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      Scheduled Intermittent Screening with Rapid Diagnostic Tests and Treatment with Dihydroartemisinin-Piperaquine versus Intermittent Preventive Therapy with Sulfadoxine-Pyrimethamine for Malaria in Pregnancy in Malawi: An Open-Label Randomized Controlled Trial

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          Abstract

          Background

          In Africa, most plasmodium infections during pregnancy remain asymptomatic, yet are associated with maternal anemia and low birthweight. WHO recommends intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). However, sulfadoxine-pyrimethamine (SP) efficacy is threatened by high-level parasite resistance. We conducted a trial to evaluate the efficacy and safety of scheduled intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with dihydroartemisinin-piperaquine (DP) as an alternative strategy to IPTp-SP.

          Methods and Findings

          This was an open-label, two-arm individually randomized superiority trial among HIV-seronegative women at three sites in Malawi with high SP resistance. The intervention consisted of three or four scheduled visits in the second and third trimester, 4 to 6 wk apart. Women in the IPTp-SP arm received SP at each visit. Women in the intermittent screening and treatment in pregnancy with DP (ISTp-DP) arm were screened for malaria at every visit and treated with DP if RDT-positive. The primary outcomes were adverse live birth outcome (composite of small for gestational age, low birthweight [<2,500 g], or preterm birth [<37 wk]) in paucigravidae (first or second pregnancy) and maternal or placental plasmodium infection at delivery in multigravidae (third pregnancy or higher). Analysis was by intention to treat.

          Between 21 July 2011 and 18 March 2013, 1,873 women were recruited (1,155 paucigravidae and 718 multigravidae). The prevalence of adverse live birth outcome was similar in the ISTp-DP (29.9%) and IPTp-SP (28.8%) arms (risk difference = 1.08% [95% CI −3.25% to 5.41%]; all women: relative risk [RR] = 1.04 [95% CI 0.90–1.20], p = 0.625; paucigravidae: RR = 1.10 [95% CI 0.92–1.31], p = 0.282; multigravidae: RR = 0.92 [95% CI 0.71–1.20], p = 0.543). The prevalence of malaria at delivery was higher in the ISTp-DP arm (48.7% versus 40.8%; risk difference = 7.85%, [95% CI 3.07%–12.63%]; all women: RR = 1.19 [95% CI 1.07–1.33], p = 0.007; paucigravidae: RR = 1.16 [95% CI 1.04–1.31], p = 0.011; multigravidae: RR = 1.29 [95% CI 1.02–1.63], p = 0.037). Fetal loss was more common with ISTp-DP (2.6% versus 1.3%; RR = 2.06 [95% CI 1.01–4.21], p = 0.046) and highest among non-DP-recipients (3.1%) in the ISTp-DP arm. Limitations included the open-label design.

          Conclusions

          Scheduled screening for malaria parasites with the current generation of RDTs three to four times during pregnancy as part of focused antenatal care was not superior to IPTp-SP in this area with high malaria transmission and high SP resistance and was associated with higher fetal loss and more malaria at delivery.

          Trial Registration

          Pan African Clinical Trials Registry PACTR201103000280319; ISRCTN Registry ISRCTN69800930

          Abstract

          In an open-label randomized controlled trial, Feiko O. ter Kuile and colleagues found that ISTp-DP was not superior to IPTp-SP in an area with high malaria transmission and high SP resistance.

          Author Summary

          Why Was This Study Done?
          • Malaria infection during the course of pregnancy can have devastating consequences on the mother and unborn child.

          • Intermittent preventive treatment in pregnancy (IPTp) with the antimalarial sulfadoxine-pyrimethamine (SP) is one of the main interventions to protect pregnant women during pregnancy in malaria endemic areas in sub-Saharan Africa.

          • The effectiveness of SP, however, is threatened by increasing resistance of the malaria parasite to this drug in east and southern Africa.

