Chemoprophylaxis and intermittent treatment for preventing malaria in children

  • Review
  • Intervention

Authors

  • MM Meremikwu,

  • AAA Omari,

  • P Garner


Dr Martin Meremikwu, Reader, Department of Paediatrics, University of Calabar, Calabar, Cross River State, PMB 1115, NIGERIA. mmeremiku@yahoo.co.uk.

Abstract

Background

Malaria causes repeated illness in children living in endemic areas. Policies of giving antimalarial drugs at regular intervals (prophylaxis or intermittent treatment) are being considered for preschool children.

Objectives

To evaluate chemoprophylaxis and intermittent treatment with antimalarial drugs to prevent malaria in young children living in malaria endemic areas.

Search strategy

We searched the Cochrane Infectious Diseases Group Specialized Register (April 2005), CENTRAL (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to April 2005), EMBASE (1974 to April 2005), LILACS (1982 to April 2005), and reference lists of identified trials. We also contacted researchers.

Selection criteria

Randomized and quasi-randomized controlled trials comparing antimalarial drugs given at regular intervals (prophylaxis or intermittent treatment) with placebo or no drug in children aged one month to six years or less living in an area where malaria is endemic.

Data collection and analysis

We independently extracted data and assessed methodological quality. We used relative risk (RR) or weighted mean difference with 95% confidence intervals (CI) for meta-analyses. Where we detected heterogeneity and considered it appropriate to combine the trials, we used the random-effects model (REM).

Main results

Nineteen trials (14,393 participants) met the inclusion criteria. Children receiving antimalarial drugs as prophylaxis or intermittent treatment had fewer clinical malaria episodes (RR 0.52, 95% CI 0.35 to 0.77, REM; 4051 participants, 8 trials), and severe anaemia was less common (RR 0.54, 95% CI 0.42 to 0.68; 2727 participants, 8 trials). We did not detect a difference in the number of deaths from any cause (RR 0.82, 95% CI 0.65 to 1.04; 7929 participants, 9 trials), but the confidence intervals do not exclude a potentially important difference. None of the trials reported serious adverse events. Three trials measured morbidity and mortality six months to two years after stopping regular antimalarial drugs; overall, there was no statistically significant difference, but participant numbers were small.

Authors' conclusions

Prophylaxis and intermittent treatment with antimalarial drugs reduce clinical malaria and severe anaemia in preschool children. There is insufficient evidence to detect an effect on mortality.

Plain language summary

Plain language summary

Preschool children taking antimalarial drugs regularly are less likely to get malaria or severe anaemia, but more trials are needed show whether survival is improved

Most children in areas where malaria is endemic are semi-immune against serious malaria by the age of seven, but for children under five the disease can be serious, and a million worldwide die each year from malaria. The review of trials found that children taking regular antimalarial prophylaxis or intermittent treatment were less likely to get malaria, severe anaemia, or be admitted to hospital, but there was no change in the overall death rate. The benefits are similar in intermittent treatment of infants and prolonged prophylaxis, but long-term deleterious effects, including the possibility that it may interfere with the development of children's immunity to malaria, are unknown for either regimen. Further trials with long-term follow up are needed.

Background

Malaria
Malaria, common in the tropics and subtropics, is caused by Plasmodium parasites transmitted to humans by the bite of infected female anopheline mosquitoes. People who live in or visit areas where malaria commonly occurs (endemic areas) are at risk of becoming infected. Infected people may show no sign of illness (asymptomatic) or may develop fever, chills, malaise, and headache (symptomatic malaria). The severity of infection varies from mild (uncomplicated) to life threatening (severe). Among the four human species of malaria parasites, Plasmodium falciparum is the main species that causes 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 lack or have low immunity to malaria (Gilles 2000). Children living in areas where malaria is endemic will have acquired natural immunity to malaria by the time they are seven to 10 years old (Branch 1998; Warrell 2001). Preschool children living in malarious areas have inadequate immunity to malaria, and this explains why most of the one million malaria deaths that occur each year in endemic areas of sub-Saharan Africa occur in this age group (Snow 1999).

Prevention using drugs
Malaria control aims to reduce illness and death from malaria. Prompt diagnosis and treatment is not always possible where services are limited. Experts advise the use of prophylaxis in malarial areas for people without immunity and pregnant women (Chulay 1998; Shanks 1995), and this is supported by findings from systematic reviews (Croft 2000; Garner 2002). However, the position with school children is less clear, and currently the World Health Organization (WHO) does not recommend drug prophylaxis for this group (Goodman 1999).

Malaria prophylaxis refers to daily or weekly doses of antimalarial drugs at a dose that is usually smaller than the therapeutic doses of antimalarial drugs (Croft 2000). Intermittent treatment refers to full therapeutic doses of an antimalarial at specified time points to cure malaria; usually sulfadoxine-pyrimethamine is used as it requires a single dose and has a long half life. The theory is that intermittent treatment has fewer adverse events than prophylaxis because it is taken less often, and it is easier to deliver through clinics, reducing poor adherence with self administration. Some people believe that intermittent presumptive treatment is of benefit through some mechanism that is qualitatively different to prophylaxis, and others suggest it is basically the same mechanism (White 2005). We have included both types of intervention in this trial, and explore whether the different types of administration explain differences in effects between trials. Even so, any such effect will be difficult to attribute to whether the administration is prophylaxis or intermittent treatment, as these two interventions are confounded by the drug used, the year of the trial, and thus the prevailing drug-resistance pattern.

Some scientists are concerned that prophylaxis and intermittent treatment 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). Research has shown that young African children who received malaria prophylaxis for a long time had lower levels of malaria antibodies than their counterparts, but there is no evidence that this increased the risk of dying from malaria later in life (Otoo 1988b). In addition, scientists are concerned 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); however, the design of a randomized controlled trial will not detect this. Drug resistance to sulfadoxine-pyrimethamine is already widespread, and it is unclear how policies of providing this drug for prophylaxis or intermittent treatment will impact on this trend or how the spread of resistance will affect its use for this purpose.

Although the questions over safety, sustainability, and public health impact of this intervention remain, the potential gains are large in terms of a possible effect on malaria episodes, anaemia, and mortality (Menon 1990; Schellenberg 2001). The uncertainties about the potential benefits and harms of giving malaria prophylaxis or intermittent treatment routinely to all young children living in endemic areas make it necessary to review available evidence on this intervention strategy.

Objectives

To evaluate chemoprophylaxis and intermittent treatment with antimalarial drugs to prevent malaria in young children living in malaria endemic areas.

Criteria for considering studies for this review

Types of studies

Randomized controlled trials; quasi-randomized controlled trials.

Types of participants

Children aged one month to six years or less living in an area where malaria is endemic.

Types of intervention

Intervention
Antimalarial drugs given at regular intervals irrespective of dose. This includes a suppressive low dose (prophylaxis) and a full treatment course (intermittent treatment).

Control
Placebo or no drug.

Types of outcome measures

Primary
Clinical malaria.
Severe anaemia (as defined by the trial authors).

Secondary
Death from any cause.
Hospital admission for any cause.
Blood transfusion.
Parasitaemia.
Enlarged spleen.
Need for second-line antimalarial drug.
Mean haemoglobin (or haematocrit).

Adverse events
Any adverse event.
Serious adverse events (defined as life threatening, or requiring the drug be discontinued).

Search methods for identification of studies

See: Unavailable methods used in reviews.

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 Table 01.

  • Cochrane Infectious Diseases Group Specialized Register (April 2005).

  • Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (Issue 1, 2005).

  • MEDLINE (1966 to April 2005).

  • EMBASE (1974 to April 2005).

  • LILACS (1982 to April 2005).

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.

Methods of the review

Trial selection
We independently screened the results of the literature search for potentially relevant trials and then obtained the full reprints of all these trials. We independently assessed their eligibility using a form based on the inclusion criteria. We resolved disagreements through discussion, and when necessary, by consulting a member of the Cochrane Infectious Diseases Group editorial team.

Assessment of the methodological quality
We independently assessed the methodological quality of each trial. We assessed generation of allocation sequence and allocation concealment as adequate, unclear, or inadequate according to Juni 2001. We considered the trials to be double blind (neither the participant or care provider/assessor know which treatment is given), single blind (the participant or care provider/assessor know which treatment is given), or open (all parties are aware of treatment). We assessed the inclusion of all randomized participants in the analysis to be adequate if at least 90% of the randomized participants were included and kept in their original groups for the analysis of the primary outcomes.

Data extraction
We independently extracted data from the included trials using a data extraction form. We resolved disagreements through discussion, and when necessary, by consulting a member of the Cochrane Infectious Diseases Group editorial team.

Data analysis
We used Review Manager 4.2 for data analysis. We computed relative risks (RR) for dichotomous data, and calculated weighted mean differences (WMD) for normally distributed continuous data, and presented both with 95% confidence intervals (CI). We performed an intention-to-treat analysis where the trial authors accounted for all randomized participants; otherwise we performed complete-case analysis.

We grouped trials into those of prophylaxis and those of intermittent treatment. We looked for heterogeneity by visually examining the forest plots and by using the chi-squared test for heterogeneity with a 10% level of statistical significance. Where we detected heterogeneity, and considered it appropriate to combine the trials, we used a random-effects model (REM) instead of the fixed-effect model. We considered exploring heterogeneity by type of antimalarial drug and malaria transmission pattern (perennial or seasonal). For severe anaemia, we stratified trials by whether the children enrolled were from the general population or were selected because they were anaemic. We intended to explore the effects of participant age when the participants started taking the antimalarial drugs, but the trial data did not allow this.

We performed sensitivity analyses using only adequately controlled trials for the clinical malaria, severe anaemia, and death outcomes. Some trials used households as the unit of randomization and did not present results adjusted for the effect of clustering. As we believe the design effect to be small (assuming that most households would only have a single child meeting the age criteria and therefore included in the trial), we have included them in the meta-analysis and highlighted the affected trials in the 'Characteristics of included studies'. As this could cause the confidence intervals around the effect estimate to be more precise than they actually are, we excluded them in a sensitivity analysis.

We used Review Manager 4.2 to examine funnel plots for asymmetry, which may be caused by factors such as publication bias, heterogeneity, and poor methodological quality. We did not observe a definite pattern (symmetry or asymmetry) because there were too few included trials for each comparison.

