Comparative effectiveness of sulfadoxine-pyrimethamine plus amodiaquine versus other antimalarial regimens for paediatric malaria chemoprevention in the context of drug resistance: a systematic review and meta-analysis

Each year, over 50 million children receive preventive malaria treatment. However, to date there has been no consensus on the most effective antimalarial drugs to use, especially given geographic differences in drug resistance. Here, we conduct a systematic review comparing the effectiveness of the most commonly used antimalarial chemopreventive regimen, sulfadoxine-pyrimethamine plus amodiaquine (SP+AQ), with other antimalarial drugs in preventing new infections. We searched MEDLINE, Embase, Global Health, PubMed and WWARN clinical trial databases until 06 December 2025 for studies satisfying the inclusion criteria. Studies were included if they were peer-reviewed, randomised-controlled studies in Africa, measuring incidence of infection or clinical episodes of Plasmodium falciparum malaria for at least 28 days post-treatment. We also compiled data on the prevalence of markers of resistance in the parasite dhfr, dhps and mdr1 genes in the study areas. We conducted meta-analyses of incidence rates, with subgroup analyses by drug resistance levels. This review is registered on PROSPERO (CRD42024577149). We identified 27 studies representing 38,252 participants in 32 sites across 13 countries. In pooled analysis, SP+AQ reduced incidence of malaria by 54.6% (95% CI: 33.8-68.8%) compared to SP alone, including significantly outperforming SP even in areas with low SP resistance. These findings suggest that countries currently using SP alone for chemoprevention should consider switching to SP+AQ. Where AQ resistance remains low, available evidence suggests SP+AQ remains efficacious for malaria chemoprevention. SP+AQ was comparable to the artemisinin-based treatment, dihydroartemisinin-piperaquine across all studies (incidence rate ratio 0.93; 95% CI 0.78-1.11). By resistance levels, SP+AQ had slightly higher efficacy in areas with low SP and AQ resistance but had comparable or slightly lower efficacy in areas with higher resistance. Using artemisinin-based treatments for chemoprevention must be balanced against the risk of worsening artemisinin resistance in Eastern and Southern Africa. This study was funded by the UK Royal Society.