          • We conducted this study to evaluate if an alternative strategy consisting of screening pregnant women for malaria with rapid diagnostic tests at regular intervals during pregnancy and then treating the test-positive women with dihydroartemisinin-piperaquine (DP) would reduce the risk of malaria infection and the adverse consequences to the mother and newborn. This strategy is called intermittent screening and treatment in pregnancy (ISTp).

          What Did the Researchers Do and Find?
          • Our team conducted a two-arm, open-label trial to compare the effect of the new ISTp with DP (ISTp-DP) strategy against the existing IPTp with SP (IPTp-SP) strategy (the control arm) in 1,873 pregnant women in southern Malawi, where almost all of the malaria parasites were highly resistant to SP.

          • We found that the rate of malaria infection was high in both groups and that the new ISTp-DP strategy was not any better than the existing IPTp-SP strategy in terms of reducing malaria infection or improving pregnancy outcomes; in fact, women in the ISTp-DP arm had more malaria than women in the IPTp-SP arm.

          What Do These Findings Mean?
          • ISTp-DP with the current generation of rapid diagnostic tests is not a viable alternative strategy to replace IPTp-SP in malaria endemic areas in sub-Saharan Africa, despite the high levels of resistance to SP.

          • IPTp with SP should still be used as one of the interventions against malaria in pregnancy in sub-Saharan Africa.

          • Further studies to explore alternative drugs that can replace SP for IPTp will be required in these areas of high SP resistance.

          Related collections

          Most cited references 33

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          New Ballard Score, expanded to include extremely premature infants.

          The Ballard Maturational Score was refined and expanded to achieve greater accuracy and to include extremely premature neonates. To test validity, accuracy, interrater reliability, and optimal postnatal age at examination, the resulting New Ballard Score (NBS) was assessed for 578 newly born infants and the results were analyzed. Gestational ages ranged from 20 to 44 weeks and postnatal ages at examination ranged from birth to 96 hours. In 530 infants, gestational age by last menstrual period was confirmed by agreement within 2 weeks with gestational age by prenatal ultrasonography (C-GLMP). For these infants, correlation between gestational age by NBS and C-GLMP was 0.97. Mean differences between gestational age by NBS and C-GLMP were 0.32 +/- 1.58 weeks and 0.15 +/- 1.46 weeks among the extremely premature infants (less than 26 weeks) and among the total population, respectively. Correlations between the individual criteria and C-GLMP ranged from 0.72 to 0.82. Interrater reliability of NBS, as determined by correlation between raters who rated the same subgroup of infants, ws 0.95. For infants less than 26 weeks of gestational age, the greatest validity (97% within 2 weeks of C-GLMP) was seen when the examination was performed before 12 hours of postnatal age. For infants at least 26 weeks of gestational age, percentages of agreement with C-GLMP remained constant, averaging 92% for all postnatal age categories up to 96 hours. The NBS is a valid and accurate gestational assessment tool for extremely premature infants and remains valid for the entire newborn infant population.
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            Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: a systematic review.

