Insecticide-treated bednets reduce mortality and severe morbidity from malaria among children on the Kenyan coast. Effect of insecticide-treated bed nets on haemoglobin values, prevalence and multiplicity of infection with Plasmodium falciparum in a randomized controlled trial in Tanzania. Efficacy of permethrin-treated bed nets in the prevention of mortality in young children in an area of high perennial malaria transmission in western Kenya. 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. Reduction of malaria during pregnancy by permethrin-treated bed nets in an area of intense perennial malaria transmission in western Kenya. A trial of intermittent preventive treatment and home-based management of malaria in a rural area of The Gambia. 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. A trial of bed nets (mosquito nets) as a malaria control strategy in a rural area of The Gambia, West Africa. Mortality and morbidity from malaria in Gambian children after introduction of an impregnated bednet programme.
New tools to prevent malaria morbidity and mortality are needed to improve child survival in sub-Saharan Africa. Insecticide treated bednets (ITBN) have been shown, in one setting (The Gambia, West Africa), to reduce childhood mortality. To assess the impact of ITBN on child survival under different epidemiological and cultural conditions we conducted a community randomized, controlled trial of permethrin treated bednets (0.5 g/m2) among a rural population on the Kenyan Coast. Between 1991 and 1993 continuous community-based demographic surveillance linked to hospital-based in-patient surveillance identified all mortality and severe malaria morbidity events during a 2-year period among a population of over 11000 children under 5 years of age. In July 1993, 28 randomly selected communities were issued ITBN, instructed in their use and the nets re-impregnated every 6 months. The remaining 28 communities served as contemporaneous controls for the following 2 years, during which continuous demographic and hospital surveillance was maintained until the end of July 1995. The introduction of ITBN led to significant reductions in childhood mortality (PE 33%, CI 7-51%) and severe, life-threatening malaria among children aged 1-59 months (PE 44%, CI 19-62). These findings confirm the value of ITBN in improving child survival and provide the first evidence of their specific role in reducing severe morbidity from malaria. A randomized controlled trial of insecticide-treated bed nets (ITNs) was conducted in an area of high malaria transmission in Tanzania in order to assess the effects of ITNs on infection and anaemia. One hundred and twenty-two children, aged 5 to 24 months, were randomly allocated to 2 groups, one of which received ITNs. Outcome measures were assessed in 6 consecutive months with monthly cross-sectional surveys. These measures were haemoglobin values, Plasmodium falciparum prevalence and density, and multiplicity of infection determined by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) of the msp2 locus. There was a significant increase in mean heamoglobin values and a significant decrease of 16.4% in microscopically determined P. falciparum prevalence in children in the ITN group six months after the start of the trial. Both effects were more pronounced in younger children. However, no significant difference was observed in parasite density or multiplicity of infection among infected children. Comparison with PCR results indicated that microscopically subpatent parasitaemia was more frequently found in children in the ITN group. This, together with the observed similar multiplicity in the 2 groups, suggests that infections are maintained despite ITN use, owing to the chronicity of infections. This study shows that ITNs reduce the risk of anaemia in highly exposed young children. The virtually unchanged multiplicity of infection indicates that the potentially protective concomitant immunity is not compromised. A group-randomized controlled trial of insecticide (permethrin)-treated bed nets (ITNs) was conducted in an area of high perennial malaria transmission in western Kenya to test the effect of ITNs on all-cause mortality in children 1-59 months of age. Child deaths were monitored over a two-year period by biannual household census in Asembo (1997-1998) and in Gem (1998-1999). Overall, 1,722 deaths occurred in children 1-59 months followed for 35,932 child-years. Crude mortality rates/1,000 child-years were 51.9 versus 43.9 in control and ITN villages in children 1-59 months old. The protective efficacy (PE) (95% confidence interval) adjusted for age, study year, study site, and season was 16% (6-25%). Corresponding figures in 1-11- and 12-59-month-old children in control and ITN villages were 133.3 versus 102.3, PE = 23% (11-34%) and 31.1 versus 28.7, PE = 7% (-6-19%). The numbers of lives saved/1,000 child-years were 8, 31, and 2 for the groups 1-59, 1-11, and 12-59 months old, respectively. Stratified analysis by time to insecticide re-treatment showed that the PE of ITNs re-treated per study protocol (every six months) was 20% (10-29%), overall and 26% (12-37%) and 14% (-1-26%) in 1-11- and 12-59-month-old children, respectively. ITNs prevent approximately one in four infant deaths in areas of intense perennial malaria transmission, but their efficacy is compromised if re-treatment is delayed beyond six months. Previous studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria. However, these studies were conducted in communities with low coverage with insecticide-treated nets (ITNs). Whether IPTc provides additional protection to children sleeping under an ITN has not been established.
