{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:42:15Z","timestamp":1791384135342,"version":"4.3.3"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U01AI141308"],"award-info":[{"award-number":["U01AI141308"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>To mitigate adverse consequences of malaria in pregnancy, the World Health Organization recommends intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine\u2013pyrimethamine. However, the effectiveness of IPTp with sulfadoxine\u2013pyrimethamine has been threatened by widespread <jats:italic>Plasmodium falciparum<\/jats:italic> resistance, especially in East and Southern Africa. For IPTp, dihydroartemisinin\u2013piperaquine has shown superior antimalarial effects compared to sulfadoxine\u2013pyrimethamine, but sulfadoxine\u2013pyrimethamine has been associated with improved birth outcomes compared to dihydroartemisinin\u2013piperaquine. We hypothesized that a combination of both dihydroartemisinin\u2013piperaquine and sulfadoxine\u2013pyrimethamine would provide superior birth outcomes compared to either drug alone.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>We conducted a double-blinded, randomized, controlled trial of 2,757 pregnant women in Uganda, where resistance of malaria parasites to sulfadoxine\u2013pyrimethamine is widespread. Women were randomly assigned (1:1:1) to monthly IPTp with sulfadoxine\u2013pyrimethamine, dihydroartemisinin\u2013piperaquine, or dihydroartemisinin\u2013piperaquine plus sulfadoxine\u2013pyrimethamine. The primary outcome was the risk of a composite adverse birth outcome defined as any of the following: spontaneous abortion, stillbirth, low birthweight (LBW,\u2009&lt;\u20092,500\u2009g), preterm delivery (&lt;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\u2013piperaquine plus sulfadoxine\u2013pyrimethamine did not reduce the risk of a composite adverse birth outcome compared to dihydroartemisinin\u2013piperaquine (30.0% versus 30.9%, relative risk (RR) 0.97 [95% CI 0.84\u20131.12]; <jats:italic>p<\/jats:italic>\u2009=\u20090.70) or sulfadoxine\u2013pyrimethamine (30.0% versus 26.4%, RR 1.14 [95% CI 0.98\u20131.33]; <jats:italic>p<\/jats:italic>\u2009=\u20090.10). The risk of a composite adverse birth outcome was higher with dihydroartemisinin\u2013piperaquine compared to sulfadoxine\u2013pyrimethamine (30.9% versus 26.4%, RR 1.17 [95% CI 1.01\u20131.36]; <jats:italic>p<\/jats:italic>\u2009=\u20090.04). Considering individual adverse birth outcomes, combining dihydroartemisinin\u2013piperaquine plus sulfadoxine\u2013pyrimethamine was associated with a higher risk of small-for-gestational age (23.4% versus 18.7%, RR 1.25 [95% CI 1.04\u20131.51]; <jats:italic>p<\/jats:italic>\u2009=\u20090.02) and low birthweight (8.6% versus 5.8%, RR 1.48 [95 CI 1.04\u20132.12]; <jats:italic>p<\/jats:italic>\u2009=\u20090.03) compared to sulfadoxine\u2013pyrimethamine and a higher risk of preterm delivery (5.3% versus 3.1%, RR 1.73 [95% CI 1.07\u20132.79]; <jats:italic>p<\/jats:italic>\u2009=\u20090.03) compared to dihydroartemisinin\u2013piperaquine. During pregnancy, compared to sulfadoxine\u2013pyrimethamine, dihydroartemisinin\u2013piperaquine 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\u20130.12]; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and a 97% reduction in the risk of microscopic parasitemia (17.7% versus 0.6%, RR 0.03 [95% CI 0.02\u20130.05]; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001), but dihydroartemisinin\u2013piperaquine plus sulfadoxine\u2013pyrimethamine was not associated with improved malaria outcomes over dihydroartemisinin\u2013piperaquine alone. There were no significant differences in the incidence of any grade 3\u20134 adverse events between the treatment arms. As this study was conducted in an area of high transmission intensity with widespread resistance to sulfadoxine\u2013pyrimethamine, findings may not be generalizable to other settings.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Despite the superior antimalarial activity of dihydroartemisinin\u2013piperaquine, sulfadoxine\u2013pyrimethamine alone was associated with improved birth outcomes. Combining dihydroartemisinin\u2013piperaquine plus sulfadoxine\u2013pyrimethamine for IPTp did not improve birth outcomes compared to either sulfadoxine\u2013pyrimethamine or dihydroartemisinin\u2013piperaquine alone.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p>ClinicalTrials.gov (NCT04336189; <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT04336189\" xlink:type=\"simple\">https:\/\/clinicaltrials.gov\/study\/NCT04336189<\/jats:ext-link>).<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pmed.1004582","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T17:21:43Z","timestamp":1758216103000},"page":"e1004582","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Dihydroartemisinin\u2013piperaquine plus sulfadoxine\u2013pyrimethamine versus either drug alone for intermittent preventive treatment of malaria in pregnancy: A double-blind, randomized, controlled phase 3 trial from Uganda"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9941-1309","authenticated-orcid":true,"given":"Abel","family":"Kakuru","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0224-4044","authenticated-orcid":true,"given":"Jimmy","family":"Kizza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Aguti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harriet","family":"Adrama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6604-2532","authenticated-orcid":true,"given":"John","family":"Ategeka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Olwoch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Nakalembe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7818-3845","authenticated-orcid":true,"given":"Joaniter I.","family":"Nankabirwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bishop","family":"Opira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nida","family":"Ozarslan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anju","family":"Ranjit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3380-5353","authenticated-orcid":true,"given":"Erin","family":"dela Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara D.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6268-0801","authenticated-orcid":true,"given":"Michelle E.","family":"Roh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0891-6964","authenticated-orcid":true,"given":"Stephanie L.","family":"Gaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6305-758X","authenticated-orcid":true,"given":"Prasanna","family":"Jagannathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Rosenthal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9106-4234","authenticated-orcid":true,"given":"Moses 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