 2008;7:123-31.
Dicko 2011 {published data only}
  • Dicko A, Diallo AI, Tembine I, Dicko Y, Dara N, Sidibe Y, et al. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial. PLoS Medicine 2011;8(2):e1000407.
Konate 2011 {published data only}
  • Konate AT, Yaro JB, Oue´draogo AZ, Diarra A, Gansane A, Soulama I, et al. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Burkina Faso: A randomised, double-blind, placebo-controlled trial. PLoS Medicine 2011;8(2):e1000408.
Kweku 2008 {published data only}
  • Conteh L, Patouillard E, Kweku M, Legood R, Greenwood B, Chandramohan D. Cost effectiveness of seasonal intermittent preventive treatment using amodiaquine and artesunate or sulphadoxine-pyrimethamine in Ghanaian children. PLoS ONE 2010;5(8):e12223.
  • Kweku M, Liu D, Adjuik M, Binka F, Seidu M, Greenwood B, et al. Seasonal intermittent preventive treatment for the prevention of anaemia and malaria in Ghanaian children: a randomized, placebo controlled trial. PloS One 2008;3(12):e4000.
Sesay 2011 {published data only}
  • Sesay S, Milligan P, Touray E, Sowe M, Webb EL, Greenwood BM, et al. A trial of intermittent preventive treatment and home-based management of malaria in a rural area of The Gambia. Malaria Journal 2011;10:2.
Tagbor 2011 {published data only}

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Akenzua 1985 {published data only}
  • Akenzua GI, Ihongbe JC, Imasuen IW. Haemopoietic response of Nigerian village children to iron, folate supplementation and malaria prophylaxis. Journal of Tropical Pediatrics 1985;31(1):59-62.
Allen 1990 {published data only}
  • Allen SJ, Otoo LN, Cooke GA, O'Donnell A, Greenwood BM. Sensitivity of Plasmodium falciparum to chlorproguanil in Gambian children after five years of continuous chemoprophylaxis. Transactions of the Royal Society of Tropical Medicine and Hygiene 1990;84(2):218.
Alonso 1993 {published data only}
  • Alonso PL, Lindsay SW, Armstrong JR, Conteh M, Hill AG, David PH, et al. The effect of insecticide-treated bed nets on mortality of Gambian children. Lancet 1991;337(8756):1499-502.
  • Alonso PL, Lindsay SW, Armstrong Schellenberg JR, Keita K, Gomez P, Shenton FC, et al. A malaria control trial using insecticide-treated bed nets and targeted chemoprophylaxis in a rural area of The Gambia, west Africa. 6. The impact of the interventions on mortality and morbidity from malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1993;87 Suppl 2:37-44.
  • Picard J, Aikins M, Alonso PL, Armstrong Schellenberg JR, Greenwood BM, Mills A. A malaria control trial using insecticide-treated bed nets and targeted chemoprophylaxis in a rural area of The Gambia, west Africa. 8. Cost-effectiveness of bed net impregnation alone or combined with chemoprophylaxis in preventing mortality and morbidity from malaria in Gambian children. Transactions of the Royal Society of Tropical Medicine and Hygiene 1993;87 Suppl 2:53-7.
  • Picard J, Mills A, Greenwood B. The cost-effectiveness of chemoprophylaxis with Maloprim administered by primary health care workers in preventing death from malaria amongst rural Gambian children aged less than five years old. Transactions of the Royal Society of Tropical Medicine and Hygiene 1992;86(6):580-1.
Archibald 1956 {published data only}
  • Archibald HM, Bruce-Chwatt LJ. Suppression of malaria with pyrimethamine in Nigerian schoolchildren. Bulletin of the World Health Organization 1956;15(3-5):775-84.
A-Schellenberg 2010 {published data only}
  • Armstrong Schellenberg JR, Shirima K, Maokola W, Manzi F, Mrisho M, Mushi A, et al. Community effectiveness of intermittent preventive treatment for infants (IPTi) in rural southern Tanzania. American Journal of Tropical Medicine and Hygiene 2009;82(5):772-81.
