Two-Dose versus Monthly Intermittent Preventive Treatment of Malaria with Sulfadoxine-Pyrimethamine in HIV-Seropositive Pregnant Zambian Women
Identifieur interne : 002F81 ( Istex/Corpus ); précédent : 002F80; suivant : 002F82Two-Dose versus Monthly Intermittent Preventive Treatment of Malaria with Sulfadoxine-Pyrimethamine in HIV-Seropositive Pregnant Zambian Women
Auteurs : Davidson H. Hamer ; Victor Mwanakasale ; William B. Macleod ; Victor Chalwe ; Doreen Mukwamataba ; Davies Champo ; Lawrence Mwananyanda ; Roma Chilengi ; Lwambwa Mubikayi ; Chikuli Kabika Mulele ; Modest Mulenga ; Donald M. Thea ; Christopher J. GillSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2007-12-01.
Abstract
Background. Intermittent preventive treatment of malaria during pregnancy (IPTp) reduces placental infection, maternal anemia, and low birth weight (LBW). However, the optimal dosing regimen in settings in which human immunodeficiency virus (HIV) is highly prevalent among pregnant women remains controversial. Methods. We conducted a randomized, double-blind, placebo-controlled study of IPTp comparing the standard 2-dose sulfadoxine-pyrimethamine (SP) regimen with monthly IPTp among a cohort of HIV-positive pregnant Zambian women. Primary outcomes included placental malaria (by smear and histology) and maternal peripheral parasitemia at delivery. Results. There were no differences between monthly IPTp ( n= 224) and standard IPTp ( n = 232) in placental malaria by histopathology (26% vs. 29%; relative risk [RR], 0.90 [95% confidence interval {CI}, 0.64–1.26]) or placental parasitemia (2% vs. 4%; RR, 0.55 [95% CI, 0.17–1.79]). There also were no differences in maternal anemia, stillbirths, preterm delivery, LBW, or all-cause mortality of infants at 6 weeks. Conclusions. In an area of mesoendemicity in Zambia, monthly SP IPTp was not more efficacious than the standard 2-dose regimen for the prevention of placental malaria or adverse birth outcomes. IPTp policy recommendations need to take into account local malaria transmission patterns and the prevalence of HIV. Trial registration. ClinicalTrials.gov identifier: NCT00270530.
Url:
DOI: 10.1086/522142
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Hamer</name><affiliation><mods:affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: dhamer@bu.edu</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprints or correspondence: Dr. Davidson H. Hamer Center for International Health and Development Boston University School of Public Health 5th Fl. 85 E. Concord St. Boston MA 02118</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: dhamer@bu.edu</mods:affiliation></affiliation></author><author><name sortKey="Mwanakasale, Victor" sort="Mwanakasale, Victor" uniqKey="Mwanakasale V" first="Victor" last="Mwanakasale">Victor Mwanakasale</name><affiliation><mods:affiliation>Tropical Diseases Research Centre, Ndola</mods:affiliation></affiliation></author><author><name sortKey="Macleod, William B" sort="Macleod, William B" uniqKey="Macleod W" first="William B." last="Macleod">William B. Macleod</name><affiliation><mods:affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</mods:affiliation></affiliation></author><author><name sortKey="Chalwe, Victor" sort="Chalwe, Victor" uniqKey="Chalwe V" first="Victor" last="Chalwe">Victor Chalwe</name><affiliation><mods:affiliation>Tropical Diseases Research Centre, Ndola</mods:affiliation></affiliation></author><author><name sortKey="Mukwamataba, Doreen" sort="Mukwamataba, Doreen" uniqKey="Mukwamataba D" first="Doreen" last="Mukwamataba">Doreen Mukwamataba</name><affiliation><mods:affiliation>Tropical Diseases Research Centre, Ndola</mods:affiliation></affiliation></author><author><name sortKey="Champo, Davies" sort="Champo, Davies" uniqKey="Champo D" first="Davies" last="Champo">Davies Champo</name><affiliation><mods:affiliation>Tropical Diseases Research Centre, Ndola</mods:affiliation></affiliation></author><author><name sortKey="Mwananyanda, Lawrence" sort="Mwananyanda, Lawrence" uniqKey="Mwananyanda L" first="Lawrence" last="Mwananyanda">Lawrence Mwananyanda</name><affiliation><mods:affiliation>Tropical Diseases Research Centre, Ndola</mods:affiliation></affiliation></author><author><name sortKey="Chilengi, Roma" sort="Chilengi, Roma" uniqKey="Chilengi R" first="Roma" last="Chilengi">Roma Chilengi</name><affiliation><mods:affiliation>Africa Malaria Network Trust, Dar es Salaam, Tanzania</mods:affiliation></affiliation></author><author><name sortKey="Mubikayi, Lwambwa" sort="Mubikayi, Lwambwa" uniqKey="Mubikayi L" first="Lwambwa" last="Mubikayi">Lwambwa Mubikayi</name><affiliation><mods:affiliation>Ndola Central Hospital, Ndola</mods:affiliation></affiliation></author><author><name sortKey="Mulele, Chikuli Kabika" sort="Mulele, Chikuli Kabika" uniqKey="Mulele C" first="Chikuli Kabika" last="Mulele">Chikuli Kabika Mulele</name><affiliation><mods:affiliation>Mines Hospital, Kitwe, Zambia</mods:affiliation></affiliation></author><author><name sortKey="Mulenga, Modest" sort="Mulenga, Modest" uniqKey="Mulenga M" first="Modest" last="Mulenga">Modest Mulenga</name><affiliation><mods:affiliation>Tropical Diseases Research Centre, Ndola</mods:affiliation></affiliation></author><author><name sortKey="Thea, Donald M" sort="Thea, Donald M" uniqKey="Thea D" first="Donald M." last="Thea">Donald M. Thea</name><affiliation><mods:affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</mods:affiliation></affiliation></author><author><name sortKey="Gill, Christopher J" sort="Gill, Christopher J" uniqKey="Gill C" first="Christopher J." last="Gill">Christopher J. Gill</name><affiliation><mods:affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published" when="2007-12-01">2007-12-01</date><biblScope unit="volume">196</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1585">1585</biblScope><biblScope unit="page" to="1594">1594</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Background. Intermittent