Description of studies

Of 70 potentially relevant articles, 19 trials met the inclusion criteria (see 'Characteristics of included studies'). Six trials were reported across eighteen publications: Alonso 1993 (four reports), David 1997 (two reports), Bradley-Moore 1985 (five reports), Greenwood 1989 (two reports), Menendez 1997 (three reports), and Otoo 1988a (two reports). We excluded five randomized controlled trials because their study population included children aged above six years (see 'Characteristics of excluded studies'). We also located eight ongoing studies (see 'Characteristics of ongoing studies').

Location
All 19 trials (14,393 participants) were conducted in Africa: Sierra Leone (one), Ethiopia (one), Liberia (one), Kenya (two), Nigeria (two), Tanzania (six), and The Gambia (six). The trials from The Gambia were conducted in the same population at different time points: Greenwood 1988 reported results from children in 15 villages between nine and 21 months of the trial; Greenwood 1989 was a subsidiary investigation comparing an additional antimalarial; Menon 1990 was conducted three to four years after the start of the prophylaxis and reported on the same villages; and Greenwood 1995 was conducted one year after the end of prophylaxis. Otoo 1988a was conducted six months after stopping prophylaxis and involved a cohort of five year olds who had at least 50% compliance with prophylaxis. Schellenberg 2005 was an extended follow-up study using the same study population as Schellenberg 2001 assessed 18 months after stopping treatment.

Malaria endemicity
The pattern of malaria transmission was perennial in trials from Nigeria, Sierra Leone, Liberia, Tanzania, and one Kenyan trial (Desai 2003), and seasonal in The Gambia, Ethiopia, and the second Kenyan trial (Verhoef 2002). Seven trials also reported that the areas were holoendemic for malaria.

Trial design
Eleven of the trials randomized individuals, five randomized household units (cluster randomized: families living within a compound usually surrounded by a wall), and two used alternate allocation of individual participants (quasi-randomized). The length of follow up varied from 10 weeks to six years, with one year being the most common duration.

Interventions
Also summarized in Table 02.

Prophylaxis (13 trials)
These earlier trials were conducted between 1985 and 1997, and used chloroquine, pyrimethamine, or pyrimethamine-dapsone.

Intermittent treatment (6 trials)
Two trials comprehensively used intermittent antimalarial treatment for the primary prevention of anaemia and malaria in healthy young infants (Massaga 2003; Schellenberg 2001), and three trials selectively gave intermittent antimalarial treatment to children who were already anaemic (Desai 2003; Tomashek 2001; Verhoef 2002). One trial, Schellenberg 2005, was an extended follow-up study of another trial, Schellenberg 2001, and assessed outcomes up to 18 months after stopping treatment.

Four trials used standard treatment doses of sulfadoxine-pyrimethamine: Schellenberg 2001 administered medication to infants attending immunization services at the ages of two, three, and nine months old; and Desai 2003, Tomashek 2001, and Verhoef 2002 administered medication every four weeks for a total of three doses. Massaga 2003 administered a treatment course of amodiaquine (25 mg/kg over three days) within intervals of 60 days over six months.

Co-interventions
Six trials gave iron supplements all participants (Desai 2003; Massaga 2003; Menendez 1997; Schellenberg 2001; Tomashek 2001; Verhoef 2002), two trials gave folic acid (Greenwood 1989; Tomashek 2001), and two trials also used insecticide-treated nets (Alonso 1993; Desai 2003). David 1997 used insecticide-treated nets, but we did not include the affected groups in the review.

Outcomes
Fifteen trials reported on the number of children developing malaria; eight reported on total episodes. Eight trials reported on severe anaemia, which had several definitions of packed cell volume (PCV) less than 25% (three trials), less than 20% (one trial), or haemoglobin less than 7 g/dL (one trial). One trial classified haemoglobin concentration of 5.0 to 8.0 g/dL (equivalent to packed cell volume 15% to 24%) as moderate anaemia, but, for the meta-analysis, we classified this as severe anaemia to be consistent with the range for other trials. Two trials did not specify the definition of severe anaemia. Other relevant outcomes reported were death (10 trials), hospital admission (three trials), parasitaemia (six trials), enlarged spleen (four trials), and adverse events (six trials). David 1997 reported only adverse events.

Methodological quality

SeeTable 03for a summary of the quality assessment.

Generation of allocation sequence
Seven trials used adequate methods to generate the allocation sequence: three used block randomization, and four used a computer. Two trials used an inadequate method (alternate allocation). The remaining 10 trials did not describe the method used; five of these randomized clusters of family unit.

Allocation concealment
Allocation concealment was adequate in the seven trials that used identical and centrally coded drugs and placebo, or sealed, opaque envelopes, and was unclear in the rest.

Blinding
Fourteen trials used double blinding. Blinding was unclear in the remaining five trials.

Inclusion of all randomized participants in the analysis
Six trials included more than 90% of randomized participants in the analysis (defined in the review methods as adequate), four had greater than 10% attrition or accounted for less than 90% of randomized participants in data analysis (inadequate), while the rest were unclear. Two trials reported an intention-to-treat analysis: Verhoef 2002 used it for the clinical malaria episodes outcome and Massaga 2003 used it for all outcomes.

Results

Part one examines the effects on children during antimalarial prophylaxis or intermittent treatment; and part two explores the effects after the drugs were stopped, seeking longer term effects on immunity.

(1) During intervention

Clinical malaria
Eight trials (4051 participants) contributed to the meta-analysis of the number of children developing a clinical malaria episode. Although the effect size varied markedly, the direction of effect consistently favoured the antimalarials within the four prophylaxis trials (RR 0.57, 95% CI 0.33 to 1.00, REM; 2806 participants) and four intermittent treatment trials (RR 0.48, 95% CI 0.33 to 0.71, REM; 1245 participants). Overall, antimalarial drugs were statistically significantly better than placebo at preventing clinical malaria (RR 0.52, 95% CI 0.35 to 0.77, REM; 4051 participants, see comparison 01-01).

Heterogeneity persisted when we analysed the trials according to type of antimalarial drug (see comparison 02-01) and seasonality (see comparison 03-01). We also stratified trials by whether the children enrolled were from the general population or were selected because they were anaemic (see comparison 04-01). In the two trials that enrolled healthy infants, severe anaemia was less frequent in the intervention group (RR 0.37, 95% CI 0.25 to 0.55; 846 participants). It was also less frequent in the intervention group in the trials that enrolled only anaemic children (RR 0.69, 95% CI 0.48 to 0.98; 399 participants).

A sensitivity analysis of trials with adequate allocation concealment did not affect the result (see comparison 05-01).

We did not include five trials in the meta-analysis because they reported only event counts of malaria episodes and not the number of children developing one or more clinical malaria episodes. Greenwood 1988 reported 32 episodes of clinical malaria in 1515 observations among children treated with pyrimethamine-dapsone and 36 episodes in 1704 observations in the placebo group. Greenwood 1989 conducted a monthly morbidity report and physical examination on all children enrolled, and reported a lower prevalence in observations of fever and parasitaemia in children with pyrimethamine-dapsone (3/1204 examinations) compared with chlorproguanil (12/1425 examinations) or placebo (17/1299). Menon 1990 reported 34 and 38 clinical episodes of malaria in the treated group (2139 observations) and control group (1883 observations) respectively, and Lemnge 1997 reported a lower rate of clinical malaria episodes in participants in the pyrimethamine-dapsone group (87/2914) than in the control group (144/2938). Hogh 1993 did not provide the number of participants with the outcome but did report that chloroquine prophylaxis was protective for episodes of "possible clinical malaria" (odds ratio 0.49, 95% CI 0.35 to 0.69; trialists' calculation).

Severe anaemia
Eight trials (2727 participants) measured severe anaemia with a clear effect favouring the intervention (RR 0.54, 95% CI 0.42 to 0.68; see comparison 01-02). The point estimate was similar for the four prophylaxis trials (RR 0.51, 95% 0.37 to 0.69; 1509 participants) and four intermittent treatment trials (RR 0.58, 95% CI 0.40 to 0.84; 1218 participants). When we excluded the three trials without adequate allocation concealment, the estimate of effect remained similar (RR 0.50, 95% CI 0.39 to 0.64; 1470 participants, 4 trials, see comparison 05-02); excluding the one cluster-randomized trial made no substantive difference (RR 0.55, 95% CI 0.43 to 0.70; 2486 participants, see comparison 06-01).

Although the analysis showed no statistically significant heterogeneity, we explored the possible influence of explanatory variables on the effect size. The analysis grouped by drug type was quite mixed, with no apparent pattern (see comparison 02-02); grouping by seasonality was uninformative as only one trial was carried out in a seasonal area (see comparison 03-02).

We stratified trials by whether the children enrolled were from the general population or were selected because they were anaemic (see comparison 04-02). In the two trials that enrolled healthy infants, severe anaemia was less frequent in the intervention group (RR 0.42, 95% CI 0.27 to 0.67; 846 participants), but this was not so in the trials that enrolled only anaemic children (RR 1.31, 95% CI 0.63 to 2.72; 372 participants).

Death from any cause
We detected no statistically significant difference in all nine trials (7929 participants) reporting on this outcome (RR 0.82, 95% CI 0.65 to 1.04; see comparison 01-03); the point estimate was in the direction of a protective effect.

Sensitivity analyses did not alter these findings. The point estimate was not statistically significant when we analysed only adequately concealed trials (one prophylaxis trial and three intermittent treatment trials) (see comparison 05-03) or when we excluded the three cluster-randomized trials (see comparison 06-02).

One intermittent treatment trial, Tomashek 2001, reported six deaths among the trial participants but did not specify their intervention group. We wrote and obtained additional data from the trial authors to clarify this, and included these data in meta-analysis.

Hospital admission for any cause
Overall, the number of hospital admissions was lower in children in the antimalarial groups in the three trials (1149 participants) that reported this outcome (RR 0.60, 95% CI 0.52 to 0.68; see comparison 01-04). In the one trial using prophylaxis, Menendez 1997, the number of hospital admissions was dramatically lower in the prophylaxis group (48/100) compared with the placebo group (199/203) (RR 0.49, 95% CI 0.40 to 0.60). The two trials that used intermittent treatment showed the frequency of hospital admissions during treatment to be statistically significantly lower in the intermittent treatment group (136/423) compared with the placebo group (205/423) (RR 0.66, 95% CI 0.56 to 0.79).