Barger 2009 {published data only}
Bell 2008 {published data only}
  • Bell DJ, Nyirongo SK, Mukaka M, Zijlstra EE, Plowe CV, Molyneux ME, et al. Sulfadoxine-pyrimethamine-based combinations for malaria: a randomised blinded trial to compare efficacy, safety and selection of resistance in Malawi. PLoS ONE 2008;3(2):e1578.
Bjorkman 1985a {published data only}
  • Bjorkman A, Brohult J, Willcox M, Pehrson PO, Rombo L, Hedman P, et al. Malaria control by chlorproguanil. I. Clinical effects and susceptibility of Plasmodium falciparum in vivo after seven years of monthly chlorproguanil administration to children in a Liberian village. Annals of Tropical Medicine and Parasitology 1985;79(6):597-601.
Bjorkman 1985b {published data only}
  • Bjorkman A, Rombo L, Hetland G, Willcox M, Hanson AP. Susceptibilty of Plasmodium falciparum to chloroquine in northern Liberia after 20 years of chemosuppression and therapy. Annals of Tropical Medicine and Parasitology 1985;79(6):603-6.
Bjorkman 1986 {published data only}
  • Bjorkman A, Brohult J, Pehrson PO, Willcox M, Rombo L, Hedman P, et al. Monthly antimalarial chemotherapy to children in a holoendemic area of Liberia. Annals of Tropical Medicine and Parasitology 1986;80(2):155-167.
Bojang 2010a {published data only}
  • Bojang K, Akor F, Bittaye O, Conway D, Bottomley C, Milligan P, et al. A randomized trial to compare the safety, tolerability and efficacy of three drug combinations for intermittent preventive treatment in children. PLoS One 2010;5(6):e11225.
Bojang 2010b {published data only}
  • Bojang KA, Milligan PJ, Conway DJ, Sisay-Joof F, Jallow M, Nwakanma DC, et al. Prevention of the recurrence of anaemia in Gambian children following discharge from hospital.. PLoS One 2010;5(6)(6):e11227.
Bradley-Moore 1985 {published data only}
  • Bradley-Moore AM, Greenwood BM, Bradley AK, Akintunde A, Attai ED, Fleming AF, et al. A comparison of chloroquine and pyrimethamine as malaria chemoprophylactics in young Nigerian children. Transactions of the Royal Society of Tropical Medicine and Hygiene 1985;79(5):722-7.
  • Bradley-Moore AM, Greenwood BM, Bradley AK, Akintunde A, Attai ED, Fleming AF, et al. Malaria chemoprophylaxis with chloroquine in young Nigerian children. IV. Its effect on haematological measurements. Annals of Tropical Medicine and Parasitology 1985;79(6):585-95.
  • Bradley-Moore AM, Greenwood BM, Bradley AK, Bartlett A, Bidwell DE, Voller A, et al. Malaria chemoprophylaxis with chloroquine in young Nigerian children. I. Its effect on mortality, morbidity and the prevalence of malaria. Annals of Tropical Medicine and Parasitology 1985;79(6):549-62.
  • Bradley-Moore AM, Greenwood BM, Bradley AK, Bartlett A, Bidwell DE, Voller A, et al. Malaria chemoprophylaxis with chloroquine in young Nigerian children. II. Effect on the immune response to vaccination. Annals of Tropical Medicine and Parasitology 1985;79(6):563-73.
  • Bradley-Moore AM, Greenwood BM, Bradley AK, Kirkwood BR, Gilles HM. Malaria chemoprophylaxis with chloroquine in young Nigerian children. III. Its effect on nutrition. Annals of Tropical Medicine and Parasitology 1985;79(6):575-84.
Chandramohan 2005 {published and unpublished data}
  • Chandramohan D, Owusu-Agyei S, Carneiro I, Awine T, Amponsa-Achiano K, Mensah N, et al. Cluster randomised trial of intermittent preventive treatment for malaria in infants in area of high, seasonal transmission in Ghana. BMJ 2005;331(7519):727-33.
Charles 1961 {published data only}
Cisse 2009 {published data only}
Clarke 2008 {published data only}
  • Clarke SE, Jukes MC, Njagi JK, Khasakhala L, Cundill B, Otido J, et al. Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled trial. Lancet 2008;372(9633):127-38.
Colbourne 1955 {published data only}
  • Colbourne MJ. The effect of malaria suppression in a group of Accra school children. Transactions of the Royal Society of Tropical Medicine and Hygiene 1955;49(4):556-69.