preventive treatment of malaria during pregnancy (IPTp) reduces placental infection, maternal anemia, and low birth weight (LBW). However, the optimal dosing regimen in settings in which human immunodeficiency virus (HIV) is highly prevalent among pregnant women remains controversial. Methods. We conducted a randomized, double-blind, placebo-controlled study of IPTp comparing the standard 2-dose sulfadoxine-pyrimethamine (SP) regimen with monthly IPTp among a cohort of HIV-positive pregnant Zambian women. Primary outcomes included placental malaria (by smear and histology) and maternal peripheral parasitemia at delivery. Results. There were no differences between monthly IPTp ( n= 224) and standard IPTp ( n = 232) in placental malaria by histopathology (26% vs. 29%; relative risk [RR], 0.90 [95% confidence interval {CI}, 0.64–1.26]) or placental parasitemia (2% vs. 4%; RR, 0.55 [95% CI, 0.17–1.79]). There also were no differences in maternal anemia, stillbirths, preterm delivery, LBW, or all-cause mortality of infants at 6 weeks. Conclusions. In an area of mesoendemicity in Zambia, monthly SP IPTp was not more efficacious than the standard 2-dose regimen for the prevention of placental malaria or adverse birth outcomes. IPTp policy recommendations need to take into account local malaria transmission patterns and the prevalence of HIV. Trial registration. ClinicalTrials.gov identifier: NCT00270530.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Dr. Davidson H. Hamer</name><affiliations><json:string>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</json:string><json:string>E-mail: dhamer@bu.edu</json:string></affiliations></json:item><json:item><name>Victor Mwanakasale</name><affiliations><json:string>Tropical Diseases Research Centre, Ndola</json:string></affiliations></json:item><json:item><name>William B. MacLeod</name><affiliations><json:string>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</json:string></affiliations></json:item><json:item><name>Victor Chalwe</name><affiliations><json:string>Tropical Diseases Research Centre, Ndola</json:string></affiliations></json:item><json:item><name>Doreen Mukwamataba</name><affiliations><json:string>Tropical Diseases Research Centre, Ndola</json:string></affiliations></json:item><json:item><name>Davies Champo</name><affiliations><json:string>Tropical Diseases Research Centre, Ndola</json:string></affiliations></json:item><json:item><name>Lawrence Mwananyanda</name><affiliations><json:string>Tropical Diseases Research Centre, Ndola</json:string></affiliations></json:item><json:item><name>Roma Chilengi</name><affiliations><json:string>Africa Malaria Network Trust, Dar es Salaam, Tanzania</json:string></affiliations></json:item><json:item><name>Lwambwa Mubikayi</name><affiliations><json:string>Ndola Central Hospital, Ndola</json:string></affiliations></json:item><json:item><name>Chikuli Kabika Mulele</name><affiliations><json:string>Mines Hospital, Kitwe, Zambia</json:string></affiliations></json:item><json:item><name>Modest Mulenga</name><affiliations><json:string>Tropical Diseases Research Centre, Ndola</json:string></affiliations></json:item><json:item><name>Donald M. Thea</name><affiliations><json:string>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</json:string></affiliations></json:item><json:item><name>Christopher J. Gill</name><affiliations><json:string>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</json:string></affiliations></json:item></author><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Background. Intermittent preventive treatment of malaria during pregnancy (IPTp) reduces placental infection, maternal anemia, and low birth weight (LBW). However, the optimal dosing regimen in settings in which human immunodeficiency virus (HIV) is highly prevalent among pregnant women remains controversial. Methods. We conducted a randomized, double-blind, placebo-controlled study of IPTp comparing the standard 2-dose sulfadoxine-pyrimethamine (SP) regimen with monthly IPTp among a cohort of HIV-positive pregnant Zambian women. Primary outcomes included placental malaria (by smear and histology) and maternal peripheral parasitemia at delivery. Results. There were no differences between monthly IPTp ( n= 224) and standard IPTp ( n = 232) in placental malaria by histopathology (26% vs. 29%; relative risk [RR], 0.90 [95% confidence interval {CI}, 0.64–1.26]) or placental parasitemia (2% vs. 4%; RR, 0.55 [95% CI, 0.17–1.79]). There also were no differences in maternal anemia, stillbirths, preterm delivery, LBW, or all-cause mortality of infants at 6 weeks. Conclusions. In an area of mesoendemicity in Zambia, monthly SP IPTp was not more efficacious than the standard 2-dose regimen for the prevention of placental malaria or adverse birth outcomes. IPTp policy recommendations need to take into account local malaria transmission patterns and the prevalence of HIV. Trial registration. ClinicalTrials.gov identifier: NCT00270530.</abstract><qualityIndicators><score>9.412</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 783 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1445</abstractCharCount><pdfWordCount>5183</pdfWordCount><pdfCharCount>33793</pdfCharCount><pdfPageCount>10</pdfPageCount><abstractWordCount>201</abstractWordCount></qualityIndicators><title>Two-Dose versus Monthly Intermittent Preventive Treatment of Malaria with Sulfadoxine-Pyrimethamine in HIV-Seropositive Pregnant Zambian Women</title><genre><json:string>research-article</json:string></genre><host><title>The Journal of Infectious Diseases</title><language><json:string>unknown</json:string></language><issn><json:string>0022-1899</json:string></issn><eissn><json:string>1537-6613</json:string></eissn><publisherId><json:string>jid</json:string></publisherId><volume>196</volume><issue>11</issue><pages><first>1585</first><last>1594</last></pages><genre><json:string>journal</json:string></genre></host><categories><wos><json:string>science</json:string><json:string>microbiology</json:string><json:string>infectious