Parasitaemia
Six of the seven available trials contributed to the meta-analysis, which showed fewer children with parasitaemia in the antimalarial group (97/885) compared with the placebo group (295/900) (RR 0.37, 95% CI 0.17 to 0.79, REM; see comparison 01-05). Within the prophylaxis and intermittent treatment groups, the effect was statistically significant for the four prophylaxis trials (RR 0.24, 95% CI 0.13 to 0.45; 1426 participants), but not the two intermittent treatment trials (RR 0.85, 0.64 to 1.13; 359 participants). A subgroup analysis of four trials, excluding the cluster-randomized trials, showed no significant difference in parasitaemia rates between the antimalarial and placebo groups (RR 0.46, 95% CI 0.17 to 1.26; 1194 participants; see comparison 06-03). The seventh trial, Bradley-Moore 1985, reported parasitaemia as the proportion of positive blood slides: 103/730 for chloroquine (198 participants), 3/119 for weekly pyrimethamine (30 participants), and 15/153 for monthly pyrimethamine (36 participants) compared with 396/660 for the placebo group (185 participants) (P < 0.05, trialists' calculation). Hogh 1993 presented parasitaemia data in graph, but we could not extract these for a meta-analysis.

Enlarged spleen
Four trials (1589 participants), all using prophylaxis, reported on this outcome. Fewer children had enlarged spleens in the prophylaxis group compared with the placebo group (RR 0.28, 95% CI 0.14 to 0.56, REM; see comparison 01-06). Hogh 1993 presented haematocrit data in graphs but were not suitable for meta-analysis.

Mean haematocrit
Three prophylaxis trials found the mean haematocrit to be statistically significantly higher in the prophylaxis group (377 participants) than the placebo group (417 participants) (WMD 2.12, 95% CI 1.47 to 2.77; see comparison 01-07). One trial using intermittent treatment, Tomashek 2001, found no difference between the mean haemoglobin concentration of the antimalarial group (10.2 g/dL, 95% CI 9.9 to 10.5 g/dL) and the control group (10.2 g/dL, 95% CI 10.0 to 10.4 g/dL); (trialists' calculation). Hogh 1993 presented haematocrit data in graphs but were not suitable for meta-analysis. Lemnge 1997 reported significantly higher mean haematocrit levels for the antimalarial group than the placebo group but provided insufficient data for meta-analysis.

Adverse events
Only six trials reported adverse events, and none reported serious adverse events. We included data from two trials in a meta-analysis (see comparison 01-08): David 1997 reported hyperpigmented macules only in the pyrimethamine-dapsone group; and Menendez 1997 reported that adverse events were mild with no statistically significant difference in the incidence of vomiting between the pyrimethamine-dapsone group (3/208) and the placebo group (1/207).

Table 04 shows details of reported adverse events that could not be included in meta-analyses (Greenwood 1988; Greenwood 1989; Lemnge 1997; Massaga 2003). Massaga 2003, which used amodiaquine for intermittent treatment, reported no serious adverse events such as agranulocytosis (Massaga 2003), and Desai 2003, which used sulfadoxine-pyrimethamine, reported no severe cutaneous reactions (Desai 2003).

(2) Impact after stopping intervention
Two trials evaluated the participants after pyrimethamine-dapsone prophylaxis had been stopped for one year (Greenwood 1995) and for six months (Otoo 1988a). One other trial evaluated participants eighteen months after stopping intermittent treatment with sulfadoxine-pyrimethamine (Schellenberg 2005).

Clinical malaria
Otoo 1988a reported no statistically significant difference in the number of clinical malaria episodes in the prophylaxis group (4/48) compared with the placebo group (5/47), but Schellenberg 2005 reported statistically significantly fewer episodes of clinical malaria in the intervention group than the placebo group 18 months after stopping treatment with sulfadoxine-pyrimethamine (RR 0.70, 95% CI 0.54 to 0.92; 555 participants; see comparison 07-01). Greenwood 1995 reported this as the number of observations; children that received pyrimethamine-dapsone had fewer episodes than those on placebo (P < 0.01, trialists' calculation).

Severe anaemia
Schellenberg 2005 reported no statistically significant difference in the incidence of severe anaemia between the intervention group (30/277) and the placebo group (27/278) 18 months after stopping treatment with sulfadoxine-pyrimethamine (RR 1.12, 95% CI 0.68 to 1.82; see comparison 07-02).

Death from any cause
Greenwood 1995 reported that the risk of dying within two years after stopping prophylaxis was similar in both groups (4/203 versus 5/200; see comparison 07-03), while Otoo 1988a reported no deaths in either group.

Parasitaemia
Otoo 1988a reported parasitaemia was marginally statistically significantly lower in the prophylaxis group (24/39) six months after stopping prophylaxis compared with the placebo group (32/38) (RR 0.73, 95% CI 0.55 to 0.97; see comparison 07-04). Greenwood 1995 reported no statistically significant difference in the number of children with parasitaemia between the prophylaxis group (47/107) and the placebo group (44/114).

Enlarged spleen
Both trials reported this outcome, and there was no statistically significant difference between the prophylaxis group (27/146) and placebo group (31/159) (RR 0.96, 95% CI 0.60 to 1.52; see comparison 07-05).

Mean haematocrit
There was no statistically significant difference between the prophylaxis group (207 participants) and control group (200 participants) in Greenwood 1995 (WMD 0.30%, 95% CI -0.59% to 1.19%; see comparison 07-06).

Protective measles antibody titres
Schellenberg 2005 reported that the prevalence of protective antibody titres against measles was not significantly different between the treated and placebo groups up to 18 months after concurrent administration of immunization and intermittent treatment with sulfadoxine-pyrimethamine in infants (RR 0.94, 95% CI 0.87 to 1.02; see comparison 07-07).

Discussion

All 18 trials included in the review were conducted in Africa. Several trials reported outcomes in different publications, but we have been careful to ensure the same participants are not included twice in each meta-analysis.

Only six trials used adequate allocation concealment, and six described adequate methods of generating the allocation sequence. As adequate allocation concealment and randomization significantly improve the internal validity of randomized controlled trials (Schulz 1995), the failure of trial authors to describe these important processes could mean that these methods may not have been adequately applied. Trials lacking these methodological qualities are prone to bias and may give misleading results.

Five trials were randomized by cluster (households), which we should theoretically take into account in adjusting the variance on the point estimates. However, children aged one to six years were the target population. We had no data on how many households included more than one child in the trial. It is unlikely that clusters included more than two or three children, and the clustering is unlikely to result in a large artificial narrowing on confidence intervals around these trial estimates. To explore possible design effects, we performed a sensitivity analysis excluding these trials and it did not affect the estimates or confidence intervals.

There was marked quantitative heterogeneity between many trials, which could be anticipated given the various regimens, endemicities, drug-resistance patterns, adherence to the regimens, and trial quality. However, there is an overall consistency towards benefit. Exploration of the heterogeneity with subgroup analysis by drug types and seasonality showed no consistent pattern.

Overall, both prophylaxis and intermittent treatment regimens consistently reduced clinical malaria, severe anaemia, and admission to hospital. Interestingly, intermittent treatment did not appear to be effective in the two trials enrolling already moderately anaemic children (secondary prevention), although it clearly was effective in preventing severe anaemia in the primary prevention trials. The children in the primary prevention trials were mainly non-anaemic and younger than those in the secondary prevention trials.

This review did not provide convincing evidence that either prophylaxis or intermittent treatment reduced the risk of death in preschool children, although the point estimate and confidence intervals are compatible with a potentially important effect. The point estimate became more marked when we included only adequately concealed trials, but this could simply be due to chance.

In terms of delivering the intervention, one trial has shown that giving intermittent treatment to infants attending routine immunization clinics helps ensure that drugs are used appropriately (Schellenberg 2001). Supervised delivery increases the resources required to provide the programme, but such a policy could minimize under-dosing and improve adherence.

It has been widely speculated that giving prophylaxis to infants and preschool children resident in malaria endemic areas would prevent natural immunity and result in (rebound) increase in morbidity and mortality after stopping prophylaxis. Only two trials reported on this (Greenwood 1995; Otoo 1988a). The data did not demonstrate any significant deleterious effects of taking the intervention, but sample sizes were small. This type of follow-up trial is not easy to conduct, and it would be helpful for future trials to build in this longer-term follow up to the design plan and trial costing.

We found no trials that explored the hypothesis that intermittent treatment allows longer periods in between treatments for children to acquire protective malarial immunity than continuous prophylaxis. There are ongoing trials of intermittent regimens involving a large consortium of researchers (Cisséongoing; Kremsner ongoing; Kweku ongoing; Lemnge ongoing; Menendez ongoing; Newman ongoing; Schellenberg ongoing; Slutsker ongoing). In addition to providing more information on the effectiveness of these regimens, we expect that these trials will conduct long-term, follow-up studies to explore this and other research questions related to cost effectiveness, relative safety, and emergence of parasite resistance.

Only six out of the 18 trials reported on adverse events. These are important when taking antimalarial drugs on a long-term basis, so future trials need to measure adverse events. The hypothesis that co-administration of childhood vaccines and antimalarial drugs could reduce the protective immunity of these vaccines has been examined in a recent narrative review, which found few studies of variable methodological quality and could not reach a conclusion (Rosen 2004).

The results of this systematic review are somewhat different to an earlier narrative review which concluded there was substantial evidence for chemoprophylaxis on mortality (Geerlings 2003). The narrative review included 64 studies. Some of these studies were not randomized and included children older than six years and were excluded from our review (see 'Characteristics of excluded studies'). The application of formal scientific methods in our review, including a refereed protocol that established the methods and intended analysis in advance, probably accounts for the differences between our results and those of the narrative review.