Coosemans 1987 {published data only}
  • Coosemans MH, Barutwanayo M, Onori E, Otoul C, Gryseels B, Wery M. Double-blind study to assess the efficacy of chlorproguanil given alone or in combination with chloroquine for malaria chemoprophylaxis in an area with Plasmodium falciparum resistance to chloroquine, pyrimethamine and cycloguanil. Transactions of the Royal Society of Tropical Medicine and Hygiene 1987;81(1):151-6.
Coulibaly 2002 {published data only}
  • Coulibaly D, Diallo DA, Thera MA, Dicko A, Guindo AB, Kone AK, et al. Impact of preseason treatment on incidence of falciparum malaria and parasite density at a site for testing malaria vaccines in Bandiagara, Mali. American Journal of Tropical Medicine and Hygiene 2002;67(6):604-10.
David 1997 {published data only}
  • David KP, Marbiah NT, Lovgren P, Greenwood BM, Petersen E. Hyperpigmented dermal macules in children following the administration of Maloprim for malaria chemoprophylaxis. Transactions of the Royal Society of Tropical Medicine and Hygiene 1997;91(2):204-8.
  • Marbiah NT, Petersen E, David K, Magbity E, Lines J, Bradley DJ. A controlled trial of lambda-cyhalothrin-impregnated bed nets and/or dapsone/pyrimethamine for malaria control in Sierra Leone. American Journal of Tropical Medicine and Hygiene 1998;58(1):1-6.
Delmont 1981 {published data only}
  • Delmont J, Ranque P, Balique H, Tounkara A, Soula G, Quilici M, et al. The influence of malaria chemoprophylaxis on health of a rural community in West Africa [Influence d'une chimiprophylaxie antipaludique sur l'etat de sante d'une communaute rurale en Afrique de l'ouest. Resultats preliminaires]. Bulletin de la Societe de Pathologie Exotique et de ses Filiales 1981;74(6):600-10.
Desai 2003 {published data only}
  • Desai MR, Mei JV, Kariuki SK, Wannemuehler KA, Philips-Howard PA, Nahlen BL, et al. Randomized, controlled trial of daily iron supplementation and intermittent sulfadoxine-pyrimethamine for the treatment of mild childhood anemia in western Kenya. Journal of Infectious Diseases 2003;187(4):658-66.
Dicko 2010 {published data only}
Escudie 1961 {published data only}
  • Escudie A, Hamon J, Ricosse JH, Chartol A. Results of 2 years of antimalarial chemoprophylaxis in the rural African area in the pilot zone of Bobo Dioulasso (Haute Volta) [Resultats de deux annees de chimioprophylaxie antipaludique en milieur rural africain dans la zone pilote de Bobo Dioulasso (Haute Volta)]. Medicine Tropicale 1961;21 Special:689-728.
Fasan 1970 {published data only}
  • Fasan PO. Field trial of cycloguanil pamoate in the treatment and suppression of malaria in Nigerian schoolchildren: a preliminary report. Transactions of the Royal Society of Tropical Medicine and Hygiene 1970;64(6):839-49.
Fasan 1971 {published data only}
  • Fasan PO. Trimethoprim plus sulphamethoxazole compared with chloroquine in the treatment and suppression of malaria in African schoolchildren. Annals of Tropical Medicine and Parasitology 1971;65(1):117-21.
Fernando 2006 {published data only}
  • Fernando D, De Silva D, Carter R, Mendis KN, Wickremasinghe R. A randomized, double-blind, placebo-controlled, clinical trial of the impact of malaria prevention on the educational attainment of school children. American Journal of Tropical Medicine and Hygiene 2006;74(3):386-93.
Gosling 2009 {published data only}
  • Gosling RD, Gesase S, Mosha JF, Carneiro I, Hashim R, Lemnge M, et al. Protective efficacy and safety of three antimalarial regimens for intermittent preventive treatment for malaria in infants: a randomised, double-blind, placebo-controlled trial. Lancet September 17, 2009;374(9700):1521-32.
Greenwood 1988 {published data only}
  • Greenwood BM, Greenwood AM, Bradley AK, Snow RW, Byass P, Hayes RJ, et al. Comparison of two strategies for control of malaria within a primary health care programme in the Gambia. Lancet 1988;1(8595):1121-7.