diseases</json:string><json:string>immunology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>biomedical research</json:string><json:string>microbiology</json:string></scienceMetrix><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string></inist></categories><publicationDate>2007</publicationDate><copyrightDate>2007</copyrightDate><doi><json:string>10.1086/522142</json:string></doi><id>9157C299F1F09A7EF956996ADF8BA3226A6AF2DB</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/9157C299F1F09A7EF956996ADF8BA3226A6AF2DB/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/9157C299F1F09A7EF956996ADF8BA3226A6AF2DB/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/9157C299F1F09A7EF956996ADF8BA3226A6AF2DB/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Two-Dose versus Monthly Intermittent Preventive Treatment of Malaria with Sulfadoxine-Pyrimethamine in HIV-Seropositive Pregnant Zambian Women</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://publisher-list.data.istex.fr">The University of Chicago Press</publisher><availability><licence><p>© 2007 by the Infectious Diseases Society of America</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</p></availability><date>2007</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Two-Dose versus Monthly Intermittent Preventive Treatment of Malaria with Sulfadoxine-Pyrimethamine in HIV-Seropositive Pregnant Zambian Women</title><author xml:id="author-0000" corresp="yes"><persName><forename type="first">Davidson H.</forename><surname>Hamer</surname></persName><roleName type="degree">Dr.</roleName><email>dhamer@bu.edu</email><email>dhamer@bu.edu</email><affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</affiliation><affiliation>Reprints or correspondence: Dr. Davidson H. Hamer Center for International Health and Development Boston University School of Public Health 5th Fl. 85 E. Concord St. Boston MA 02118</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Victor</forename><surname>Mwanakasale</surname></persName><affiliation>Tropical Diseases Research Centre, Ndola</affiliation></author><author xml:id="author-0002"><persName><forename type="first">William B.</forename><surname>MacLeod</surname></persName><affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Victor</forename><surname>Chalwe</surname></persName><affiliation>Tropical Diseases Research Centre, Ndola</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Doreen</forename><surname>Mukwamataba</surname></persName><affiliation>Tropical Diseases Research Centre, Ndola</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Davies</forename><surname>Champo</surname></persName><affiliation>Tropical Diseases Research Centre, Ndola</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Lawrence</forename><surname>Mwananyanda</surname></persName><affiliation>Tropical Diseases Research Centre, Ndola</affiliation></author><author xml:id="author-0007"><persName><forename type="first">Roma</forename><surname>Chilengi</surname></persName><affiliation>Africa Malaria Network Trust, Dar es Salaam, Tanzania</affiliation></author><author xml:id="author-0008"><persName><forename type="first">Lwambwa</forename><surname>Mubikayi</surname></persName><affiliation>Ndola Central Hospital, Ndola</affiliation></author><author xml:id="author-0009"><persName><forename type="first">Chikuli Kabika</forename><surname>Mulele</surname></persName><affiliation>Mines Hospital, Kitwe, Zambia</affiliation></author><author xml:id="author-0010"><persName><forename type="first">Modest</forename><surname>Mulenga</surname></persName><affiliation>Tropical Diseases Research Centre, Ndola</affiliation></author><author xml:id="author-0011"><persName><forename type="first">Donald M.</forename><surname>Thea</surname></persName><affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</affiliation></author><author xml:id="author-0012"><persName><forename type="first">Christopher J.</forename><surname>Gill</surname></persName><affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</affiliation></author><idno type="istex">9157C299F1F09A7EF956996ADF8BA3226A6AF2DB</idno><idno type="ark">ark:/67375/HXZ-0L92FXXJ-B</idno><idno type="DOI">10.1086/522142</idno></analytic><monogr><title level="j">The Journal of Infectious Diseases</title><title level="j" type="abbrev">The Journal of Infectious Diseases</title><idno type="pISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><idno type="publisher-id">jid</idno><idno type="PublisherID-hwp">jinfdis</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published" when="2007-12-01"></date><biblScope unit="volume">196</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1585">1585</biblScope><biblScope unit="page" to="1594">1594</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2007</date></creation><abstract><p>Background. Intermittent preventive treatment of malaria during pregnancy (IPTp) reduces placental infection, maternal anemia, and low birth weight (LBW). However, the optimal dosing regimen in settings in which human immunodeficiency virus (HIV) is highly prevalent among pregnant women remains controversial. Methods. We conducted a randomized, double-blind, placebo-controlled study of IPTp comparing the standard 2-dose sulfadoxine-pyrimethamine (SP) regimen with monthly IPTp among a cohort of HIV-positive pregnant Zambian women. Primary outcomes included placental malaria (by smear and histology) and maternal peripheral parasitemia at delivery. Results. There were no differences between monthly IPTp ( n= 224) and standard IPTp ( n = 232) in placental malaria by histopathology (26% vs. 29%; relative risk [RR], 0.90 [95% confidence interval {CI}, 0.64–1.26]) or placental parasitemia (2% vs. 4%; RR, 0.55 [95% CI, 0.17–1.79]). There also were no differences in maternal anemia, stillbirths, preterm delivery, LBW, or all-cause mortality of infants at 6 weeks. Conclusions. In an area of mesoendemicity in Zambia, monthly SP IPTp was not more efficacious than the standard 2-dose regimen for the prevention of placental malaria or adverse birth outcomes. IPTp policy recommendations need to take into account local malaria transmission patterns and the prevalence of HIV. Trial registration. ClinicalTrials.gov identifier: NCT00270530.