Dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine versus either drug alone for intermittent preventive treatment of malaria in pregnancy: A double-blind, randomized, controlled phase 3 trial from Uganda

Abstract

Background: To 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 findings: We 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, < 2,500 g), 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/tolerability. Combining dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine did not reduce the risk of a composite adverse birth outcome compared to dihydroartemisinin-piperaquine (30.0% versus 30.9%, relative risk (RR) 0.97 [95% CI 0.84-1.12]; 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 < 0.001) and a 97% reduction in the risk of microscopic parasitemia (17.7% versus 0.6%, RR 0.03 [95% CI 0.02-0.05]; p < 0.001), 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. As this study was conducted in an area of high transmission intensity with widespread resistance to sulfadoxine-pyrimethamine, findings may not be generalizable to other settings.

Conclusions: Despite 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 registration: ClinicalTrials.gov (NCT04336189; https://clinicaltrials.gov/study/NCT04336189).

Fig 1. Trial profile.

Fig 2. Primary endpoint and individual adverse birth outcomes, including stratification by gravidity.

All pairwise comparisons included in sub-figures A–C. DP, dihydroartemisinin–piperaquine; SP, sulfadoxine–pyrimethamine; and RR, relative risk. P_interaction denotes p-values from two-way interaction terms evaluating differences in treatment effects between gravidity subgroups.

Fig 3. Continuous maternal and birth outcomes, including stratification by gravidity.

All pairwise comparisons included in sub-figures A–C. DP, dihydroartemisinin–piperaquine; SP, sulfadoxine–pyrimethamine; and MD, mean difference. P_interaction denotes p-values from two-way interaction terms evaluating differences in treatment effects between gravidity subgroups.