Greenwood 1989 {published data only}
  • Fuller NJ, Bates CJ, Hayes RJ, Bradley AK, Greenwood AM, Tulloch S, et al. The effects of antimalarials and folate supplements on haematological indices and red cell folate levels in Gambian children. Annals of Tropical Paediatrics 1988;8(2):61-7.
  • Greenwood BM, Greenwood AM, Smith AW, Menon A, Bradley AK, Snow RW, et al. A comparative study of Lapudrine (chlorproguanil) and Maloprim (pyrimethamine and dapsone) as chemoprophylactics against malaria in Gambian children. Transactions of the Royal Society of Tropical Medicine and Hygiene 1989;83(2):182-8.
Greenwood 1995 {published data only}
  • Greenwood BM, David PH, Otoo-Forbes LN, Allen SJ, Alonso PL, Armstrong Schellenberg JR, et al. Mortality and morbidity from malaria after stopping malaria chemoprophylaxis. Transactions of the Royal Society of Tropical Medicine and Hygiene 1995;89(6):629-33.
Grobusch 2007 {published data only}
  • Grobusch MP, Lell B, Schwarz NG, Gabor J, Dornemann J, Potschke M, et al. Intermittent preventive treatment against malaria in infants in Gabon - a randomized, double-blind, placebo-controlled trial. Journal of Infectious Diseases 2007;196(11):1595-602.
Harland 1975 {published data only}
  • Harland PS, Frood JD, Parkin JM. Some effects of partial malaria suppression in Ugandan children during the first three years of life. Transactions of the Royal Society of Tropical Medicine and Hygiene 1975;69(2):261-2.
Hogh 1993 {published data only}
  • Hogh B, Marbiah NT, Petersen E, Dolopaye E, Willcox M, Bjorkman A, et al. Classification of clinical falciparum malaria and its use for the evaluation of chemosuppression in children under six years of age in Liberia, West Africa. Acta Tropica 1993;54(2):105-15.
Hogh 1994 {published data only}
  • Hogh B, Thompson R, Lobo V, Dgedge M, Dziegiel M, Borre M, et al. The influence of Maloprim chemoprophylaxis on cellular and humoral immune responses to Plasmodium falciparum asexual blood stage antigens in schoolchildren living in a malaria endemic area of Mozambique. Acta Tropica 1994;57(4):265-77.
Karunakaran 1980 {published data only}
  • Karunakaran CS. A clinical trial of malaria prophylaxis using a single dose of chloroquine at different intervals in an endemic malarious area. Journal of Tropical Medicine and Hygiene 1980;83(5):195-201.
Karwacki 1990 {published data only}
Kobbe 2007 {published data only}
  • Kobbe R, Kreuzberg C, Adjei S, Thompson B, Langefeld I, Thompson PA, et al. A randomized controlled trial of extended intermittent preventive antimalarial treatment in infants. Journal of Infectious Diseases 2007;45(1):16-25.
  • Marks F, von Kalckreuth V, Kobbe R, Adjei S, Adjei O, Horstmann RD, et al. Parasitological rebound effect and emergence of pyrimethamine resistance in Plasmodium falciparum after single-dose sulfadoxine-pyrimethamine. Journal of Infectious Diseases 2005;192(11):1962-5.
Kollaritsch 1988 {published data only}
  • Kollaritsch H, Stemberger H, Mailer H, Kremsner P, Kollaritsch R, Leimer R, et al. Tolerability of long-term malaria prophylaxis with the combination mefloquine + sulfadoxine + pyrimethamine (Fansimef): results of a double blind field trial versus chloroquine in Nigeria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1988;82(4):524-9.
Kweku 2009 {published data only}
Laing ABG 1970 {published data only}
  • Laing AB. Malaria suppression with fortnightly doses of pyrimethamine with sulfadoxine in the Gambia. Bulletin of the World Health Organization 1970;43(4):513-20.
Lell 1998 {published data only}
Lell 2000 {published data only}
Lemnge 1997 {published data only}
  • Lemnge MM, Msangeni HA, Ronn AM, Salum FM, Jakobsen PH, Mhina JI, et al. Maloprim malaria prophylaxis in children living in a holoendemic village in north-eastern Tanzania. Transactions of the Royal Society of Tropical Medicine and Hygiene 1997;91(1):68-73.
