For personal use. Only reproduce with permission from The Lancet Publishing Group. ARTICLES THE LANCET • Vol 357 • May 12, 2001 1471 Summary Background Clinical malaria and severe anaemia are major causes of paediatric hospital admission and death in many malaria-endemic settings. In the absence of an effective and affordable vaccine, control programmes continue to rely on case management while attempting the large-scale deployment of insecticide-treated nets. We did a randomised, placebo-controlled trial to assess the efficacy and safety of intermittent sulphadoxine-pyrimethamine treatment on the rate of malaria and severe anaemia in infants in a rural area of Tanzania. Methods We randomly assigned 701 children living in Ifakara, southern Tanzania, sulphadoxine-pyrimethamine or placebo at 2, 3, and 9 months of age. All children received iron supplementation between 2 and 6 months of age. The intervention was given alongside routine vaccinations delivered through WHO’s Expanded Program on Immunisation (EPI). The primary outcome measures were first or only episode of clinical malaria, and severe anaemia in the period from recruitment to 1 year of age. Morbidity monitoring through a hospital-based passive case-detection system was complemented by cross-sectional surveys at 12 and 18 months of age. Results were expressed in terms of protective efficacy (100 [1-hazard ratio] %) and analysis was by intention to treat. Findings 40 children dropped out (16 died, 11 migrated, 12 parents withdrew consent, and one for other reasons). Intermittent sulphadoxine-pyrimethamine treatment was well tolerated and no drug-attributable adverse events were recorded. During the first year of life, the rate of clinical malaria (events per person-year at risk) was 0·15 in the sulphadoxine-pyrimethamine group versus 0·36 in the placebo group (protective efficacy 59% [95% CI 41–72]), and the rate of severe anaemia was 0·06 in the sulphadoxine- pyrimethamine group versus 0·11 in the placebo group (50% [8–73]). Serological responses to EPI vaccines were not affected by the intervention. Interpretation This new approach to malaria control reduced the rate of clinical malaria and severe anaemia by delivering an available and affordable drug through the existing EPI system. Data are urgently needed to assess the potential cost-effectiveness of intermittent treatment in areas with different patterns of malaria endemicity. Lancet 2001; 357: 1471–77 Introduction An estimated 1000 000 malaria deaths per year underline the need for improved malaria control. National malaria control programmes continue to rely on effective case management while attempting the large-scale deployment of insecticide-treated nets and waiting for an effective and affordable vaccine. The dearth of new developments in malaria control makes the optimisation of currently available interventions a priority. Efficient malaria control depends on targeting measures at the groups at highest risk of disease and death. These groups are defined by the level and pattern of malaria endemicity, since the intensity of Plasmodium falciparum transmission and the age pattern of clinical malaria are inversely related. In areas of high falciparum transmission, such as the Kilombero Valley in southern Tanzania, about half of all malaria hospital admissions and deaths are in children younger than 1 year. 1 The clinical manifestations of falciparum infection can also be dependent on the age and intensity of transmission, since younger children tend to present with more severe anaemia than older ones. Because the signs and symptoms of anaemia are non-specific, this disorder commonly goes unrecognised and untreated. Hence a preventive, rather than curative, approach is appealing and would reduce the impact of poor access to curative services. The well-established Expanded Program on Immunisation (EPI) routinely delivers vaccinations to infants and, in the absence of adverse interactions with the vaccines, could be used to deliver antimalarial interventions to the target group in certain settings. Antimalarial chemoprophylaxis in endemic areas has been shown to reduce malaria morbidity, school absenteeism, and all-cause mortality. 2–5 Chemo- prophylaxis has been used in some African schoolchildren, 6,7 but was abandoned due to the threat of resistance. 7 Chemoprophylaxis can also result in the loss of acquired immunity 8 or delay its acquisition, 9–11 leading to a period of increased clinical malaria on cessation of the intervention. There is no evidence of an associated increase in mortality, 10 and the relevance of this rebound still needs to be established. A trial in Tanzania, in which infants aged 2–12 months received weekly Deltaprim (3·125 mg pyrimethamine and 25 mg dapsone), showed the potential positive and negative effects of chemoprophylaxis in this age group. 9 The rate of clinical malaria and severe anaemia was reduced by 61% and 60%, respectively, but discontinuation of chemo- prophylaxis was followed by a period of increased clinical malaria and severe anaemia. The rebound effect, fears over the spread of resistance, costs, and logistical Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo- controlled trial David Schellenberg, Clara Menendez, Elizeus Kahigwa, John Aponte, Josep Vidal, Marcel Tanner, Hassan Mshinda, Pedro Alonso Unidad de Epidemiologia (D Schellenberg MRCP, C Menendez MD, J Aponte MD, P Alonso MD) and Departamento de Microbiologia (J Vidal MD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain; Ifakara Health Research and Development Centre, Kilombero, Tanzania (E Kahigwa MSc, D Schellenberg, H Mshinda PhD); Swiss Tropical Institute, Basel, Switzerland (Prof M Tanner PhD); and St Francis Designated District Hospital, Ministry of Health, Tanzania (E Kahigwa MSc). Correspondence to: Dr Pedro Alonso, Unidad de Epidemiologia, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain (e-mail: alonso@medicina.ub.es)