            In malaria-endemic regions, strategies to control malaria during pregnancy rely on case management of malaria illness and anemia, and preventive measures such as insecticide-treated nets and intermittent preventive therapy (IPT). To determine the effect of increasing resistance to sulfadoxine-pyrimethamine on the efficacy of IPT during pregnancy in Africa. The 6 databases of MEDLINE, EMBASE, SCOPUS, LILACS, Cochrane CENTRAL, and the trial register and bibliographic database of the Malaria in Pregnancy Library were searched for relevant studies regardless of language, published between 1966 and December 2006. The reference lists of all trials identified were searched and researchers were contacted about relevant data. Nine trials of IPT with sulfadoxine-pyrimethamine during pregnancy in Africa were identified and matched by year and location with treatment studies of sulfadoxine-pyrimethamine among symptomatic children. Data on the efficacy of IPT with sulfadoxine-pyrimethamine on placental and peripheral malaria, birth weight, and hemoglobin level/anemia were independently abstracted by 2 investigators. Sulfadoxine-pyrimethamine resistance was defined as the proportion of total treatment failures in symptomatic children by day 14. Four trials compared 2-dose IPT with sulfadoxine-pyrimethamine to case management or placebo in women during their first or second pregnancy. The IPT reduced placental malaria (relative risk [RR], 0.48; 95% CI, 0.35-0.68), low birth weight (RR, 0.71; 95% CI, 0.55-0.92), and anemia (RR, 0.90; 95% CI, 0.81-0.99). The effect did not vary by sulfadoxine-pyrimethamine resistance levels (range, 19%-26%). Efficacy of IPT with sulfadoxine-pyrimethamine was lower among women using insecticide-treated nets. Three trials compared 2-dose with monthly IPT with sulfadoxine-pyrimethamine during pregnancy. Among HIV-positive women in their first or second pregnancy, monthly IPT resulted in less placental malaria (RR, 0.34; 95% CI, 0.18-0.64) and higher birth weight (mean difference, 112 g; 95% CI, 19-205 g) over the range of sulfadoxine-pyrimethamine resistance tested (8%-39%). Among HIV-negative women, there was no conclusive additional effect of monthly dosing (2 trials; 24% and 39% resistance). In areas in which 1 of 4 treatments with sulfadoxine-pyrimethamine fail in children by day 14, the 2-dose IPT with sulfadoxine-pyrimethamine regimen continues to provide substantial benefit to HIV-negative semi-immune pregnant women. However, more frequent dosing is required in HIV-positive women not using cotrimoxazole prophylaxis for opportunistic infections.
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              Intermittent preventive therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine-pyrimethamine and risk of low birth weight in Africa: systematic review and meta-analysis.

              Intermittent preventive therapy with sulfadoxine-pyrimethamine to control malaria during pregnancy is used in 37 countries in sub-Saharan Africa, and 31 of those countries use the standard 2-dose regimen. However, 2 doses may not provide protection during the last 4 to 10 weeks of pregnancy, a pivotal period for fetal weight gain. To perform a systematic review and meta-analysis of trials to determine whether regimens containing 3 or more doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy are associated with a higher birth weight or lower risk of low birth weight (LBW) (<2500 g) than standard 2-dose regimens. ISI Web of Knowledge, EMBASE, SCOPUS, PubMed, LILACS, the Malaria in Pregnancy Library, Cochrane CENTRAL, and trial registries from their inception to December 2012, without language restriction. Eligible studies included randomized and quasi-randomized trials of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine monotherapy. Data were independently abstracted by 2 investigators. Relative risk (RR), mean differences, and 95% CIs were calculated with random-effects models. Of 241 screened studies, 7 trials of 6281 pregnancies were included. The median birth weight in the 2-dose group was 2870 g (range, 2722-3239 g) and on average 56 g higher (95% CI, 29-83 g; I2 = 0%) in the ≥3-dose group. Three or more doses were associated with fewer LBW births (RR, 0.80; 95% CI, 0.69-0.94; I 2 = 0%), with a median LBW risk per 1000 women in the 2-dose group (assumed control group risk) of 167 per 1000 vs 134 per 1000 in the ≥3-dose group (absolute risk reduction, 33 per 1000 [95% CI, 10-52]; number needed to treat = 31). The association was consistent across a wide range of sulfadoxine-pyrimethamine resistance (0% to 96% dihydropteroate-synthase K540E mutations). There was no evidence of small-study bias. The ≥3-dose group had less placental malaria (RR, 0.51; 95% CI, 0.38-0.68; I 2 = 0%, in 6 trials, 63 vs 32 per 1000; absolute risk reduction, 31 per 1000 [95% CI, 20-39]). In primigravid plus secundigravid women, the risk of moderate to severe maternal anemia was lower in the ≥3-dose group (RR, 0.60; 95% CI, 0.36-0.99; I2 = 20%; in 6 trials, 36 vs 22 per 1000; absolute risk reduction, 14 per 1000 [95% CI, 0.4-23]). There were no differences in rates of serious adverse events. Among pregnant women in sub-Saharan Africa, intermittent preventive therapy with 3 or more doses of sulfadoxine-pyrimethamine was associated with a higher birth weight and lower risk of LBW than the standard 2-dose regimens. These data provide support for the new WHO recommendations to provide at least 3 doses of intermittent preventive therapy during pregnancy at each scheduled antenatal care visit in the second and third trimester.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                plos
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                1549-1277
                1549-1676
                13 September 2016
                September 2016
                : 13
                : 9
                Affiliations
                [1 ]College of Medicine, University of Malawi, Blantyre, Malawi
                [2 ]Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
                [3 ]National Malaria Control Programme, Ministry of Health, Lilongwe, Malawi
                [4 ]Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [5 ]Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
                [6 ]Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America
                [7 ]Duke Global Health Institute, Duke University, Durham, North Carolina, United States of America
                Mahidol-Oxford Tropical Medicine Research Unit, THAILAND
                Author notes