Lewis 1975 {published data only}
  • Lewiw AN, Ponnampalam JT. Suppression of malaria with monthly administration of combined sulphadoxine and pyrimethamine. Annals of Tropical Medicine and Parasitology 1975;69(1):1-12.
Limsomwong 1988 {published data only}
  • Limsomwong N, Pang LW, Singharaj P. Malaria prophylaxis with proguanil in children living in a malaria-endemic area. American Journal of Tropical Medicine and Hygiene 1988;38(2):231-6.
  • Pang LW, Limsomwong N, Singharaj P, Canfield CJ. Malaria prophylaxis with proguanil and sulfisoxazole in children living in a malaria endemic area. Bulletin of the World Health Organisation 1989;67(1):51-58.
Lucas 1969 {published data only}
  • Lucas AO, Hendrickse RG, Okubadejo OA, Richards WH, Neal RA, Kofie BA. The suppression of malarial parasitaemia by pyrimethamine in combination with dapsone or sulphormethoxine. Transactions of the Royal Society of Tropical Medicine and Hygiene 1969;63(2):216-229.
Lwin 1997 {published data only}
  • Lwin M, Lin H, Linn N, Kyaw MP, Ohn M, Maung NS, et al. The use of personal protective measures in control of malaria in a defined community. Southeast Asian Journal of Tropical Medicine and Public Health 1997;28(2):254-8.
MacCormack 1983 {published data only}
  • MacCormack CP, Lwihula G. Failure to participate in a malaria chemosuppression programme: North Mara, Tanzania. Journal of Tropical Medicine and Hygiene 1983;86(3):99-107.
Macete 2006 {published data only}
  • Macete E, Aide P, Aponte JJ, Sanz S, Mandomando I, Espasa M, et al. Intermittent preventive treatment for malaria control administered at the time of routine vaccination in Mozambican infants: a randomised, placebo-controlled trial. Journal of Infectious Diseases 2006;194(3):276-85.
Massaga 2003 {published data only}
  • Massaga JJ, Kitua AY, Lemnge MM, Akida JA, Malle LN, Ronn AM, et al. Effect of intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial. Lancet 2003;361(9372):1853-60.
McGregor 1966 {published data only}
  • McGregor IA, Williams K, Walker GH, Rahman AK. Cycloguanil pamoate in the treatment and suppression of malaria in the Gambia, West Africa. British Medical Journal 1966;5489:695-701.
Menendez 1997 {published data only}
  • Alonzo Gonzalez M, Menendez C, Font F, Kahigwa E, Kimario J, Mshinda H, et al. Cost-effectiveness of iron supplementation and malaria chemoprophylaxis in the prevention of anaemia and malaria among Tanzanian infants. Bulletin of the World Health Organization 2000;78(1):97-107.
  • Beck HP, Felger I, Vounatsou P, Hirt R, Tanner M, Alonso P, et al. Effect of iron supplementation and malaria prophylaxis in infants on Plasmodium falciparum genotypes and multiplicity of infection. Transactions of the Royal Society of Tropical Medicine and Hygiene 1999;93 Suppl 1:41-5.
  • Menendez C, Kahigwa E, Hirt R, Vounatsou P, Aponte JJ, Font F, et al. Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. Lancet 1997;350(9081):844-50.
Menon 1990 {published data only}
  • Menon A, Snow RW, Byass P, Greenwood BM, Hayes RJ, N'Jie AB. Sustained protection against mortality and morbidity from malaria in rural Gambian children by chemoprophylaxis given by village health workers. Transactions of the Royal Society of Tropical Medicine and Hygiene 1990;84(6):768-72.
Miller 1954 {published data only}
  • Miller MJ. A comparison of the antimalarial effects of suppressive doses of chloroquine amodiaquin and pyrimethamine. American Journal of Tropical Medicine and Hygiene 1954;3(3):458-63.
Mockenhaupt 2007 {published data only}
  • Mockenhaupt FP, Reither K, Zanger P, Roepcke F, Danquah I, Saad E, et al. Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana. Antimicrobial agents and chemotherapy 2007;51(9):3273-81.
