Impact of Intermittent Preventive Treatment of Malaria in Pregnancy with Dihydroartemisinin-Piperaquine Versus Sulfadoxine-Pyrimethamine on the Incidence of Malaria in Infancy: A Randomised Controlled Trial

Abstract

Background: Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine significantly reduces the burden of malaria during pregnancy compared to the current standard of care, sulfadoxine-pyrimethamine, but its impact on the incidence of malaria during infancy is unknown. Methods: We conducted a double-blind randomised trial to compare the incidence of malaria during infancy among infants born to HIV-uninfected pregnant women who were randomised to monthly IPTp with either dihydroartemisinin-piperaquine or sulfadoxine-pyrimethamine. Infants were followed for all their medical care in a dedicated study clinic including routine assessments conducted every 4 weeks. At any visit, infants with fever and a positive thick blood smear were diagnosed and treated for malaria. The primary outcome was the incidence of malaria during the first 12 months of life. All analyses were done by modified intention to treat. Results: Among 782 women enrolled, 687 were followed through delivery resulting in 678 live births between December 9, 2016 and December 5, 2017; 339 born to mothers randomised to receive sulfadoxine-pyrimethamine and 339 born to mothers randomised to receive dihydroartemisinin-piperaquine. A total of 581 infants (85·7%) were followed to 12 months of age. Overall, the incidence of malaria was lower among infants born to mothers randomised to dihydroartemisinin-piperaquine compared to sulfadoxine-pyrimethamine, but the difference was not statistically significant (1·71 vs 1·98 episodes per person year, incidence rate ratio (IRR) 0·87, 95% CI 0·73-1·03, p=0·11). When stratifying by infant sex and age, IPTp with dihydroartemisinin-piperaquine was associated with a lower incidence of malaria among male infants (IRR 0·75, 95% CI 0·58-0·98, p=0·03) and infants >3-9 months of age (IRR 0·79, 95% CI 0·64-0·98, p=0·03). Interpretation: Compared to IPTp with sulfadoxine-pyrimethamine, IPTp with dihydroartemisinin-piperaquine was associated with a lower incidence of malaria during infancy among male infants and infants >3-9 months of age. Trial Registration: This trial was registered at ClinicalTrials.gov (NCT02793622) Funding Statement: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill and Melinda Gates Foundation. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study was approved by Makerere University School of Biomedical Sciences Ethics Committee, the Uganda National Council of Science and Technology, and the University of California San Francisco Research Ethics Committee. In addition, retrospective approval for the infancy phase of the study was obtained from the London School of Hygiene and Tropical Medicine Ethics Committee. The parents/guardians of all participants provided written informed consent before enrollment.