Authors' conclusions

Implications for practice

Giving antimalarial drugs at regular intervals (malaria prophylaxis or intermittent treatment) reduces clinical malaria, severe anaemia, and admissions to hospital. There are currently insufficient data to know whether such preventive interventions impact on mortality or if there are any detrimental impacts on health when the prophylaxis or intermittent treatment is stopped. There are insufficient data to justify implementing these interventions on a wide scale. There are some large trials in progress evaluating intermittent treatment that will help inform policy.

Implications for research

There is a need to further evaluate the benefits of intermittent treatment and prophylaxis in areas of perennial and seasonal malaria transmission. These trials should measure mortality and have long-term follow up to examine potential impact on the person's natural immunity. These studies could also assess the possible effects on parasite susceptibility. In addition, the hypothesis that co-administration of antimalarial drugs and childhood vaccines could make the vaccines less effective needs clarifying. Trials should also aim to ensure that reliable surveillance strategies are used to detect and appropriately report adverse events. Current trials should provide some of the answers to these research questions in the near future.

Research to explore alternative antimalarial drugs for intermittent treatment is a priority given that increasing resistance to sulfadoxine-pyrimethamine may compromise benefits.

Potential conflict of interest

None known.

Acknowledgements

The protocol for this review 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.

Characteristics of included studies

StudyAlonso 1993
MethodsRandomized controlled trial*
Length of follow up: 1 year
ParticipantsNumber enrolled: 1898 children
Inclusion criteria: children aged 6 months to 5 years
InterventionsProphylaxis: weekly dose for 5 months (during rainy season)
(1) Pyrimethamine-dapsone (Maloprim): 12.5 mg pyrimethamine and 50 mg dapsone; 952 children
(2) Placebo: 946 children

Nets: all used insecticide-treated nets
Outcomes(1) Clinical episodes of malaria
(2) Death
(3) Parasitaemia
(4) Enlarged spleen
NotesLocation: The Gambia (17 rural villages)
Malaria transmission: seasonal/holoendemic
Allocation concealmentB – Unclear
StudyBradley-Moore 1985
MethodsQuasi-randomized controlled trial*
Length of follow up: 1 to 2 years
ParticipantsNumber enrolled: 449 infants
Inclusion criteria: babies born in Gamzago between August 1976 and April 1978; enrolled as early after naming ceremony as possible (1 to 2 weeks of age)
Exclusion criteria: residence outside Gamzago
InterventionsProphylaxis: weekly chloroquine for 2 years; or monthly pyrimethamine until 1 year old or weekly until 2 years old
(1) Chloroquine: 100 mg (< 1 year old) or 200 mg (1 to 2 years); 198 children
(2) Pyrimethamine: 3.13 mg (< 1 year old) or 6.25 mg (1 to 2 years old); 66 children
(3) Placebo: 185 children
Outcomes(1) Clinical episodes of malaria
(2) Deaths
(3) Severe anaemia
(4) Parasitaemia
(5) Mean packed cell volume (haematocrit)
NotesLocation: Gamzago, northern Nigeria
Malaria transmission: perennial/holoendemic
Allocation concealmentB – Unclear
StudyDavid 1997
MethodsRandomized controlled trial*
Length of follow up: 1 year
ParticipantsNumber enrolled: 2000 children.
Inclusion criteria: children living in the area aged 3 months to 6 years
InterventionsProphylaxis: twice weekly for 1 year
(1) Pyrimethamine-dapsone (Maloprim): 1.6 mg pyrimethamine for 3 to 11 months old, 3.1 mg for 1 to 4 years old, 9.4 mg for > 5 years old; 12.5 mg dapsone for 3 to 11 months old, 50 mg for 1 to 4 years, 75 mg for > 5 years old; 436 children
(2) Placebo: 450 children
We have not included the following two arms in this review:
(3) Pyrimethamine-dapsone (Maloprim) and insecticide-treated nets: 467 children
(4) Insecticide-treated nets: 470 children
Outcomes(1) Adverse events
NotesLocation: Bo, Sierra Leone
Malaria transmission: perennial
Allocation concealmentB – Unclear
StudyDesai 2003
MethodsRandomized controlled trial*
Length of follow up: 1 to 2 years
ParticipantsNumber enrolled: 546 children
Inclusion criteria: children aged 2 to 36 months; consent; mild anaemia (haemoglobin concentration 7.0 to 10.9 g/dL); aparasitaemia or parasite count < 20,000/cubic mm
Exclusion criteria: intake of iron supplement; sulfadoxine-pyrimethamine treatment or blood transfusion within the last 2 weeks
InterventionsIntermittent treatment: sulfadoxine-pyrimethamine given every 4 weeks for 3 doses; iron given daily for 12 weeks
(1) Sulfadoxine-pyrimethamine: 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine per tablet with 1/2 tablet for children < 10 kg or 1 tablet for children >/= 10 kg; 271 children
(2) Iron (ferrous sulphate): 3 to 6 mg/kg/day; 139 children
(3) Iron and sulfadoxine-pyrimethamine: 135 children
(4) Placebo: 275 children
Outcomes(1) Clinical episodes of malaria
(2) Severe anaemia
(3) Death
(4) Parasitaemia
(5) Adverse events
NotesLocation: Asemo, Bondo district, Western Kenya
Malaria transmission: perennial/holoendemic
Allocation concealmentA – Adequate
StudyGreenwood 1988
MethodsCluster randomized controlled trial (households)*
Length of follow up: 1 year
ParticipantsNumber enrolled: 1488 children
Inclusion criteria: age 3 to 59 months; resident in the area
InterventionsProphylaxis: every 2 weeks for 1 year
(1) Pyrimethamine-dapsone (Maloprim): 6.25 mg pyrimethamine and 25 mg dapsone with 1 tablet for 3 to 11 months old or 2 tablets for 1 to 4 years old; 783 children
(2) Placebo: 705 children
Outcomes(1) Clinical malaria episodes
(2) Severe anaemia
(3) Death
(4) Parasitaemia
(5) Enlarged spleen
(6) Mean packed cell volume (haematocrit)

Outcomes assessed after stopping intervention: clinical episodes of malaria and death
NotesLocation: Farafeni, The Gambia
Malaria transmission: seasonal
Completion rates: 96% (1982) and 94% (1984)
The Gambian trials were conducted in the same population at different time points: this is the main study and provided results from children in 38 villages (13 intervention and 25 placebo) between 9 and 21 months of the trial
Allocation concealmentB – Unclear
StudyGreenwood 1989
MethodsCluster randomized controlled trial
(households)*
Length of follow up: 3 years
ParticipantsNumber analysed: 560 children
Inclusion criteria: age 3 to 59 months; resident in the area
InterventionsProphylaxis: every 2 weeks for 3 years
(1) Pyrimethamine-dapsone (Maloprim) and folic acid: 6.25 mg pyrimethamine and 25 mg dapsone per tablet with 1 tablet for 3 to 11 months old or 2 tablets for 1 to 4 years old
(2) Pyrimethamine-dapsone (Maloprim) and placebo: 76 children (all Maloprim)
(3) Chlorproguanil and folic acid: 20 mg
(4) Chlorproguanil and placebo: 192 children (all chlorproguanil)
(5) Placebo and folic acid
(6) Placebo and placebo: 192 children (all placebo)
Outcomes(1) Clinical malaria episodes
(2) Death

Same outcomes assessed after stopping intervention
NotesLocation: Sarakund, The Gambia
Malaria transmission: seasonal
The Gambian trials were conducted in the same population at different time points: this is a subsidiary investigation to Greenwood 1988 (main study) comparing an additional antimalarial
Allocation concealmentB – Unclear
StudyGreenwood 1995
MethodsCluster randomized controlled trial
(households)*
Length of follow up: 1 year
ParticipantsNumber analysed: 408 children
Inclusion criteria: age 3 to 59 months; resident in the area
InterventionsProphylaxis: every 2 weeks for 1 year
(1) Pyrimethamine-dapsone (Maloprim): 6.25 mg pyrimethamine and 25 mg dapsone per tablet with 1 tablet for 3 to 11 months old or 2 tablets for 1 to 4 years old: 208 children
(2) Placebo: 200 children
Outcomes(1) Clinical malaria episodes
(2) Death
(3) Parasitaemia
(4) Enlarged spleen
(5) Mean packed cell volume (haematocrit)
NotesLocation: Farafeni, The Gambia
Malaria transmission: seasonal
Completion rates 96% (1982) and 94% (1984)
The Gambian trials were conducted in the same population at different time points: this trial was conducted one year after the end of prophylaxis described in Greenwood 1988 (main study)
Allocation concealmentB – Unclear
StudyHogh 1993
MethodsRandomized controlled trial*
Length of follow up: 1 year
ParticipantsNumber enrolled: 262 children
Inclusion criteria: children aged 6 months to 6 years; resident in the area; consent
InterventionsProphylaxis: every 3 weeks for 1 year
(1) Chloroquine: 5 mg/kg; 158 children
(2) Placebo: 104 children
Outcomes(1) Clinical malaria episodes
(2) Parasitaemia
(3) Splenomegaly (enlarged spleen)
(4) Packed cell volume (haematocrit)

Not included in review:
(5) Inoculation rate
(6) Haemoglobinopathies
NotesLocation: Mount Nimba region, north-western Liberia
Malaria transmission: perennial
Allocation concealmentB – Unclear
StudyLemnge 1997
MethodsRandomized controlled trial*
Length of follow up: 1 year
ParticipantsNumber enrolled: 249 children; we included only the 117 children in the subgroup of those aged 1 to 4 years
Inclusion criteria: age 1 to 9 years at admission and permanent residence in village
Exclusion criteria: gross malnutrition; severe illness; severe anaemia (packed cell volume < 20%); severe glucose-6-phosphate dehydrogenase deficiency
InterventionsProphylaxis: once weekly for 1 year
(1) Pyrimethamine-dapsone (Maloprim): 3.125 mg pyrimethamine and 25 mg dapsone with 1 tablet for 1 to 4 years old or 2 tablets for 5 to 9 years old; 58 children
(2) Placebo: 59 children
Outcomes(1) Clinical malaria episodes
(2) Death
(3) Parasitaemia
(4) Splenomegaly (enlarged spleen)
(5) Packed cell volume (haematocrit)
(6) Adverse effects

