Dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine versus either drug alone for intermittent preventive treatment of malaria in pregnancy: a double-blind, randomized, controlled trial

BackgroundTo mitigate adverse consequences of malaria in pregnancy, the World Health Organization recommends intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine. However, the effectiveness of IPTp with sulfadoxine-pyrimethamine has been threatened by widespread P. falciparum resistance, especially in East and southern Africa. For IPTp, dihydroartemisinin-piperaquine has shown superior antimalarial effects compared to sulfadoxine-pyrimethamine, but sulfadoxine-pyrimethamine has been associated with improved birth outcomes. We hypothesized that a combination of both dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine would provide superior birth outcomes compared to either drug alone. Methods and FindingsWe conducted a double-blinded, randomized, controlled trial of 2757 pregnant women in Uganda, where resistance of malaria parasites to sulfadoxine-pyrimethamine is widespread. Women were randomly assigned (1:1:1) to monthly IPTp with sulfadoxine-pyrimethamine, dihydroartemisinin- piperaquine, or dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine. The primary outcome was the risk of a composite adverse birth outcome defined as any of the following: spontaneous abortion, stillbirth, low birthweight (LBW, <2500 gm), preterm delivery (<37 weeks), small-for-gestational age, or neonatal death. Secondary outcomes included specific individual adverse birth outcomes, measures of malaria during pregnancy, and safety. The risk of a composite adverse birth outcome was lower with sulfadoxine-pyrimethamine compared to dihydroartemisinin-piperaquine (26.4% vs. 30.9%, p=0.04). Combining dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine did not reduce the risk of a composite birth outcome compared to dihydroartemisinin-piperaquine (30.0% vs. 30.9%, p=0.70) or sulfadoxine-pyrimethamine (30.0% vs. 26.4%; p=0.10). Considering individual adverse birth outcomes, compared to sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine was associated with a lower risk of preterm birth (3.1% vs. 5.9%, p=0.007) and a higher risk of small-for-gestational age (22.4% vs. 14.8%, p=0.0006) and low birthweight (6.4% vs. 3.4%, p=0.016) among multigravidae. Combining DP+SP was associated with a higher risk of small-for-gestational age (19.4% vs. 14.8%, p=0.031) and low birthweight (7.1% vs. 3.4%, p=0.0039) among multigravidae compared to sulfadoxine-pyrimethamine. During pregnancy, compared to sulfadoxine-pyrimethamine, dihydroartemisinin- piperaquine was associated with a 94% [88%-97%] reduction in the incidence of symptomatic malaria (0.46 vs. 0.03 episodes per person-year, p<0.0001) and a 97% [95%-98%] reduction in the risk of microscopic parasitaemia (17.7% vs. 0.6%, p<0.0001), but dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine was not associated with improved malaria outcomes over dihydroartemisinin-piperaquine alone. There were no significant differences in the incidence of any grade 3-4 adverse events between the treatment arms. ConclusionsDespite the superior antimalarial activity of dihydroartemisinin-piperaquine, sulfadoxine-pyrimethamine was associated with improved birth outcomes. Combining dihydroartemisinin- piperaquine plus sulfadoxine-pyrimethamine for IPTp did not improve birth outcomes compared to either sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine alone. FundingNational Institute of Allergy and Infectious Diseases, National Institutes of Health (U01AI141308). Trial registrationClinicalTrials.gov (NCT04336189)