</p></abstract><textClass><keywords scheme="Journal Subject"><list><head></head><item><term>Parasites</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head></head><item><term>Major Article</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head></head><item><term>Global Theme Issue: Poverty and Human Development</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2007-12-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/9157C299F1F09A7EF956996ADF8BA3226A6AF2DB/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article">
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<abbrev-journal-title>The Journal of Infectious Diseases</abbrev-journal-title>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher>
<publisher-name>The University of Chicago Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.1086/522142</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Major Articles and Brief Reports</subject>
<subj-group>
<subject>Parasites</subject>
<subj-group>
<subject>Major Article</subject>
<subj-group>
<subject>Global Theme Issue: Poverty and Human Development</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Two-Dose versus Monthly Intermittent Preventive Treatment of Malaria with Sulfadoxine-Pyrimethamine in HIV-Seropositive Pregnant Zambian Women</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Hamer</surname>
<given-names>Davidson H.</given-names>
<prefix>Dr.</prefix>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="corresp" rid="cor1"></xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mwanakasale</surname>
<given-names>Victor</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>MacLeod</surname>
<given-names>William B.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chalwe</surname>
<given-names>Victor</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mukwamataba</surname>
<given-names>Doreen</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Champo</surname>
<given-names>Davies</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mwananyanda</surname>
<given-names>Lawrence</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chilengi</surname>
<given-names>Roma</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mubikayi</surname>
<given-names>Lwambwa</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mulele</surname>
<given-names>Chikuli Kabika</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mulenga</surname>
<given-names>Modest</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Thea</surname>
<given-names>Donald M.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Gill</surname>
<given-names>Christopher J.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<aff id="A1">
<label>1</label>
<institution>Center for International Health and Development, Boston University School of Public Health</institution>, <addr-line>Boston, Massachusetts</addr-line>
</aff>
<aff id="A2">
<label>2</label>
<institution>Tropical Diseases Research Centre</institution>, <addr-line>Ndola</addr-line>
</aff>
<aff id="A3">
<label>3</label>
<institution>Ndola Central Hospital</institution>, <addr-line>Ndola</addr-line>
</aff>
<aff id="A4">
<label>4</label>
<institution>Mines Hospital</institution>, <addr-line>Kitwe, Zambia</addr-line>
</aff>
<aff id="A5">
<label>5</label>
<institution>Africa Malaria Network Trust</institution>, <addr-line>Dar es Salaam, Tanzania</addr-line>
</aff>
</contrib-group>
<author-notes>
<corresp id="cor1">Reprints or correspondence: Dr. Davidson H. Hamer Center for International Health and Development Boston University School of Public Health 5th Fl. 85 E. Concord St. Boston MA 02118 (<email>dhamer@bu.edu</email>).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>1</day>
<month>12</month>
<year>2007</year>
</pub-date>
<volume>196</volume>
<issue>11</issue>
<fpage>1585</fpage>
<lpage>1594</lpage>
<history>
<date date-type="received">
<day>20</day>
<month>12</month>
<year>2006</year>
</date>
<date date-type="accepted">
<day>12</day>
<month>6</month>
<year>2007</year>
</date>
</history>
<permissions>
<copyright-statement>© 2007 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2007</copyright-year>
</permissions>
<abstract>
<p><bold><italic>Background.</italic></bold> Intermittent preventive treatment of malaria during pregnancy (IPTp) reduces placental infection, maternal anemia, and low birth weight (LBW). However, the optimal dosing regimen in settings in which human immunodeficiency virus (HIV) is highly prevalent among pregnant women remains controversial.</p>
<p><bold><italic>Methods.</italic></bold> We conducted a randomized, double-blind, placebo-controlled study of IPTp comparing the standard 2-dose sulfadoxine-pyrimethamine (SP) regimen with monthly IPTp among a cohort of HIV-positive pregnant Zambian women. Primary outcomes included placental malaria (by smear and histology) and maternal peripheral parasitemia at delivery.</p>
<p><bold><italic>Results.</italic></bold> There were no differences between monthly IPTp ( <italic>n</italic>= 224) and standard IPTp ( <italic>n</italic> = 232) in placental malaria by histopathology (26% vs. 29%; relative risk [RR], 0.90 [95% confidence interval {CI}, 0.64–1.26]) or placental parasitemia (2% vs. 4%; RR, 0.55 [95% CI, 0.17–1.79]). There also were no differences in maternal anemia, stillbirths, preterm delivery, LBW, or all-cause mortality of infants at 6 weeks.</p>