                To assess whether IPTc provides additional protection to children sleeping under an ITN, we conducted a randomised, double-blind, placebo-controlled trial of IPTc with sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) in three localities in Kati, Mali. After screening, eligible children aged 3-59 mo were given a long-lasting insecticide-treated net (LLIN) and randomised to receive three rounds of active drugs or placebos. Treatments were administered under observation at monthly intervals during the high malaria transmission season in August, September, and October 2008. Adverse events were monitored immediately after the administration of each course of IPTc and throughout the follow-up period. The primary endpoint was clinical episodes of malaria recorded through passive surveillance by study clinicians available at all times during the follow-up. Cross-sectional surveys were conducted in 150 randomly selected children weekly and in all children at the end of the malaria transmission season to assess usage of ITNs and the impact of IPTc on the prevalence of malaria, anaemia, and malnutrition. Cox regression was used to compare incidence rates between intervention and control arms. The effects of IPTc on the prevalence of malaria infection and anaemia were estimated using logistic regression. 3,065 children were screened and 3,017 (1,508 in the control and 1,509 in the intervention arm) were enrolled in the study. 1,485 children (98.5%) in the control arm and 1,481 (98.1%) in the intervention arm completed follow-up. During the intervention period, the proportion of children reported to have slept under an ITN was 99.7% in the control and 99.3% in intervention arm (p = 0.45). A total of 672 episodes of clinical malaria defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microlitre (incidence rate of 1.90; 95% confidence interval [CI] 1.76-2.05 episodes per person year) were observed in the control arm versus 126 (incidence rate of 0.34; 95% CI 0.29-0.41 episodes per person year) in the intervention arm, indicating a protective effect (PE) of 82% (95% CI 78%-85%) (p<0.001) on the primary endpoint. There were 15 episodes of severe malaria in children in the control arm compared to two in children in the intervention group giving a PE of 87% (95% CI 42%-99%) (p = 0.001). IPTc reduced the prevalence of malaria infection by 85% (95% CI 73%-92%) (p<0.001) during the intervention period and by 46% (95% CI 31%-68%) (p<0.001) at the end of the intervention period. The prevalence of moderate anaemia (haemoglobin [Hb] <8 g/dl) was reduced by 47% (95% CI 15%-67%) (p<0.007) at the end of intervention period. The frequencies of adverse events were similar between the two arms. There was no drug-related serious adverse event.
                IPTc given during the malaria transmission season provided substantial protection against clinical episodes of malaria, malaria infection, and anaemia in children using an LLIN. SP+AQ was safe and well tolerated. These findings indicate that IPTc could make a valuable contribution to malaria control in areas of seasonal malaria transmission alongside other interventions.
                ClinicalTrials.gov NCT00738946. Please see later in the article for the Editors' Summary. The impact of insecticide (permethrin)-treated bed nets (ITNs) on malaria in pregnancy was studied in a rural area in western Kenya with intense perennial malaria transmission. All households in 40 of 79 villages were randomized to receive ITNs by January 1997. The ITNs were distributed in control villages two years later. Complete data on birth outcome were available on 2,754 (89.6%) of 3,072 deliveries. Women (n = 780) were followed monthly throughout pregnancy in 19 of 79 villages. Among gravidae 1-4, ITNs were associated with reductions of 38% (95% confidence interval [CI] = 17-54%) in the incidence of malaria parasitemia and 47% (95% CI = 6-71%) in the incidence of severe malarial anemia (hemoglobin level < 8 g/dL with parasitemia) during pregnancy. At the time of delivery, mean hemoglobin levels were 0.6 g/dL (95% CI = 0.01-1.2 g/dL) higher, the prevalence of placental or maternal malaria was reduced by 35% (95% CI = 20-47%), and the prevalence of low birth weight was reduced by 28% (95% CI = 2-47%) in gravidae 1-4 from ITN villages. No beneficial impact was observed in gravidae five or higher. In areas of intense perennial malaria transmission, permethrin-treated bed nets reduce the adverse effect of malaria during the first four pregnancies. Individual malaria interventions provide only partial protection in most epidemiological situations. Thus, there is a need to investigate whether combining interventions provides added benefit in reducing mortality and morbidity from malaria. The potential benefits of combining IPT in children (IPTc) with home management of malaria (HMM) was investigated.
                During the 2008 malaria transmission season, 1,277 children under five years of age resident in villages within the rural Farafenni demographic surveillance system (DSS) in North Bank Region, The Gambia were randomized to receive monthly IPTc with a single dose of sulphadoxine/pyrimethamine (SP) plus three doses of amodiaquine (AQ) or SP and AQ placebos given by village health workers (VHWs) on three occasions during the months of September, October and November, in a double-blind trial. Children in all study villages who developed an acute febrile illness suggestive of malaria were treated by VHWs who had been taught how to manage malaria with artemether-lumefantrine (Coartem™). The primary aims of the project were to determine whether IPTc added significant benefit to HMM and whether VHWs could effectively combine the delivery of both interventions.
                The incidence of clinical attacks of malaria was very low in both study groups. The incidence rate of malaria in children who received IPTc was 0.44 clinical attacks per 1,000 child months at risk while that for control children was 1.32 per 1,000 child months at risk, a protective efficacy of 66% (95% CI -23% to 96%; p = 0.35). The mean (standard deviation) haemoglobin concentration at the end of the malaria transmission season was similar in the two treatment groups: 10.2 (1.6) g/dL in the IPTc group compared to 10.3 (1.5) g/dL in the placebo group. Coverage with IPTc was high, with 94% of children receiving all three treatments during the study period.