Not included in review:
(7) Compliance
NotesLocation: Magoda village, north-eastern Tanzania
Malaria endemicity: holoendemic
Allocation concealmentA – Adequate
StudyMassaga 2003
MethodsRandomized controlled trial*
Length of follow up: 10 months
Intention-to-treat analysis
ParticipantsNumber enrolled: 291 infants
Inclusion criteria: infants aged 12 to 16 weeks attending Maternal and Child Health (MCH) clinics for growth monitoring or to receive their third diphtheria-pertussis-tetanus and oral poliovirus vaccine
Exclusion criteria: congenital malformation; severe conditions that needed treatment in hospital; fever within past 2 days; packed cell volume < 24; taking chemoprophylaxis
InterventionsIntermittent treatment: amodiaquine every 2 months and daily iron for 6 months
(1) Amodiaquine and iron: 25 mg/kg over 3 days, with 10 mg/kg on first 2 days and 5 mg/kg on third day; 72 children
(2) Amodiaquine and placebo: 74 children
(3) Iron and placebo: 7.5 mg elemental iron; 73 children
(4) Placebo and placebo: 72 children
Outcomes(1) Clinical malaria episodes
(2) Hospital admissions
(3) Death
(4) Adverse events

Not included in review:
(5) Anaemia
NotesLocation: Muheza district, north-eastern Tanzania
Malaria transmission/endemicity: perennial/holoendemic
Allocation concealmentA – Adequate
StudyMenendez 1997
MethodsRandomized controlled trial*
Length of follow up: 1 year
ParticipantsNumber enrolled: 832 infants
Inclusion criteria: infant aged 8 to 52 weeks; born at district hospital; permanent resident in Ifakara
Exclusion criteria: birth weight > 1.5 kg; congenital malformation; cerebral asphyxia; congenital/neonatal infection; packed cell volume < 25
InterventionsProphylaxis: weekly pyrimethamine-dapsone (Deltaprim) and daily iron for 40 weeks
(1) Pyrimethamine-dapsone (Deltaprim) and placebo: 2.5 ml of syrup containing 3.125 mg pyrimethamine and 25 mg dapsone/5 ml syrup; 208 children
(2) Pyrimethamine-dapsone (Deltaprim) and iron: 213 children
(3) Iron and placebo: 2 mg/kg iron syrup; 204 children
(4) Placebo and placebo: 207 children
Outcomes(1) Hospital admissions
(2) Death
(3) Severe anaemia
(4) Adverse events
NotesLocation: Ifakara, south-eastern Tanzania.
Malaria transmission: perennial/holoendemic
Allocation concealmentA – Adequate
StudyMenon 1990
MethodsCluster randomized controlled trial
(households)*
Length of follow up: 1 year
ParticipantsNumber enrolled: 1792 children
Inclusion criteria: age 3 to 59 months; resident in study area
InterventionsProphylaxis: every 2 weeks for up to 1 year
(1) Pyrimethamine-dapsone (Maloprim): 6.25 mg pyrimethamine and 25 mg dapsone per tablet with 1 tablet for 3 to 11 months old or 2 tablets for 1 to 4 years old; 888 children
(2) Placebo: 904 children
Outcomes(1) Clinical episodes of malaria
(2) Death
(3) Parasitaemia
(4) Enlarged spleen
(5) Mean packed cell volume (haematocrit)
NotesLocation: Farafeni, The Gambia
Malaria transmission: seasonal
The Gambian trials were conducted in the same population at different time points: this trial was conducted three to four years after the start of the prophylaxis in the main study (Greenwood 1988) and reported on 41 villages (15 intervention and 26 placebo; 3 villages that initially declined to participate later joined the trial)
Allocation concealmentB – Unclear
StudyOtoo 1988a
MethodsCluster randomized controlled trial
(households)*
Length of follow up: 1 year
ParticipantsNumber analysed: 95 children
Inclusion criteria: aged 5 years; stopped chemoprophylaxis with Maloprim during the preceding 6 months and had achieved at least 50% compliance during the preceding 2 years
Exclusion criteria: none stated
InterventionsProphylaxis: every 2 weeks for 2 years
(1) Pyrimethamine-dapsone (Maloprim): 6.25 mg pyrimethamine and 25 mg dapsone per tablet with 1 tablet for 3 to 11 months old or 2 tablets for 1 to 4 years old; 48 children
(2) Placebo: 47 children
Outcomes(1) Clinical episodes of malaria
(2) Death
(3) Parasitaemia
(4) Enlarged spleen

Not included in review:
(5) Malaria antibody levels

Also assessed 6 months after stopping intervention
NotesLocation: Farafenni, The Gambia
Malaria transmission: seasonal
Same population as Greenwood 1988 and Otoo 1989 but 2.5 years after stopping chemoprophylaxis
Allocation concealmentB – Unclear
StudyOyediran 1993
MethodsQuasi-randomized controlled trial*
Length of follow up: 6 years
ParticipantsNumber enrolled: 696 children
Inclusion criteria: age 6 weeks to 4 years
InterventionsProphylaxis: weekly until 5 years old
(1) Chloroquine: 5 mg/kg; 235 children
(2) Pyrimethamine: 6.25 to 25 mg (adjusted for age); 226 children
(3) Placebo (Multivite): 235 children
Outcomes(1) Clinical episodes of malaria
(2) Severe anaemia (packed cell volume < 20)
(3) Death
NotesLocation: Igbora, south-western Nigeria
Malaria transmission: perennial/holoendemic
Allocation concealmentB – Unclear
StudySchellenberg 2001
MethodsRandomized controlled trial*
Length of follow up: 18 months
ParticipantsNumber enrolled: 701 children aged 2, 3, and 9 months attending routine immunization clinics for second dose of diphtheria-pertussis-tetanus vaccine
Inclusion criteria: children have just received second dose of diphtheria-pertussis-tetanus and oral poliovirus vaccine. immunization
Exclusion criteria: illness requiring admission in hospital
InterventionsIntermittent treatment: first dose at 2 months, second dose at 3 months, and third at 9 months
(1) Sulfadoxine-pyrimethamine: 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine, with 1/4 tablet for children < 5 kg, 1/2 tablet for children 5 to 10 kg, or 1 tablet for children > 10 kg; 350 children
(2) Placebo: 351 children
Outcomes(1) Clinical episodes of malaria
(2) Severe anaemia
(3) Hospital admissions
(4) Death
(5) Adverse events
NotesLocation: Ifakara, Tanzania
Malaria transmission: perennial/holoendemic
Allocation concealmentA – Adequate
StudySchellenberg 2005
MethodsRandomized controlled trial*
Length of follow up: 18 months
ParticipantsNumber analysed: 555 children aged up to 2 years at time of assessment; and 2, 3 and 9 months at time of treatment during routine immunization for diphtheria-pertussis-tetanus and measles
Inclusion and exclusion criteria: as applied to the initial enrolment (Schellenberg 2001)
InterventionsIntermittent treatment with full dose of sulfadoxine-pyrimethamine: first dose at 2 months, second dose at 3 months, and third at 9 months

(1) Sulfadoxine-pyrimethamine: 1/4 tablet (< 5 kg); 1/2 tablet (5 to 10 kg); 1 tablet (> 10 kg); 277 children
(2) Placebo; 278 children
Outcomes(1) Clinical episodes of malaria
(2) Severe anaemia

Assessed 18 months following treatment
NotesLocation: Ifakara, Tanzania
Malaria transmission: perennial/ holoendemic
This trial used the same population as Schellenberg 2001
Allocation concealmentA – Adequate
StudyTomashek 2001
MethodsRandomized controlled trial*
Length of follow up: 12 weeks
ParticipantsNumber enrolled: 238 children
Inclusion criteria: age 6 to 59 months; haemoglobin 5.0 to 8.0 g/dL; parental consent
Exclusion criteria: signs or symptoms of heart failure; severe malaria infection, splenomegaly, or sickle cell disease or trait
InterventionsIntermittent treatment: iron and folic acid given 3 times weekly for 12 weeks; sulfadoxine-pyrimethamine given at weeks 4, 8, and 12 follow-up visits; vitamins A and C both given 3 times weekly
(1) Sulfadoxine-pyrimethamine, iron, folic acid, and vitamins A and C: 75 children
(2) Sulfadoxine-pyrimethamine, iron, and folic acid: 81 children
(3) Placebo, iron, and folic acid: 82 children
Iron: ferrous sulphate (60 mg elemental iron for children 18 months or 30 mg for children < 18 months) and folic acid (250 g for children 18 months or 125 g for children < 18 months)
Sulfadoxine-pyrimethamine: 500 mg sulfadoxine and 25 mg pyrimethamine per tablet with 1 tablet for children > 48 months, 1/2 tablet for children 12 to 47 months, or 1/4 tablet for children 6 to 12 months
Vitamin A: 400 g all age groups
Vitamin C: 75 mg for children 18 months, 30 mg for children < 18 months
Outcomes(1) Malaria blood smear (parasitaemia)
(2) Mean haemoglobin (haematocrit)
(3) Death

Not included in review:
(3) Anaemia prevalence
(4) Iron-deficiency anaemia
NotesLocation: Nduta refugee camp, Kigoma Region, western Tanzania
Malaria transmission: intense (perennial)
Allocation concealmentB – Unclear
StudyVerhoef 2002
MethodsRandomized controlled trial*
Length of follow up: 12 weeks
ParticipantsNumber enrolled: 328 children
Inclusion criteria: age 2 to 36 months; haemoglobin 60 to 110 g/L; axillary temperature < 37.5 °C; resident in area; parental consent
Exclusion criteria: symptom suggestive of malaria or anaemia; systemic illness occurring in combination with a blood dipstick test result indicating current or recent malarial infection
InterventionsIntermittent treatment: sulfadoxine-pyrimethamine given every 4 weeks for 3 doses; iron given twice weekly for 12 weeks; supervised by clinical officer
(1) Sulfadoxine-pyrimethamine: 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine; 82 children
(2) Iron (ferrous fumarate 6.25 g/L): 6 mg elemental iron/kg; 82 children
(3) Sulfadoxine-pyrimethamine and iron: 82 children
(4) Placebo: 82 children
Outcomes(1) Clinical episodes of malaria