<p><bold><italic>Conclusions.</italic></bold> In an area of mesoendemicity in Zambia, monthly SP IPTp was not more efficacious than the standard 2-dose regimen for the prevention of placental malaria or adverse birth outcomes. IPTp policy recommendations need to take into account local malaria transmission patterns and the prevalence of HIV.</p>
<p><bold><italic>Trial registration.</italic></bold> ClinicalTrials.gov identifier: NCT00270530.</p>
</abstract>
</article-meta>
</front>
<body>
<p><italic>Plasmodium falciparum</italic> malaria during pregnancy is a risk factor for fetal death, prematurity, intrauterine growth retardation, low birth weight (LBW), maternal anemia, and maternal mortality [<xref ref-type="bibr" rid="R1">1</xref>–<xref ref-type="bibr" rid="R5">5</xref>]. The riskis greater in women infected with HIV, who have higher rates of malarial parasitemia, higher parasite densities and anemia rates, and more frequent placental infections and birth complications than do HIV-negative women [<xref ref-type="bibr" rid="R6">6</xref>–<xref ref-type="bibr" rid="R8">8</xref>].</p>
<p>In Zambia, both HIV and malaria are common, so their interaction has important public health implications. An estimated 3.4 million malaria cases, corresponding to 308 infections/1000 persons/year, occur in Zambia each year [<xref ref-type="bibr" rid="R9">9</xref>]. HIV seroprevalence among pregnant women ranges from 14.4% in rural locales to 26.8% in urban areas [<xref ref-type="bibr" rid="R10">10</xref>].</p>
<p>To address this problem, Zambia's Ministry of Health currently recommends intermittent preventive treatment of malaria during pregnancy (IPTp) using sulfadoxine-pyrimethamine (SP) [<xref ref-type="bibr" rid="R11">11</xref>]. However, the optimal dosing regimen in settings in which HIV is prevalent among pregnant women remains controversial. Asubgroup analysis of HIV-positive pregnant women receiving IPTp in Kenya suggested that, for HIV-positive women, monthly SP was superior to 2 doses given once each in the latter 2 trimesters [<xref ref-type="bibr" rid="R12">12</xref>]. Given the post-hoc nature of this observation and its evident public health implications, we conducted a trial comparing the standard 2-dose SP IPTp regimen (S-IPTp) with intensive monthly SP IPTp (I-IPTp) among a cohort of HIV-positive pregnant Zambian women.</p>
<sec sec-type="methods">
<title>Methods</title>
<p>Between January 2003 and October 2004, we conducted a randomized, double-blind, placebo-controlled study. Our primary outcomes were histological evidence of acute or chronic placental malaria, placental parasitemia, and maternal peripheral parasitemia at delivery. Secondary outcomes included birth weight (including LBW), prematurity, cord blood parasitemia, spontaneous miscarriage, stillbirth or neonatal death, neonatal jaundice, maternal anemia at delivery, third trimester maternal anemia, severe maternal adverse reactions to SP, and symptomatic maternal malarial infection during pregnancy.</p>
<p><bold><italic>Study setting.</italic></bold> The study was conducted at 3 district health clinics (Masala, Lubuto, and Chipokota-Mayamba) in Ndola, an urban center in the Copperbelt Province of Zambia (population, 347,757) [<xref ref-type="bibr" rid="R13">13</xref>]. Malaria transmission in Ndola peaks during the rainy season (November–March). <italic>Anopheles gambiae</italic> and <italic>An. funestus</italic> are the main mosquito vectors.</p>
<p>Starting in December 2003, coincident with the start of our study, the Ndola District Health Management Team launched a campaign of indoor residual spraying (IRS) with pyrethroids and DDT within the Masala catchment area but not in the other 2 study clinic neighborhoods (Lubuto and Chipokota-Mayamba). During the study period, the National Malaria Control Center carried out annual rounds of in vivo efficacy testing of SP in children <5 years old at sentinel sites throughout Zambia. The adequate clinical response to SP was 92% in 2002 in Mpongwe, a district in the Copperbelt Province near Ndola [<xref ref-type="bibr" rid="R14">14</xref>]. In 2003 and 2004, testing was not performed in Mpongwe, but data from the nearest sentinel site, Mansa, revealed a rise in SP total treatment failure rates, from 14.5% in 2003 to 37% in 2004 [<xref ref-type="bibr" rid="R15">15</xref>].</p>
<p><bold><italic>Sample size.</italic></bold> Assuming a frequency of smear-positive placental malaria among HIV-positive women of 25% (as in Parise et al.'s study [<xref ref-type="bibr" rid="R12">12</xref>]) and a 15% decline in placental malaria in the intervention group, with an <italic>a</italic> of 5% and 80% power, 113 HIV-infected women were needed in each arm. Although Parise et al. enrolled only primigravidae and secundigravidae, we assumed similar rates of placental infection among women of all gravidity [<xref ref-type="bibr" rid="R16">16</xref>]. Assuming that 90% of those delivering in the health facility would have their placentas collected and 50% loss to follow-up [<xref ref-type="bibr" rid="R12">12</xref>], our sample size target was 454 subjects.</p>
<p><bold><italic>Enrollment.</italic></bold> At the start of the study, we helped expand voluntary counseling and testing (VCT) for HIV and nevirapine availability at each clinic. HIV-positive women were offered nevirapine for prevention of mother-to-child transmission of HIV. Potential participants were approached about the study only after completing VCT.</p>
<p>HIV-1—seropositive pregnant women of all gravidities who were between 16 and 28 weeks of gestation, were free of an acute illness requiring hospitalization, and were willing to deliver at a study clinic were eligible. Exclusion criteria included age <18 years, prior enrollment in this study, residence outside of or intent to move out of the clinics' catchment area, severe anemia (hemoglobin [Hb] level <6 g/dL), history of allergic reactions to sulfa drugs, prior major pregnancy complications (e.g., breech presentation, severe preeclampsia, and ⩾2 cesarean sections), and major illnesses likely to influence pregnancy outcomes.</p>