Murphy 1993 {published data only}
Nahum 2007 {published data only}
  • Nahum A, Erhart A, Gazard D, Agbowai C, Van Overmeir C, van Loen H, et al. Adding artesunate to sulphadoxine-pyrimethamine greatly improves the treatment efficacy in children with uncomplicated falciparum malaria on the coast of Benin, West Africa. Malaria Journal 2007;6:170. [DOI: 10.1186/1475-2875-6-170]
Nakibuuka 2009 {published data only}
  • Nakibuuka V, Ndeezi G, Nakiboneka D, Ndugwa CM, Tumwine JK. Presumptive treatment with sulphadoxine-pyrimethamine versus weekly chloroquine for malaria prophylaxis in children with sickle cell anaemia in Uganda: a randomized controlled trial. Malaria Journal 2009;8:237. [DOI: 10.1186/1475-2875-8-237]
Nevill 1988 {published data only}
Nevill 1994 {published data only}
  • Nevill CG, Lury JD, Mosobo MK, Watkins HM, Watkins WM. Daily chlorproguanil is an effective alternative to daily proguanil in the prevention of Plasmodium falciparum malaria in Kenya. Transactions of the Royal Society of Tropical Medicine and Hygiene 1994;88(3):319-20.
Nsimba 2008 {published data only}
  • Nsimba B, Guiyedi V, Mabika-Mamfoumbi M, Mourou-Mbina JR, Ngoungou E, Bouyou-Akotet M, et al. Sulphadoxine/pyrimethamine versus amodiaquine for treating uncomplicated childhood malaria in Gabon: a randomized trial to guide national policy. Malaria Journal 2008:31.
Nwokolo 2001 {published data only}
  • Nwokolo C, Wambebe C, Akinyanju O, Raji AA, Audu BS, Emordi IJ, et al. Mefloquine versus proguanil in short-term malaria chemoprophylaxis in sickle cell anaemia. Clinical Drug Investigation 2001;21(8):537-44.
Odhiambo 2010 {published data only}
  • Odhiambo FO, Hamel MJ, Williamson J, Lindblade K, ter Kuile FO, Peterson E, et al. Intermittent preventive treatment in infants for the prevention of malaria in rural Western Kenya: a randomized, double-blind placebo-controlled trial. PLoS ONE 2010;5(4):e10016.
Onori 1982 {published data only}
  • Onori E, Grab B, Ambroise-Thomas P, Thelu J. Incipient resistance of Plasmodium falciparum to chloroquine among a semi-immune population of the United Republic of Tanzania. 2. The impact of chloroquine used as a chemosuppressant on the immune status of the population. Bulletin of the World Health Organization 1982;60(6):899-906.
Otoo 1988a {published data only}
  • Otoo LN, Riley EM, Menon A, Byass P, Greenwood BM. Cellular immune responses to Plasmodium falciparum antigens in children receiving long term anti-malarial chemoprophylaxis. Transactions of the Royal Society of Tropical Medicine and Hygiene 1989;83(6):778-782.
  • Otoo LN, Snow RW, Menon A, Byass P, Greenwood BM. Immunity to malaria in young Gambian children after a two-year period of chemoprophylaxis. Transactions of the Royal Society of Tropical Medicine and Hygiene 1988;82(1):59-65.
Oyediran 1993 {published data only}
  • Oyediran AB, Topley E, Osunkoya BO, Bamgboye A, Williams AI, Ogunba EO, et al. Severe morbidity among children in a trial malaria chemoprophylaxis with pyrimethamine or chloroquine in Ibarapa, Nigeria. African Journal of Medicine and Medical Sciences 1993;22(1):55-63.
Pang 1989 {published data only}
  • Pang LW, Limsomwong N, Singharaj P, Canfield CJ. Malaria prophylaxis with proguanil and sulfisoxazole in children living in a malaria endemic area. Bulletin of the World Health Organization 1989;67(1):51-8.
Panton 1985 {published data only}
  • Panton LJ, Tulloch S, Bradley AK, Greenwood BM. Susceptibility of Plasmodium falciparum in the Gambia to pyrimethamine, Maloprim and chloroquine. Transactions of the Royal Society of Tropical Medicine and Hygiene 1985;79(4):484-90.