Not included in review:
(2) Haemoglobin
(3) Iron-deficiency anaemia
NotesLocation: Mtito Andei, eastern Kenya
Malaria transmission: seasonal
Allocation concealmentA – Adequate
  1. a

    Allocation concealment: A = adequate, B = unclear, *see 'Methods of the review' for details and a summary of the methodological quality assessment in Table 02

StudyWolde 1994
MethodsRandomized controlled trial*
Length of follow up: 10 weeks
ParticipantsNumber enrolled: 1005 children (age group 1 to 5 years only)
Inclusion criteria: aged 1 to 14 years, stratified as 1 to 5 and 6 to 14 years
InterventionsProphylaxis: weekly for 10 weeks
(1) Chloroquine: 5 mg/kg base; 504 children
(2) Placebo (multivitamin tablets): 501 children
Outcomes(1) Clinical episodes of malaria
NotesLocation: Awash Rift Valley, Ethiopia
Malaria transmission: seasonal
Allocation concealmentB – Unclear

Characteristics of excluded studies

StudyReason for exclusion
Akenzua 1985Randomized controlled trial with participants aged 1 to 14 years
Allen 1990Cross-sectional survey to determine sensitivity of Plasmodium falciparum after chemoprophylaxis
Archibald 1956Non-randomized intervention trial
Bjorkman 1985aNon-randomized prospective study to investigate susceptibility of Plasmodium falciparum following a period of chemosuppression
Bjorkman 1985bSurveys
Bjorkman 1986Non-randomized study
Charles 1961Randomized controlled trial with participants aged 5 to 14 years
Colbourne 1955Non-randomized intervention study
Coosemans 1987Randomized controlled trial with participants aged 6 to 14 years and no group given placebo only
Delmont 1981Mass drug administration with participants > 5 years
Escudie 1961Not a randomized controlled trial
Fasan 1970Randomized controlled trial with participants aged 6 to 12 years
Fasan 1971Randomized controlled trial with participants aged 5 to 12 years
Harland 1975Longitudinal study
Hogh 1994Randomized controlled trial with participants aged 7 to 12 years
Karunakaran 1980Small sample size: randomized controlled trial but only 8 out of 230 participants were below 5 years old
Karwacki 1990Two randomized controlled trials with participants aged 6 to 15 years
Kollaritsch 1988Randomized controlled trial with participants > 5 years
Laing ABG 1970Non-randomized controlled trial
Lell 1998Randomized controlled trial with participants aged 4 to 16 years
Lell 2000Randomized controlled trial with participants aged 12 to 20 years
Lewis 1975Not randomized controlled trial
Limsomwong 1988Randomized controlled trial with participants aged 5 to 16 years
Lucas 1969Randomized controlled trial with participants aged 8 to 17 years
Lwin 1997Possible randomized controlled trial with participants of all ages
MacCormack 1983Malaria suppression project with chloroquine (not a randomized controlled trial)
McGregor 1966Randomized controlled trial with both children and adult participants
Miller 1954Not randomized controlled trial
Murphy 1993Chemoprophylaxis for Plasmodium vivax malaria (not a randomized controlled trial)
Nevill 1988Randomized controlled trial with participants aged 6 to 18 years
Nevill 1994Randomized controlled trial with participants aged 8 to 9 years
Nwokolo 2001Randomized controlled trial with both children and adult participants
Onori 1982Seroepidemiological survey to determine whether chloroquinized salt affected immunity to malaria.
Pang 1989Randomized controlled trial with participants aged 6 to 15 years
Panton 1985Drug sensitivity survey
Pividal 1992Randomized controlled trial with participants aged 7 to 12 years
Pribadi 1986Chemoprophylaxis given to all villagers (including adults)
Pringle 1966Observational study following chemoprophylaxis to document early course of untreated falciparum malaria in semi-immune children
Ringwald 1989Randomized controlled trial with adult participants
Robert 1989Prospective non-randomized study
Rooth 1991Randomized controlled trial with participants aged 6 to 14 years
Saarinen 1988Not randomized controlled trial
Schapira 1988Randomized controlled trial with participants aged 7 to 14 years
Schellenberg 2004Open label randomized controlled trial of participants aged 2 months to 4 years old in which sulfadoxine-pyrimethamine was given to both the control group (one dose) and intervention group (three doses at monthly intervals)
Schneider 1962Randomized trial in which the control group received a different antimalarial and not placebo
Stace 1981Not randomized controlled trial
Sukwa 1999Randomized controlled trial with adult participants
Vrbova 1992Randomized controlled trial with participants aged 7 to 14 years
Watkins 1987Randomized controlled trial with participants aged 6 to 10 years
Weiss 1995Randomized controlled trial with participants aged 9 to 14 years
Win 1985Randomized controlled trial with adult participants aged 18 to 40 years

Characteristics of ongoing studies

StudyCissé ongoing
Trial name or title"A randomised trial to compare the efficacy, safety and impact on drug resistance of 4 potential drugs regimens for sIPTc in Niakhar, rural Senegal"
Participants2088 children under 5 years of age (522 for each of the four arms)
Interventions(1) Artesunate (1 d) plus sulfadoxine-pyrimethamine (SP)
(2) Artesunate (3 d) plus SP
(3) Artesunate (3 d) plus amodiaquine (AQ) (3 d)
(4) Amodiaquine (3 d) plus SP
Given at monthly intervals for 3 months (September, October, and November 2004)
Outcomes(1) Morbidity
(2) Efficacy
(3) Safety
(4) Effect on drug resistance
Starting dateSeptember 2004
Contact informationDr Badara Cissé
Room M/LG17
London School of Hygiene and Tropical Medicine
50 Bedford Square
London WC1B 3DP
UK
Tel: +44 20 7299 4664
Fax: +44 20 7299 4720
E-mail: badara.cisse@lshtm.ac.uk
NotesLocation: Senegal

Open-label randomized trial
StudyKremsner ongoing
Trial name or title"Intermittent sulfadoxine/pyrimethamine administration to infants to reduce malaria morbidity in Gabon: assessment of efficacy, safety, and potential for malaria rebound"
Participants531 children in each group
InterventionsSP or placebo given during EPI at 3, 9, and 15 months of age
Outcomes(1) Episodes of anaemia
(2) Efficacy
(3) Safety
(4) Rebound effects
Starting dateDecember 2002
Contact informationProf Peter Kremsner
Institute of Tropical Medecine
Eberhard Karls University
Wilhelmstrasse 27
D-72074 Tuebingen
Germany
Tel: +49 7071 298 7179
Fax: +49 7071 298 0234
E-mail: peter.kremsner@uni-tuebingen.de
NotesLocation: Gabon

Randomized, double blind, placebo-controlled trial
StudyKweku ongoing
Trial name or title"A study of impact of intermittent preventive treatment In children with amodiaquine plus artesunate versus sulphadoxine-pyrimethamine on hemoglobin levels and malaria morbidity in Hohoe District of Ghana"
Participants2240 children aged 3 to 59 months will be randomly allocated to 4 groups (560 per arm)

Inclusion criteria:
children between the ages of 3 and 59 months resident in the selected communities; children likely to be available for follow up for 18 months; consent by parent/guardian of child

Exclusion criteria: chronic illness; history of hypersensitivity to any of the study drugs
Interventions(1) Artesunate-amodiaquine given at 2 different intervals (monthly or bimonthly)
(2) SP
(3) Placebo
OutcomesPrimary outcome: mean haemoglobin at end of high transmission season

Secondary outcomes:
(1) incidence of moderate (haemoglobin < 8.0 g/dL > 5.0 g/dL) and severe anaemia (haemoglobin < 5.0 g/dL) during the period of the intervention
(2) Incidence of severe and clinical malaria during the period of the intervention
(3) Prevalence of anaemia at the post intervention survey
(4) Prevalence of parasitaemia and gametocytemia at the post intervention survey
(5) Prevalence of molecular markers of resistance to SP among children who have malaria at the post-intervention survey
Starting dateStudy start: June 2005
Expected completion: June 2007
Contact informationMargaret Kweku MBChB, MPH
Principal Investigator
London School of Hygiene and Tropical Medicine
Tel: +233 208175487 E-mail: margaret.kweku@lshtm.ac.uk

Daniel Chandramohan MBBS, PhD
Principal Investigator
London School of Hygiene and Tropical Medicine

Brian Greenwood FRCP, FRS
Principal Investigator
London School of Hygiene and Tropical Medicine
NotesLocation: Ghana

Randomized, double blind, placebo control, parallel assignment, safety/efficacy study

ClinicalTrials.gov identifier NCT00119132
StudyLemnge ongoing
Trial name or title"Drug options for intermittent presumptive treatment for malaria in infants in an area with high resistance to sulfadoxine/pyrimethamine: an evaluation of short and long-acting antimalarial drugs"
Participants1280 infants in western Usambara and 2440 infants in south Pare
InterventionsFollowing drugs, or placebo, given during EPI at 2, 3, and 9 months of age:
(1) Mefloquine for 1 d
(2) LapDap (chlorproguanil/dapsone) for 3 d
(3) SP for 1 d
OutcomesPrimary outcome measure: incidence of malaria in infancy

Secondary outcome measures include:
(1) Mean haemoglobin level at 10 to 12 months of age
(2) Incidence of severe anaemia during infancy
(3) Prevalence of malaria parasitaemia at 10 to 12 months of age
(4) Incidence of malaria in the second year of life
Starting dateSeptember 2004
Contact informationDr Martha Lemnge
National Institute for Medical Research (NIMR)
Amani Medical Research Centre
P.O. Box 4
Amani
Tanga
Tanzania
Tel: +255 27 2640303
Fax: +255 27 2643869
E-mail: mlemnge@amani.mimcom.net

Prof Brian Greenwood
London School of Hygiene and Tropical Medicine
50 Bedford Square
London WC1B 3DP
UK
Tel: +44 207 299 4707
Fax: +44 207 299 4720
E-mail: Brian.Greenwood@lshtm.ac.uk

Prof Thor G. Theander
Centre for Medical Parasitology
Institute for Medical Microbiology and Immunology
University of Copenhagen
Panum Institute
24.2 Blegdamsvej 3
DK-2200 Copenhagen N
Denmark
Tel: + 45 35 32 76 75
E-mail: theander@cmp.dk
NotesLocation: Tanzania