<p>To minimize stigma, we initially offered enrollment to every tenth HIV-negative woman and later to every fifth HIV-negative woman. HIV-negative women were not randomized but received the standard 2-dose regimen.</p>
<p><bold><italic>Randomization.</italic></bold> HIV-positive participants were assigned sequential identification numbers during enrollment corresponding to a sealed package of study drugs. Each pack contained 6 medication sheets, representing single monthly doses of medication or placebo. Each sheet consisted of 3 blister-packed tablets. Active tablets contained a total of 500 mg of sulfadoxine and 25 mg of pyrimethamine. Roche Pharmaceuticals prepared the study drugs and placebos in individual patient drug packs according to our randomization scheme.</p>
<p>HIV-positive mothers were randomized in blocks of20 to 1 of 2 dosing schedules: 1 treatment course of SP per month (I-IPTp) or 1 course of SP per trimester (S-IPTp). Randomization codes were retained by the study statistician and stored in a locked cabinet at Boston University. The code was broken when data collection was complete and preliminary blinded analyses had been performed. To ensure that all mothers received at least the 2-dose SP regimen, the first and fourth monthly sheets of each pack always contained active SP, whereas sheets 2, 3, 5, and 6 contained SP (I-IPTp) or placebo (S-IPTp). Pregnant women who began the study at weeks 25 or 26 of gestation were administered their second SP treatment course at their second follow-up visit (i.e., 2 months after their initial study visit).</p>
<p>For quality control, we submitted 2 unused sets of drugs corresponding to the placebo and intervention arms to the World Health Organization's Centre for Quality Assurance of Medicines (Potchefstroom, South Africa). Analysis by high-pressure liquid chromatography confirmed that the intervening month (months 2, 3, 5, and 6) tablets contained either SP or placebo, whereas months 1 and 4 contained SP, as expected.</p>
<p><bold><italic>Study procedures.</italic></bold> At baseline, we collected a mother's demographic information, measured fundal height, and obtained a drop of blood by fingerprick to measure Hb level and for preparation of thick and thin blood smears. Mothers were dewormed with mebendazole, received their first study treatment, and were provided with monthly folate and iron supplements. At monthly follow-up visits, participants completed a questionnaire, underwent an obstetrical examination, and had measurements of temperature and Hb. Study drug was administered monthly under direct observation until mothers reached 36 weeks of gestation. No doses were administered after 36 weeks because of the risk of neonatal kernicterus from sulfonamides. Pregnant women with documented fever or history of recent fever and a positive malaria smear were treated with oral quinine. Team members attempted to contact women if they were >2 days overdue for a scheduled follow-up visit.</p>
<p>At delivery, we measured maternal axillary temperature and maternal and infant Hb levels, obtained biopsy samples from the maternal and fetal sides of the placenta, and prepared thick blood smears of maternal peripheral blood, of maternal and fetal sides of the placenta, and of fetal cord blood. We measured infant weight and estimated the infant‘s gestational age using the Dubowitz criteria [<xref ref-type="bibr" rid="R17">17</xref>]. Mothers returned for follow-up visits at 1 and 6 weeks post partum for determination of the infant’s vital status and screening for residual drug adverse effects.</p>
<p><bold><italic>Laboratory analyses.</italic></bold> A 2-step HIV testing protocol using Determine HIV 1/2 (Abbott Laboratories) as the screening test and Capillus (Cambridge Biotech) as the confirmatory test was performed, with the Bionor assay (Skien) used for indeterminate or discordant results.</p>
<p>Hb levels were measured using a HemoCue machine (HemoCue AB). Thick smears were prepared with a single drop of peripheral or placental blood and air dried. Slides were fixed in methanol and stained in 10% Giemsa at the Tropical Diseases Research Centre (TDRC) and were read independently by 2 parasitologists. The parasite density per microliter was the number of parasites per 200 leukocytes times 40 or the number per 500 leukocytes times 16 if no parasites were seen after counting 200 cells [<xref ref-type="bibr" rid="R18">18</xref>]. Slides were declared to be negative if no parasites were seen after counting 500 leukocytes.</p>
<p>Two 1-cm-wide full-thickness wedge placental biopsy samples were taken by measuring 5 cm centrifugally from the cord.</p>
<p>Samples were fixed in 20% formalin and embedded in paraffin wax. Sections that were 3 μm thick were cut using a Rotary microtome (Lipshaw Manufacturing), fixed to a glass slide, and dehydrated in sequential ethanol baths. The slides were then stained in 0.1% hematoxylin and 1% eosin stains for 5 and 1 min, respectively.</p>
<p>Each slide was read independently by 2 Zambian pathologists (L.M. and C.K.M.). Slides were interpreted according to the classification scheme shown in <xref ref-type="fig" rid="T1">table 1</xref>. Because pathological evidence of malaria might not be uniformly distributed throughout a placental sample, we assigned the interpretation with highest malaria intensity as the final classification. Thus, if a slide from a given section was interpreted as CN by one pathologist and as C3 on another section or by the second pathologist, the final reading was classified as C3.</p>
