Safety outcomes.

BackgroundTo mitigate adverse consequences of malaria in pregnancy, the World Health Organization recommends intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine–pyrimethamine. However, the effectiveness of IPTp with sulfadoxine–pyrimethamine has been threatened by widespread Plasmodium 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 compared to dihydroartemisinin–piperaquine. 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 2,757 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, p = 0.70) or sulfadoxine–pyrimethamine (30.0% versus 26.4%, RR 1.14 [95% CI 0.98–1.33]; p = 0.10). The risk of a composite adverse birth outcome was higher with dihydroartemisinin–piperaquine compared to sulfadoxine–pyrimethamine (30.9% versus 26.4%, RR 1.17 [95% CI 1.01–1.36]; p = 0.04). Considering individual adverse birth outcomes, combining dihydroartemisinin–piperaquine plus sulfadoxine–pyrimethamine was associated with a higher risk of small-for-gestational age (23.4% versus 18.7%, RR 1.25 [95% CI 1.04–1.51]; p = 0.02) and low birthweight (8.6% versus 5.8%, RR 1.48 [95 CI 1.04–2.12]; p = 0.03) compared to sulfadoxine–pyrimethamine and a higher risk of preterm delivery (5.3% versus 3.1%, RR 1.73 [95% CI 1.07–2.79]; p = 0.03) compared to dihydroartemisinin–piperaquine. During pregnancy, compared to sulfadoxine–pyrimethamine, dihydroartemisinin–piperaquine was associated with a 94% reduction in the incidence of symptomatic malaria (0.46 versus 0.03 episodes per person-year, incidence rate ratio 0.06 [95% CI 0.03–0.12]; p p ConclusionsDespite the superior antimalarial activity of dihydroartemisinin–piperaquine, sulfadoxine–pyrimethamine alone 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.Trial registrationClinicalTrials.gov (NCT04336189; https://clinicaltrials.gov/study/NCT04336189).