Randomiaed, double-blind, placebo-controlled trial
StudyMenendez ongoing
Trial name or title"Intermittent preventive treatment in infants delivered through the EPI scheme in Mozambique: community response and cost effectiveness, and impact on morbidity and development of malaria immunity"
Participants750 children in each group
InterventionsSP or placebo is given during EPI at 3, 4, and 9 months of age
Outcomes(1) Clinical malaria
(2) Anaemia
(3) Frequency and type of potential side effects
(4) Development of resistance and the spread of molecular markers associated with SP resistance
(5) Immune response to routine EPI immunizations
(6) Development of specific and non-specific immune responses to P. falciparum infection
(7) Cost effectiveness of intervention under close to programme conditions
(8) Community perception and response to the introduction of intervention within the EPI scheme
Starting dateSeptember 2002
Contact informationDr Clara Menendez
Centre de Salut Internacional Hospital Clínic
Universitat de Barcelona
Rosselló 132, 2-2, 08036
Barcelona
Spain
Tel: +34 93 227 5706
Fax: +34 93 227 9853
E-mail: cmenendez@clinic.ub.es
NotesLocation: Mozambique

Randomized, double blind, placebo-controlled trial
StudyNewman ongoing
Trial name or title"Efficacy and safety of pediatric immunization-linked preventive intermittent treatment with antimalarials in decreasing anemia and malaria morbidity in rural western Kenya"
ParticipantsAge 5 to 16 weeks

Expected total enrollment: 1516

Inclusion criteria: presenting for Pentavalent 1 immunization; age 5 weeks to 16 weeks; parent or guardian currently resident in study catchment area; parent or guardian has given permission for their child to participate

Exclusion criteria: known allergy to any of the study drugs; current cotrimoxazole prophylaxis; concomitant disease requiring hospitalization or transfusion; plans to be away from the study area for more than 6 months during the next year
InterventionsCompare the efficacy of iron supplementation and intermittent preventive treatment with one of 3 antimalarial regimens (SP + 3 doses of artesunate, chlorproguanil-dapsone (Lapdap), or amodiaquine + 3 doses of artesunate) given at routine EPI visits with iron supplementation alone (+ placebo)
OutcomesPrimary outcome: clinical malaria in the first year of life

Secondary outcomes:
(1) Moderate and severe anemia in the first year of life
(2) Serologic responses to EPI vaccines (polio, diphtheria, tetanus, pertussis, hepatitis B, Hemophilus Influenzae type B, and measles)
(3) Nasal carriage rates of Haemophilus influenza type b
(4) All-cause hospitalization in the first year of life
Starting dateMarch 2004
Contact informationRobert D Newman MD, MPH
Principal Investigator
U.S. Centers for Disease Control and Prevention
Tel: +1 770 488 7559
E-mail: ren5@cdc.gov

Laurence Slutsker MD, MPH
Principal Investigator
U.S. Centers for Disease Control and Prevention
NotesLocation: Kenya

Prevention, randomized, double blind, placebo control, single group assignment, safety/efficacy study

ClinicalTrials.gov identifier NCT00111163
StudySchellenberg ongoing
Trial name or title"Community effectiveness of intermittent preventive treatment delivered through the Expanded Programme of Immunisation for malaria and anaemia control in Tanzanian infants"
Participants12,000 infants per year
InterventionsSP will be given during EPI at 2, 3, and 9 months of age

Evaluation will be based on comparisons between areas with and without intervention
Outcomes(1) All-cause mortality
(2) Anaemia
(3) Parasitaemia
(4) Probable malaria episodes
(5) Cost effectiveness
(6) Effect of the intervention on community perceptions of, and compliance with, the EPI program
(7) Impact of intervention on rate of development of drug resistance
(8) Consolidate the safety profile of SP in infants
Starting dateJanuary 2005
Contact informationDr David Schellenberg
Ifakara Health Research & Development Centre
P.O. Box 78373
Dar es Salaam
Tanzania
Fax: +255 22 130 660
E-mail: DMSchellenberg@aol.com

Prof Marcel Tanner
Swiss Tropical Institute
Socinstrasse 57
P.O. Box 4002
Basel, Switzerland
Tel: +41 61 2848283
Fax: +41 61 2717951
E- mail: marcel.tanner@unibas.ch
NotesLocation: Tanzania
  1. a

    EPI: Expanded Programme of Immunization; SP: sulfadoxine-pyrimethamine

StudySlutsker ongoing
Trial name or title"Efficacy and safety of paediatric, immunization-linked, intermittent preventive treatment with antimalarials in decreasing anaemia and malaria morbidity in rural western Kenya"
Participants379 children recruited in each group

Enrolled children followed through active and passive surveillance until 18 months of age
InterventionsFollowing drugs, or placebo, given during EPI at 2, 3, and 9 months of age:
(1) SP for 1 d and artesunate for 3 d
(2) LapDap (chlorproguanil/dapsone) for 3 d
(3) Amodiaquine for 3 d and artesunate for 3 d
(4) Iron supplementation alone

Infants will receive iron supplementation from 2 to 6 months of age and 1 of 4 treatments at EPI visits
Outcomes(1) Clinical malaria
(2) Moderate and severe anaemia
(3) Serological responses to EPI vaccines
Starting dateMarch 2004
Contact informationDr Larry Slutsker
CDC/KEMRI Research Station
P.O. Box 1578
Kisumu
Kenya
Tel: +254 57 22902/59/83
Fax: +254 57 22981
E- mail: LSlutsker@kisian.mimcom.net
NotesLocation: Kenya

Randomized, double-blind, placebo-controlled trial

Additional tables

Table 01. Detailed search strategies
Search setCIDG SR*CENTRALMEDLINE**EMBASE**LILACS**
1malariamalariaMALARIAMALARIAmalaria
2prophylaxisprophylaxismalariamalariaprophylaxis
3intermittent treatmentintermittent treatment1 or 21 or 2prevention
4-presumptive treatmentprophylaxisprophylaxis2 or 3
5-2 or 3 or 4chemoprophylaxischemoprophylaxis1 and 4
6-1 and 5preventionprevention-
7--intermittent treatmentintermittent treatment-
8--presumptive treatmentpresumptive treatment-
9--4 or 5 or 6 or 7 or 84 or 5 or 6 or 7 or 8-
10--3 and 93 and 9-
 *Cochrane Infectious Diseases Group Specialized Register **Search terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2005); Upper case: MeSH or EMTREE heading; Lower case: free text term  
Table 02. Types of intervention
TrialNo. armsInterventionIron or folic acidITNs*
Alonso 19931Pyrimethamine-dapsoneNoYes
 2PlaceboNoYes
Bradley-Moore 19851ChloroquineNoNo
 2PyrimethamineNoNo
 3PlaceboNoNo
David 19971Pyrimethamine-dapsoneNoNo
 2PlaceboNoNo
Desai 20031Sulfadoxine-pyrimethamineNoYes**
 2--IronYes**
 3Sulfadoxine-pyrimethamineIronYes**
 4PlaceboNoYes**
Greenwood 19881Pyrimethamine-dapsoneNoNo
 2PlaceboNoNo
Greenwood 19891Pyrimethamine-dapsoneFolic acidNo
 2Pyrimethamine-dapsoneNoNo
 3ChlorproguanilFolic acidNo
 4ChlorproguanilNoNo
 5PlaceboFolic acidNo
 6PlaceboNoNo
Greenwood 19951Pyrimethamine-dapsoneNoNo
 2PlaceboNoNo
Hogh 19931ChloroquineNoNo
 2PlaceboNoNo
Lemnge 19971Pyrimethamine-dapsoneNoNo
 2PlaceboNoNo
Massaga 20031AmodiaquineIronNo
 2AmodiaquineNoNo
 3PlaceboIronNo
 4PlaceboNoNo
Menendez 19971Pyrimethamine-dapsoneNoNo
 2Pyrimethamine-dapsoneIronNo
 3PlaceboIronNo
 4PlaceboNoNo
Menon 19901Pyrimethamine-dapsoneNoNo
 2PlaceboNoNo
Otoo 19881Pyrimethamine-dapsoneNoNo
 2PlaceboNoNo
Oyediran 19931ChloroquineNoNo
 2PyrimethamineNoNo
 3PlaceboNoNo
Schellenberg 20011Sulfadoxine-pyrimethamineNoNo
 2PlaceboNoNo
Schellenberg 20051Sulfadoxine-pyrimethamineNoNo
 2PlaceboNoNo
Tomashek 20011Sulfadoxine-pyrimethamine plus vitamins A and CIron, folic acidNo
 2Sulfadoxine-pyrimethamineIron, folic acidNo
 3PlaceboIron, folic acidNo
Verhoef 20021Sulfadoxine-pyrimethamineNoNo
 2--IronNo
 3Sulfadoxine-pyrimethamineIronNo
 4PlaceboNoNo
Wolde 19941ChloroquineNoNo
 2PlaceboNoNo
Footnotes
*ITNs: insecticide-treated nets
**ITNs not given to participants but reported that they benefited from their "area-wide deployment"
    