                Due to the very low incidence of malaria, no firm conclusion can be drawn on the added benefit of IPTc in preventing clinical episodes of malaria among children who had access to HMM in The Gambia. However, the study showed that VHWs can successfully combine provision of HMM with provision of IPTc. Intermittent preventive treatment of malaria in children (IPTc) is a promising new approach to the control of malaria in areas of seasonal malaria transmission but it is not known if IPTc adds to the protection provided by an insecticide-treated net (ITN).
                An individually randomised, double-blind, placebo-controlled trial of seasonal IPTc was conducted in Burkina Faso in children aged 3 to 59 months who were provided with a long-lasting insecticide-treated bednet (LLIN). Three rounds of treatment with sulphadoxine pyrimethamine plus amodiaquine or placebos were given at monthly intervals during the malaria transmission season. Passive surveillance for malaria episodes was established, a cross-sectional survey was conducted at the end of the malaria transmission season, and use of ITNs was monitored during the intervention period. Incidence rates of malaria were compared using a Cox regression model and generalized linear models were fitted to examine the effect of IPTc on the prevalence of malaria infection, anaemia, and on anthropometric indicators. 3,052 children were screened and 3,014 were enrolled in the trial; 1,505 in the control arm and 1,509 in the intervention arm. Similar proportions of children in the two treatment arms were reported to sleep under an LLIN during the intervention period (93%). The incidence of malaria, defined as fever or history of fever with parasitaemia ≥ 5,000/µl, was 2.88 (95% confidence interval [CI] 2.70-3.06) per child during the intervention period in the control arm versus 0.87 (95% CI 0.78-0.97) in the intervention arm, a protective efficacy (PE) of 70% (95% CI 66%-74%) (p<0.001). There was a 69% (95% CI 6%-90%) reduction in incidence of severe malaria (p = 0.04) and a 46% (95% CI 7%-69%) (p = 0.03) reduction in the incidence of all-cause hospital admissions. IPTc reduced the prevalence of malaria infection at the end of the malaria transmission season by 73% (95% CI 68%-77%) (p<0.001) and that of moderately severe anaemia by 56% (95% CI 36%-70%) (p<0.001). IPTc reduced the risks of wasting (risk ratio [RR] = 0.79; 95% CI 0.65-1.00) (p = 0.05) and of being underweight (RR = 0.84; 95% CI 0.72-0.99) (p = 0.03). Children who received IPTc were 2.8 (95% CI 2.3-3.5) (p<0.001) times more likely to vomit than children who received placebo but no drug-related serious adverse event was recorded.
                IPT of malaria provides substantial protection against malaria in children who sleep under an ITN. There is now strong evidence to support the integration of IPTc into malaria control strategies in areas of seasonal malaria transmission.
                ClinicalTrials.govNCT00738946. Please see later in the article for the Editors' Summary. An intervention trial was undertaken in a rural area of The Gambia to assess the impact on malaria morbidity of the use of bed nets. Bed nets were allocated at random among a group of 16 Fula hamlets, where they were previously rarely used. The incidence of febrile episodes with associated malaria parasitaemias throughout the rainy season and the prevalence of splenomegaly and parasitaemia at the end of the rainy season were determined in 233 children aged 1-9 years who slept under bed nets and in 163 children who did not. Bed nets were used correctly by the children in the study cohort, but direct observations showed that a significant number of children left their nets for a period during the night. There was no significant difference in the incidence of clinical attacks of malaria or in any other malariometric measurement between the 2 groups. Thus, bed nets were not effective in reducing malaria morbidity in this group of children. The apparent protection from bed nets demonstrated in previous retrospective surveys may have been due to an increased number of infective bites being received by exposed individuals sleeping close to users of bed nets. After the success of a controlled trial of insecticide-treated bednets in lowering child mortality, The Gambia initiated a National Insecticide Impregnated Bednet Programme (NIBP) in 1992 with the objective of introducing this form of malaria control into all large villages in The Gambia. Five areas (population 115,895) were chosen as sentinel sites for evaluation of the NIBP. During the first year of intervention a 25% reduction was achieved in all-cause mortality in children 1-9 years old living in treated villages (rate ratio 0.75 [95% CI 0.57-0.98], p = 0.04). If one area where the programme was ineffective was excluded, the reduction was 38% (0.62 [0.46-0.83), p = 0.001). A decrease in rates of parasitaemia and high-density parasitaemia, an increase in mean packed-cell volume (rate ratio 0.75 [95% CI 0.59-0.98], p = 0.04) and an improvement in the nutritional status of children living in treated villages were also detected. In a country such as The Gambia, where nets were widely used and which has a good primary health care system, it is possible to achieve insecticide-treatment of bednets at a national level with a significant reduction in child mortality; but at a cost which the country cannot afford.
ITNs are highly effective in reducing childhood mortality and morbidity from malaria. Widespread access to ITNs is currently being advocated by Roll Back Malaria, but universal deployment will require major financial, technical, and operational inputs.