<p><bold><italic>Definitions.</italic></bold> Pregnant women who presented with fever or a recent history of fever plus any level of parasitemia were categorized as having symptomatic uncomplicated malaria. Maternal peripheral parasitemia was defined as asexual stage parasites in thick smears made from maternal venous blood; placental malaria as positive histological evidence of malaria (C1, C2, or C3); placental parasitemia as the presence of parasites in thick smears of maternal-side placental blood; anemia as Hb level <11 g/dL; severe anemia as Hb level <6 g/dL; LBW as birth weight <2500 g; prematurity as ⩽37 weeks of gestation by the Dubowitz criteria; stillborn as dead delivery after 28 weeks of gestation; spontaneously aborted as delivery before 28 weeks; and neonatal death as death occurring between days 0 ansud 28 post partum.</p>
<p><bold><italic>Statistical analysis.</italic></bold> Data were double-entered into CS-Pro (United States Census Bureau). We used SAS (version 8.2; SAS Institute) for all analyses. Mothers with twins were excluded from the analysis of birth outcomes. We compared the proportions of the main study outcomes by calculating relative risks (RRs) and 95% confidence intervals (CIs) and compared continuous variables using independent <italic>t</italic> tests. Concordance between the pathologists' readings was estimated with the <italic>κ</italic> statistic.</p>
<p>Gestational age was estimated from the last menstrual period (LMP) using a pregnancy calculator. Dubowitz scores were translated into gestational age on the basis of the original regression equation <italic>Y</italic> = gestational age in weeks = 0.2642<italic>x</italic> + 24.595, where <italic>x</italic> = the Dubowitz score [<xref ref-type="bibr" rid="R17">17</xref>]. If the discrepancy between the LMP- and Dubowitz-derived gestational age was >14 days, the Dubowitz score was used.</p>
<p><bold><italic>Ethical considerations.</italic></bold> The Institutional Review Board of the Boston University Medical Center and the TDRC Ethics Committee approved the study. A data safety monitoring board consisting of 2 experts in international child and maternal health research and a statistician conducted a blinded interim safety analysis contrasting rates of serious adverse events midway through study enrollment.</p>
</sec>
<sec sec-type="results">
<title>Results</title>
<p><bold><italic>Study population.</italic></bold> Of 456 HIV-positive women enrolled, 224 were randomized to the intensive regimen and 232 women to the standard regimen (<xref ref-type="fig" rid="F1">figure 1</xref>). Baseline demographic and clinical characteristics were comparable in the 2 groups (<xref ref-type="fig" rid="T2">table 2</xref>). There were significantly more primigravidae in the S-IPTp group, al though the absolute difference between groups was small (8%). Notably, there were no differences in insecticide-treated bed net use, recent antimalarial treatment, or proportion with peripheral parasitemia at baseline. Most participants in both groups had anemia at baseline. Baseline parasitemia rates increased during the rainy season (<xref ref-type="fig" rid="F2">figure 2</xref>).</p>
<p>Similar proportions of mothers were lost to follow-up before delivery in the 2 groups (16.1% for I-IPTp vs. 13.8% for S-IPTp) (<xref ref-type="fig" rid="F1">figure 1</xref>). Placental samples were collected from 95% of the 200 mothers in the S-IPTp group and from 91% of the 188 mothers in the I-IPTp group. There were 3 mothers who delivered twins in each group. Women who completed the study were more likely to be single and to have a flush toilet and were less likely to rent a house.</p>
<p><bold><italic>Efficacy of study regimens.</italic></bold> Women in the I-IPTp group received a median of 4 doses, with 1% receiving only 1 dose, 5% receiving 2 doses, 29% receiving 3 doses, 36% receiving 4 doses, and 29% receiving 5 or more doses. In contrast, 84% of the S-IPTp group received 2 courses of SP, and the remainder received only 1 treatment course. The mean time between the last SP treatment and delivery was 6.7 weeks (SD, 4.3 weeks) in the standard group and 3.4 weeks (SD, 2.5 weeks) in the intensive therapy group. There were no significant differences between the 2 groups in terms oftheir mean Hb levels or proportion with anemia during monthly antenatal visits (data not shown). Symptomatic uncomplicated malaria occurred less frequently in the I-IPTp group; this difference was significant (<italic>P</italic> = .048) (<xref ref-type="fig" rid="T3">table 3</xref>).</p>
<p>Placental biopsy samples were available for 78% (355/456) of the participants. At delivery, the proportion of women was similar in the 2 groups for placental malaria, any evidence of placental malaria by histology (C1+C2+C3), or placental parasitemia (<xref ref-type="fig" rid="T3">table 3</xref>). Substantially more women delivering around the rainy season had histological evidence of placental malaria (<xref ref-type="fig" rid="F3">figure 3</xref>). Similar seasonal trends were noted for placental parasitemia (data not shown). There were also no differences for maternal anemia at delivery, birth weight, or proportion with LBW.</p>
<p>Stratification of the study participants by gravidity revealed that primigravidae and secundigravidae had a lower proportion of maternal parasitemia, placental malaria, and placental parasitemia in the I-IPTp than the S-IPTp group (<xref ref-type="fig" rid="T4">table 4</xref>); however, none of these differences was statistically significant. There were no differences for any of these outcomes between the multigravidae in the 2 groups. Similarly, for secondary outcomes, there were lower rates of symptomatic malaria, maternal anemia, cord blood parasitemia, and LBW in the combined primigravidae and secundigravidae group in the I-IPTp treatment arm relative to the S-IPTp arm (<xref ref-type="fig" rid="T5">table 5</xref>), but these findings were also not statistically significant. With the exception of symptomatic malaria episodes, which were nonsignificantly lower in the I-IPTp group, there were no differences between multigravidae in the 2 study arms.</p>