Pividal 1992 {published data only}
  • Pividal J, Viktinski V, Streat E, Schapira A. Efficacy of dapsone with pyrimethamine (Maloprim) for malaria prophylaxis in Maputo, Mozambique. East African Medical Journal 1992;69(6):303-5.
Pribadi 1986 {published data only}
  • Pribadi W, Muzaham F, Santoso T, Rasidi R, Rukmono B, Soeharto. The implementation of community participation in the control of malaria in rural Tanjung Pinang, Indonesia. Southeast Asian Journal of Tropical Medicine and Public Health 1986;17(3):371-8.
Pringle 1966 {published data only}
  • Pringle G, Avery-Jones S. Observations on the early course of untreated falciparum malaria in semi-immune African children following a short period of protection. Bulletin of the World Health Organization 1966;34(2):269-72.
Ringwald 1989 {published data only}
  • Ringwald P, Le Bras J, Havermann K, Flachs H. A study of the efficacy of the chemoprevention of malaria using chlorproguanil alone or in combination with chloroquine in French expatriates in Dar-es-Salaam, Tanzania [Etude de l'efficacite d'une chimioprophylaxie du paludisme par le chlorproguanil associe ou non a la chloroquine chez des expatries francais a Dar-es-Salaam, Tanzanie]. Bulletin de la Societe de Pathologie Exotique et de ses Filiales 1989;82(1):124-9.
Robert 1989 {published data only}
  • Robert V, Hervy JP, Baudon D, Roux J, Legros F, Carnevale P. The effect of 2 chloroquine-based drug strategies (prevention and therapy of febrile cases] on malaria transmission [Influence de deux strategies medicamenteuses par chloroquine (prophylaxie et therape des acces febriles) sur la transmission du paludisme]. Bulletin de la Societe de Pathologie Exotique et de ses Filiales 1989;82(2):243-7.
Rohner 2010 {published data only}
  • Rohner F, Zimmermann MB, Amon RJ, Vounatsou P, Tschannen AB, N'Goran EK, et al. In a randomized controlled trial of iron fortification, anthelmintic treatment, and intermittent preventive treatment of malaria for anemia control in Ivorian children, only anthelmintic treatment shows modest benefit. Journal of Nutrition 2010;140(3):635-41.
Rooth 1991 {published data only}
  • Rooth I, Sinani HM, Bjorkman A. Proguanil daily or chlorproguanil twice weekly are efficacious against falciparum malaria in a holoendemic area of Tanzania. Journal of Tropical Medicine and Hygiene 1991;94(1):45-9.
Rosen 2005 {published data only}
  • Rosen JB, Breman JG, Manclark CR, Meade BD, Collins WE, Lobel HO, et al. Malaria chemoprophylaxis and the serologic response to measles and diphtheria-tetanus-whole-cell pertussis vaccines. Malaria Journal 2005;4:53.
Saarinen 1988 {published data only}
  • Saarinen M, Thoren E, Iyambo N, Caristedt A, Shinyafa L, Fernanda M, et al. Malaria prophylaxis with proguanil to Namibian refugee children in Angola. Tropical Medicine and Parasitology 1988;39(1):40-2.
Schapira 1988 {published data only}
  • Schapira A, Da Costa F. Studies on malaria prophylaxis with chlorproguanil or chloroquine in Mozambique. Central African Medical Journal of Medicine 1988;34(3):44-9.
Schellenberg 2001 {published data only}
  • Schellenberg D, Menendez C, Kahigwa E, Aponte J, Vidal J, Tanner M, et al. Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial. Lancet 2001;357(9267):1471-7.
Schellenberg 2004 {published data only}
  • Schellenberg D, Kahigwa E, Sanz S, Aponte JJ, Mshinda H, Alonso P, et al. A randomized comparison of two anemia treatment regimens in Tanzanian children. American Journal of Tropical Medicine and Hygiene 2004;71(4):428-33.
Schellenberg 2005 {published data only}
  • Aponte J, Schellenberg D, Menendez C, Kahigwa E, Tanner M, Mshinda H, et al. Extended follow-up of intermittent preventive anti-malarial treatment in Tanzanian infants. 4th MIM Malaria Conference; Yaounde, Cameroon. 2005.
