Safety and efficacy of intermittent presumptive treatment with sulfadoxine-pyrimethamine using rapid diagnostic test screening and treatment with dihydroartemisinin-piperaquine at the first antenatal care visit (IPTp-SP+): study protocol for a randomized controlled trial

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Abstract

Background

Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by the World Health Organization for the prevention of malaria in pregnancy (MIP)-associated adverse outcomes in high burden areas. However, the efficacy of IPTp-SP has decreased in step with increasing parasite drug resistance. Suitable alternative strategies are needed.

Methods

This is a protocol for a phase IIIb open-label, two-armed randomized controlled superiority trial to assess the safety and efficacy of a hybrid approach to IPTp combining screening and treatment with dihydroartemisinin-piperaquine (DP) to the current IPTp-SP regimen at the first antenatal care clinic visit. Pregnant women without HIV infection and without signs or symptoms of malaria will be randomized to either standard IPTp-SP or hybrid IPTp-SP plus screening and treatment (IPTp-SP+). In the IPTp-SP+ arm, participants who screen positive by rapid diagnostic test for P. falciparum will be treated with DP at the first antenatal visit while those who screen negative will receive SP per current guidelines. All participants will be administered SP on days 35 and 63 and will be actively followed biweekly up to day 63 and then monthly until delivery. Infants will be followed until 1 year after delivery. The primary endpoint is incident PCR-confirmed MIP at day 42. Secondary endpoints include incident MIP at other time points, placental malaria, congenital malaria, hemoglobin trends, birth outcomes, and incidence of adverse events in infants up to the first birthday.

Discussion

A hybrid approach to IPTp that combines screening and treatment with an artemisinin-based combination therapy at the first visit with standard IPTp-SP is hypothesized to confer added benefit over IPTp-SP alone in a high malaria transmission area with prevalent SP resistant parasites.

Trial registration

Pan African Clinical Trials Registry 201905721140808. Registered retrospectively on 11 May 2019

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-021-05745-0.

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Most cited references 49

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SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials

An-Wen Chan, Jennifer Tetzlaff, Peter C. Gøtzsche … (2014)

High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.

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Epidemiology and burden of malaria in pregnancy.

Meghna Desai, Feiko ter Kuile, François Nosten … (2007)

We reviewed evidence of the clinical implications and burden of malaria in pregnancy. Most studies come from sub-Saharan Africa, where approximately 25 million pregnant women are at risk of Plasmodium falciparum infection every year, and one in four women have evidence of placental infection at the time of delivery. P falciparum infections during pregnancy in Africa rarely result in fever and therefore remain undetected and untreated. Meta-analyses of intervention trials suggest that successful prevention of these infections reduces the risk of severe maternal anaemia by 38%, low birthweight by 43%, and perinatal mortality by 27% among paucigravidae. Low birthweight associated with malaria in pregnancy is estimated to result in 100,000 infant deaths in Africa each year. Although paucigravidae are most affected by malaria, the consequences for infants born to multigravid women in Africa may be greater than previously appreciated. This is because HIV increases the risk of malaria and its adverse effects, particularly in multigravidae, and recent observational studies show that placental infection almost doubles the risk of malaria infection and morbidity in infants born to multigravidae. Outside Africa, malaria infection rates in pregnant women are much lower but are more likely to cause severe disease, preterm births, and fetal loss. Plasmodium vivax is common in Asia and the Americas and, unlike P falciparum, does not cytoadhere in the placenta, yet, is associated with maternal anaemia and low birthweight. The effect of infection in the first trimester, and the longer term effects of malaria beyond infancy, are largely unknown and may be substantial. Better estimates are also needed of the effects of malaria in pregnancy outside Africa, and on maternal morbidity and mortality in Africa. Global risk maps will allow better estimation of potential impact of successful control of malaria in pregnancy.

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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.

Kassoum Kayentao, Paul Garner, Anne Maria van Eijk … (2013)

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

Jean-Bertin Bukasa Kabuya:

ORCID: http://orcid.org/0000-0003-0339-9101

jeanbertinkabuya@yahoo.com

Matthew M. Ippolito: mippolito@jhu.edu

Jay Sikalima: jsikalima@gmail.com

Clifford Tende: tendeclifford@gmail.com

Davies Champo: dchampo@gmail.com

David Mwakazanga: david.mwakazanga@gmail.com

Anna Marie P. Young: ayoung93@jhmi.edu

Modest Mulenga: m.mulenga@hotmail.com

Gershom Chongwe: gchongwe@gmail.com

Christine Manyando: cmanyando@yahoo.com

Journal

Journal ID (nlm-ta): Trials

Journal ID (iso-abbrev): Trials

Title: Trials

Publisher: BioMed Central (London )

ISSN (Electronic): 1745-6215

Publication date (Electronic): 20 November 2021

Publication date PMC-release: 20 November 2021

Publication date Collection: 2021

Volume: 22

Electronic Location Identifier: 820

Affiliations

[1 ]GRID grid.420155.7, Department of Clinical Sciences, , Tropical Diseases Research Centre, ; P.O. Box 71769, Copperbelt Province, Ndola, Zambia

[2 ]GRID grid.21107.35, ISNI 0000 0001 2171 9311, Johns Hopkins University School of Medicine, ; Baltimore, MD USA

[3 ]GRID grid.21107.35, ISNI 0000 0001 2171 9311, Johns Hopkins Bloomberg School of Public Health, ; Baltimore, MD USA

Author information

Jean-Bertin Bukasa Kabuya http://orcid.org/0000-0003-0339-9101

Article

Publisher ID: 5745

DOI: 10.1186/s13063-021-05745-0

PMC ID: 8605457

SO-VID: 775772a8-ad3b-4c06-a6a0-8a120ef6c303

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 21 April 2021

Date accepted : 20 October 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001713, European and Developing Countries Clinical Trials Partnership;

Award ID: TMA2016CDF-1584

Award Recipient : Jean-Bertin Bukasa Kabuya

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: malaria in pregnancy,intermittent presumptive therapy,zambia,sulfadoxine-pyrimethamine,dihydroartemisinin-piperaquine

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ScienceOpen disciplines: Medicine

Keywords: malaria in pregnancy, intermittent presumptive therapy, zambia, sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine

Safety and efficacy of intermittent presumptive treatment with sulfadoxine-pyrimethamine using rapid diagnostic test screening and treatment with dihydroartemisinin-piperaquine at the first antenatal care visit (IPTp-SP+): study protocol for a randomized controlled trial

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Abstract

Background

Methods

Discussion

Trial registration

Supplementary Information

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Karger: Ophthalmology

Most cited references 49

SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials

Epidemiology and burden of malaria in pregnancy.

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.

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