Table 03. Methodological quality of included trials
TrialSequence*Concealment*BlindingPrimary outcome (n)Number at follow upPercentage loss
Alonso 1993UnclearUnclearDoubleClinical malaria (1898 participants)NANA
Bradley-Moore 1985Inadequate (alternate allocation)UnclearUnclearClinical malaria, severe anaemia (449 participants)NANA
David 1997UnclearUnclearUnclear-NANA
Desai 2003Adequate (block randomization)Adequate (identical and centrally coded drugs and placebo)DoubleClinical malaria (428 participants)46814% (inadequate)
Greenwood 1988UnclearUnclearDoubleClinical malaria, severe anaemia (2718 participants)NANA
Greenwood 1989UnclearUnclearDoubleClinical malaria (560 participants)NANA
Greenwood 1995**UnclearUnclearDouble-NA19% to 22% (inadequate)
Hogh 1993UnclearUnclearUnclear-NANA
Lemnge 1997UnclearAdequate (identical and centrally coded drugs and placebo)Double-2346% (adequate)
Massaga 2003Adequate (computer-generated random numbers)Adequate (identical and centrally coded drugs and placebo)DoubleClinical malaria (291 participants)23121% (inadequate)
Menendez 1997Adequate (block randomization)Adequate (identical and centrally coded drugs and placebo)DoubleSevere anaemia (832 participants)NA7% (adequate)
Menon 1990UnclearUnclearDouble-NANA
Otoo 1988a**UnclearUnclearDoubleClinical malaria (95 participants)NA16% (inadequate)
Oyediran 1993Inadequate (alternate allocation)UnclearUnclearClinical malaria, severe anaemia (696 participants)NANA
Schellenberg 2001Adequate (computer-generated)Adequate (sealed, opaque envelopes and identical, centrally coded drugs and placebo)DoubleClinical malaria, severe anaemia (701 participants)6773% (adequate)
Schellenberg 2005Adequate (computer-generated)Adequate (sealed, opaque envelopes and identical, centrally coded drugs and placebo)DoubleClinical malaria, severe anaemia, protective antibody titres against measles (555)555NA
Tomashek 2001Adequate (computer-generated)UnclearDoubleAnaemia prevalence (238 participants)2159.7% (adequate)
Verhoef 2002Adequate (block randomization)Adequate (identical and centrally coded drugs and placebo)DoubleClinical malaria (328 participants)3096% (adequate)
Wolde 1994UnclearUnclearUnclearClinical malaria (1005 participants)9979% (adequate)
Footnotes
*Generation of allocation sequence; concealment of allocation
**Late impact trials
NA: not available
Footnotes
*Generation of allocation sequence; concealment of allocation
**Late impact trials
NA: not available
      
Table 04. Adverse event information not appropriate for meta-analysis
TrialMethod to detect AE*Results
Greenwood 1988White cell count in randomly selected subset of 68 participants on Maloprim (pyrimethamine-dapsone) and 78 on placeboAlmost identical mean white cell count for the Maloprim group (9.3 x 10^L) and placebo group (9.6 x 10^/L)

Lowest white cell count recorded was 2.8 x 10^/L (study group not indicated)

No severe adverse event reported

Almost identical mean white cell count for the Maloprim group (9.3 x 10^L) and placebo group (9.6 x 10^/L)

Lowest white cell count recorded was 2.8 x 10^/L (study group not indicated)

No severe adverse event reported
Greenwood 1989Clinical assessment and white cell count

White cell counts on alternate participants in 1983 and attempted on all participants in 1984
White cell count and clinical assessment showed no features suggestive of agranulocytosis in treatment (Maloprim) and placebo groups

Results from Fuller 1988 (reporting on the Greenwood 1989 trial): "Mean WBC [white blood cell] count of children and the distribution of WBC counts were very similar in children who received Maloprim, chlorproguanil and placebo during each survey."
Lemnge 1997White cell count; weight and heightResults available for 242 participants: 65 placebo, 58 iron, 60 amodiaquine, and 59 amodiaquine and iron

"No serious side effect was observed."

"Reduction in … neutrophil counts, in children with normal baseline values, were sometimes seen but these were temporary."

"No pronounced weight loss was observed in any child."
Massaga 2003Total and differential white cell counts"No clinical adverse effects such as sore throat or agranulocytosis were reported or observed during the study."

"No significant difference in mean leucocyte counts between the groups."
Footnotes
AE: adverse event
  

Analyses

Comparison 01. Antimalarial versus placebo: main analysis
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
01 Clinical malaria84051Relative Risk (Random) 95% CI0.52 [0.35, 0.77]
02 Severe anaemia82727Relative Risk (Fixed) 95% CI0.54 [0.42, 0.68]
03 Death from any cause117929Relative Risk (Fixed) 95% CI0.82 [0.65, 1.04]
04 Hospital admission for any cause31149Relative Risk (Fixed) 95% CI0.60 [0.52, 0.68]
05 Parasitaemia61785Relative Risk (Random) 95% CI0.37 [0.17, 0.79]
06 Enlarged spleen41589Relative Risk (Random) 95% CI0.28 [0.14, 0.56]
07 Mean haematocrit3794Weighted Mean Difference (Fixed) 95% CI2.12 [1.47, 2.77]
08 Adverse events  Relative Risk (Fixed) 95% CISubtotals only
Analysis 01.01.

Comparison 01 Antimalarial versus placebo: main analysis, Outcome 01 Clinical malaria

Analysis 01.02.

Comparison 01 Antimalarial versus placebo: main analysis, Outcome 02 Severe anaemia

Analysis 01.03.

Comparison 01 Antimalarial versus placebo: main analysis, Outcome 03 Death from any cause

Analysis 01.04.

Comparison 01 Antimalarial versus placebo: main analysis, Outcome 04 Hospital admission for any cause

Analysis 01.05.

Comparison 01 Antimalarial versus placebo: main analysis, Outcome 05 Parasitaemia

Analysis 01.06.

Comparison 01 Antimalarial versus placebo: main analysis, Outcome 06 Enlarged spleen

Analysis 01.07.

Comparison 01 Antimalarial versus placebo: main analysis, Outcome 07 Mean haematocrit

Analysis 01.08.

Comparison 01 Antimalarial versus placebo: main analysis, Outcome 08 Adverse events

Comparison 02. Antimalarial versus placebo: by drug group
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
01 Clinical malaria84051Relative Risk (Random) 95% CI0.52 [0.35, 0.77]
02 Severe anaemia82727Relative Risk (Fixed) 95% CI0.54 [0.42, 0.68]
Analysis 02.01.

Comparison 02 Antimalarial versus placebo: by drug group, Outcome 01 Clinical malaria

Analysis 02.02.

Comparison 02 Antimalarial versus placebo: by drug group, Outcome 02 Severe anaemia

Comparison 03. Antimalarial versus placebo: by seasonality
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
01 Clinical malaria84053Relative Risk (Random) 95% CI0.52 [0.35, 0.77]
02 Severe anaemia82727Relative Risk (Fixed) 95% CI0.54 [0.42, 0.68]
Analysis 03.01.

Comparison 03 Antimalarial versus placebo: by seasonality, Outcome 01 Clinical malaria

Analysis 03.02.

Comparison 03 Antimalarial versus placebo: by seasonality, Outcome 02 Severe anaemia

Comparison 04. Intermittent treatment versus placebo: by presence of anaemia
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
01 Clinical malaria  Relative Risk (Random) 95% CISubtotals only
02 Severe anaemia  Relative Risk (Random) 95% CISubtotals only
Analysis 04.01.

Comparison 04 Intermittent treatment versus placebo: by presence of anaemia, Outcome 01 Clinical malaria

Analysis 04.02.

Comparison 04 Intermittent treatment versus placebo: by presence of anaemia, Outcome 02 Severe anaemia

Comparison 05. Antimalarial versus placebo: adequately concealed trials
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
01 Clinical malaria41245Relative Risk (Random) 95% CI0.48 [0.33, 0.71]
02 Severe anaemia41470Relative Risk (Fixed) 95% CI0.50 [0.39, 0.64]
03 Death from any cause41495Relative Risk (Fixed) 95% CI0.64 [0.34, 1.22]
Analysis 05.01.

Comparison 05 Antimalarial versus placebo: adequately concealed trials, Outcome 01 Clinical malaria

Analysis 05.02.

Comparison 05 Antimalarial versus placebo: adequately concealed trials, Outcome 02 Severe anaemia

Analysis 05.03.

Comparison 05 Antimalarial versus placebo: adequately concealed trials, Outcome 03 Death from any cause

Comparison 06. Antimalarial versus placebo: excluding cluster-randomized controlled trials
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
01 Severe anaemia72486Relative Risk (Fixed) 95% CI0.55 [0.43, 0.70]
02 Death from any cause74247Relative Risk (Fixed) 95% CI1.02 [0.76, 1.39]
03 Parasitaemia41194Relative Risk (Random) 95% CI0.46 [0.17, 1.26]
Analysis 06.01.

Comparison 06 Antimalarial versus placebo: excluding cluster-randomized controlled trials, Outcome 01 Severe anaemia

Analysis 06.02.

Comparison 06 Antimalarial versus placebo: excluding cluster-randomized controlled trials, Outcome 02 Death from any cause

Analysis 06.03.

Comparison 06 Antimalarial versus placebo: excluding cluster-randomized controlled trials, Outcome 03 Parasitaemia

Comparison 07. Antimalarial versus placebo: impact after stopping intervention
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
01 Clinical malaria  Relative Risk (Fixed) 95% CITotals not selected
02 Severe anaemia  Relative Risk (Fixed) 95% CITotals not selected
03 Death from any cause (within 2 years of stopping intervention)  Relative Risk (Fixed) 95% CISubtotals only
04 Parasitaemia  Relative Risk (Fixed) 95% CISubtotals only
05 Enlarged spleen2305Relative Risk (Fixed) 95% CI0.96 [0.60, 1.52]
06 Mean haematocrit  Weighted Mean Difference (Fixed) 95% CISubtotals only
07 Protective measles antibody titres  Relative Risk (Fixed) 95% CISubtotals only
Analysis 07.01.

Comparison 07 Antimalarial versus placebo: impact after stopping intervention, Outcome 01 Clinical malaria

Analysis 07.02.

Comparison 07 Antimalarial versus placebo: impact after stopping intervention, Outcome 02 Severe anaemia

Analysis 07.03.

Comparison 07 Antimalarial versus placebo: impact after stopping intervention, Outcome 03 Death from any cause (within 2 years of stopping intervention)

Analysis 07.04.

Comparison 07 Antimalarial versus placebo: impact after stopping intervention, Outcome 04 Parasitaemia

Analysis 07.05.

Comparison 07 Antimalarial versus placebo: impact after stopping intervention, Outcome 05 Enlarged spleen

Analysis 07.06.

Comparison 07 Antimalarial versus placebo: impact after stopping intervention, Outcome 06 Mean haematocrit

Analysis 07.07.

Comparison 07 Antimalarial versus placebo: impact after stopping intervention, Outcome 07 Protective measles antibody titres

Sources of support

External sources of support

  • Department for International Development UK

Internal sources of support

  • University of Calabar NIGERIA

  • Liverpool School of Tropical Medicine UK

Ancillary