                The authors have declared that no competing interests exist.

                • Conceived and designed the experiments: LK BF SMT SM FtK.

                • Performed the experiments: MM LK VM AvE DA CP JS KLT BL SMT.

                • Analyzed the data: MM CK BL DW AK SMT FtK.

                • Contributed reagents/materials/analysis tools: AvE CP JS KLT BL SM.

                • Wrote the first draft of the manuscript: MM FtK.

                • Contributed to the writing of the manuscript: MM LK VM AvE CK DA CP JS KLT BL DW AK BF SMT SM FtK.

                • Enrolled patients: MM LK VM.

                • Agree with the manuscript’s results and conclusions: MM LK VM AvE CK DA CP JS KLT BL DW AK BF SMT SM FtK.

                • All authors have read, and confirm that they meet, ICMJE criteria for authorship.

                Article
                PMEDICINE-D-16-00511
                10.1371/journal.pmed.1002124
                5021271
                27622558
                © 2016 Madanitsa et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 4, Tables: 1, Pages: 19
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001713, European and Developing Countries Clinical Trials Partnership;
                Award ID: #IP.2007.31080.003
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: 46099
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000030, Centers for Disease Control and Prevention;
                Award ID: U01CK000146
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: K08AI100924
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: UL1TR001117
                This study was funded by a grant from the European & Developing Countries Clinical Trials Partnership (Award Number IP.2007.31080.003 to FOtK) ( http://www.edctp.org/), supplemented by funds from the Malaria in Pregnancy Consortium, which is funded through a grant by the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine (Award Number 46099 to FOtK) ( http://www.gatesfoundation.org/). FOtK and CK thank the US Centers for Disease Control and Prevention for salary support through a cooperative agreement between the Division of Parasitic Diseases and Malaria (Centers for Disease Control and Prevention, USA) and the Malaria Epidemiology Unit of the Liverpool School of Tropical Medicine (LSTM) held by FOtK (Award Number U01CK000146) ( https://www.cdc.gov/malaria/). SMT is supported by the National Institute of Allergy and Infectious Diseases (Award Number K08AI100924) ( https://www.niaid.nih.gov). Parasite genotyping was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (Award Number UL1TR001117) ( https://ncats.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Parasitic Diseases
                Malaria
                Medicine and Health Sciences
                Tropical Diseases
                Malaria
                Biology and Life Sciences
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                Protozoans
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                Custom metadata
                The complete patient-level data have been made available for access with the WorldWide Antimalarial Resistance Network (WWARN) at www.WWARN.org. Requests for access will be reviewed by a Data Access Committee to ensure that use of data protects patient privacy according to the terms of consent and ethics approval.

                Medicine

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