  • Schellenberg D, Menendez C, Aponte JJ, Kahigwa E, Tanner M, Mshinda H, et al. Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial. Lancet 2005;365(9469):1481-3.
Schneider 1962 {published data only}
  • Schneider J, Escudie A, Ouedraogo A, Sales P. Chemioprophylaxis of malaria by weekly distributions of chloroquine or a chloroquine-primaquine-pyrimethamine combination [Chimioprophylaxie du paludisme par distributions herbomadaires de chloroquine ou d'une association chloroquine-primaquine-pyrimethamine]. Bulletin de la Societe de Pathologie Exotique et des ses Filiales 1962;55:280-90.
Sokhna 2008 {published data only}
  • Sokhna C, Cisse B, Ba el H, Milligan P, Hallett R, Sutherland C, et al. A trial of the efficacy, safety and impact on drug resistance of four drug regimens for seasonal intermittent preventive treatment for malaria in Senegalese children. PLoS ONE 2008;3(1):e1471.
Stace 1981 {published data only}
  • Stace JD, Pariwa S. Reduction in malaria parasite rate in young children by distribution of prophylactic amodiaquine through voluntary village workers. Papua New Guinea Medical Journal 1981;24(4):254-60.
Sukwa 1999 {published data only}
  • Sukwa TY, Mulenga M, Chisdaka N, Roskell NS, Scott TR. A randomized, double-blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. American Journal of Tropical Medicine and Hygiene 1999;60(4):521-5.
Thera 2005 {published data only}
  • Thera MA, Sehdev PS, Coulibaly D, Traore K, Garba MN, Cissoko Y, et al. Impact of trimethoprim-sulfamethoxazole prophylaxis on falciparum malaria infection and disease. Journal of Infectious Diseases 2005;192(10):1823-9.
Verhoef 2002 {published data only}
  • Verhoef H, West CE, Nzyuko SM, de Vogel S, van der Valk R, Wanga MA, et al. Intermittent administration of iron and sulfadoxine-pyrimethamine to control anaemia in Kenyan children: a randomised controlled trial. Lancet 2002;360(9337):908-14.
von Seidlein 2003 {published data only}
  • von Seidlein L, Walraven G, Milligan PJ, Alexander N, Manneh F, Deen JL, et al. The effect of mass administration of sulfadoxine-pyrimethamine combined with artesunate on malaria incidence: a double-blind, community-randomized, placebo-controlled trial in The Gambia. Transactions of the Royal Society of Tropical Medicine and Hygiene 2003;97(2):217-25.
Vrbova 1992 {published data only}
  • Vrbova H, Gibney S, Gibson FD, Jolley D, Heywood PF, Stace J, et al. Chemoprophylaxis against malaria in Papua New Guinea: trial of amodiaquine and a combination of dapsone and pyrimethamine. Papua New Guinea Medical Journal 1992;35(4):275-84.
Watkins 1987 {published data only}
  • Watkins WM, Brandling-Bennet AD, Oloo AJ, Howells RE, Gilles HM, Koech DK. Inadequacy of chlorproguanil 20 mg per week as chemoprophylaxis for falciparum malaria in Kenya. Lancet 1987;1(8525):125-8.
Weiss 1995 {published data only}
  • Weiss WR, Oloo AJ, Johnson A, Koech D, Hoffman SL. Daily primaquine is effective for prophylaxis against falciparum malaria in Kenya: comparison with mefloquine doxycycline and chloroquine plus proguanil. Journal of Infectious Diseases 1995;171(6):1569-75.
Win 1985 {published data only}
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Wolde 1994 {published data only}
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Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Alexander 2007
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Aponte 2009
  • Aponte JJ, Schellenberg D, Egan A, Breckenridge A, Carneiro L, Critchley J, et al. Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials. Lancet 2009;374:1533-42.
Branch 1998
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Garner 2006
Gilles 2000
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Greenwood 2006
Greenwood 2010
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Lengeler 2004
Otoo 1988b
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References to other published versions of this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Meremikwu 2002
  • Meremikwu M, Omari AAA. Antimalarial drugs given at regular intervals for preventing clinical malaria and severe anaemia in preschool children. Cochrane Database of Systematic Reviews 2002, Issue 3. [DOI: 10.1002/14651858.CD003756]
Meremikwu 2005
Meremikwu 2008