Background To 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 Findings We 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.

Conclusions Despite 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.

Funding National Institute of Allergy and Infectious Diseases, National Institutes of Health (U01AI141308).

The authors have declared no competing interest.

The study was registered with ClinicalTrials.gov (NCT04336189 https://clinicaltrials.gov/)

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The study was approved by the Makerere University School of Biomedical Sciences Research Ethics Committee (SBS 714), the Uganda National Council for Science and Technology (HS 2746), the Uganda National Drug Authority (CTC 0135/2020), and the University of California San Francisco Human Research Protection Program (19-29105).

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