<p>When stratifying outcomes by the number of SP doses received rather than by randomization group, single-dose SP IPTp (34/387 mothers [8.8%]), compared with 2 or more doses (353/ 387 mothers [91.8%]), was associated with worse maternal and neonatal outcomes (see Gill et al. [<xref ref-type="bibr" rid="R19">19</xref>]).</p>
<p><bold><italic>Adverse events.</italic></bold> Rates of mild adverse events were similar for the 2 groups (data not shown). Rates of serious adverse events were low and did not differ between the study groups for infants (RR for I-IPTp vs. S-IPTp, 1.49 [95% CI, 0.79–2.8]) or mothers (RR for I-IPTp vs. S-IPTp, 1.13 [95% CI, 0.56–2.18]). There was 1 case (1/189 [0.5%]) of neonatal jaundice in the I-IPTp group and none in the S-IPTp group. One mother from the intervention arm died of presumed Stevens-Johnson syndrome. Her symptoms began 3 weeks after receiving her first and only dose of SP. Whether she received sulfonamides through a different source is unknown.</p>
<p>At 6 weeks, all-cause mortality was higher among the I-IPTp infants, but this difference was not significant (9/189 live deliveries for I-IPTp vs. 3/198 for S-IPTp; RR, 3.1 [95% CI, 0.86–11.4]). All but 1 of the deaths occurred during the neonatal period. Of the 9 deaths in the I-IPTp group, 6 occurred in the delivery room, including 4 from birth asphyxia and 2 from severe prematurity; the other 3 deaths were from sepsis. All 3 deaths in the S-IPT group were from birth aspyhxia. Slightly more S-IPT infant deaths were stillbirths, but this difference was not significant (2/191 total deliveries vs. 5/203; RR, 0.43 [95% CI, 0.1–2.2]).</p>
</sec>
<sec sec-type="discussion">
<title>Discussion</title>
<p>We found no evidence that intensive monthly dosing was superior to standard dosing of SP IPTp in HIV-seropositive women in terms of placental malaria, maternal anemia, or birth outcomes. Although rates of 2 primary outcomes (placental parasitemia and maternal peripheral parasitemia) and 2 secondary outcomes (symptomatic malaria episodes and cord blood parasitemia) were lower in the I-IPTp group, none of these differences were statistically significant, and the absolute reduction for each parameter was relatively small. However, since the 95% CIs are relatively wide for most outcomes (with the exception of placental malaria histopathology), we cannot be sure that these do not represent true differences.</p>
<p>A significant strength of this study was its double-blind, placebo-controlled design, considered the gold standard, which avoided theoretical biases associated with the open-label designs of prior IPTp studies [<xref ref-type="bibr" rid="R12">12</xref>, <xref ref-type="bibr" rid="R20">20</xref>]. Additionally, we used the more sensitive primary outcome measure of placental histology [<xref ref-type="bibr" rid="R21">21</xref>], rather than placental impression smears.</p>
<p>Although we were unable to prove that I-IPTp was superior to S-IPTp, the findings are nevertheless highly relevant to the debate over the IPTp optimal policy. Compared with previous studies by Parise et al. [<xref ref-type="bibr" rid="R12">12</xref>] and Filler et al. [<xref ref-type="bibr" rid="R20">20</xref>], the intensity of malaria transmission in our trial was lower, due perhaps to the periurban study sites, drier-than-usual rainy seasons, concurrent expansion of insecticide-treated bed net and IRS use in the Ndola region, and different study population characteristics. In Kenya, with high malaria transmission, Parise et al. [<xref ref-type="bibr" rid="R12">12</xref>] found that I-IPTp was more beneficial than S-IPTp—but only in the HIV-positive group. In Malawi, in a rural location with intense malaria transmission, I-IPTp was superior for HIV-positive and HIV-negative women alike [<xref ref-type="bibr" rid="R20">20</xref>]. In our study, with less intense malaria transmission, there was no difference between the regimens. This difference might be due to a lack of power secondary to lower rates of primary outcomes, with the notable exception of placental malaria based on histopathology, or to study design differences, such as enrollment of pregnant women of all gravidities in our study versus only primigravidae and secundigravidae in the Kenya and Malawi studies [<xref ref-type="bibr" rid="R12">12</xref>, <xref ref-type="bibr" rid="R20">20</xref>]. We chose to evaluate IPTp in HIV-positive women of all gravidities given evidence that HIV-positive primigravidae had a risk of malaria similar to that of multigravid women [<xref ref-type="bibr" rid="R8">8</xref>, <xref ref-type="bibr" rid="R16">16</xref>] and because use of broader eligibility criteria would make the results more generalizable.</p>
<p>Restricting our analysis to women in their first or second pregnancy revealed that rates of placental and peripheral parasitemia were lower in the I-IPTp group. Although the magnitude of this difference was similar to the Kenyan and Malawian studies, the absolute difference in placental parasitemia in our study was small and not statistically significant, perhaps because of lower-than-expected malaria transmission. In contrast, placental malaria occurred slightly less frequently and past placental infection more often in the monthly dosing group among primigravidae and secundigravidae. There were few differences in these outcome measures among the multigravidae. Because of different malaria transmission dynamics and the need for a policy that addresses the needs of all pregnant women and not just those in their first or second pregnancy, our findings highlight the challenges in formulating a single, simple IPT policy that can be widely applied in sub-Saharan Africa.</p>
<p>Concerns have been raised about the continuing efficacy of SP IPT in areas of sub-Saharan Africa with high levels of SP treatment failures [<xref ref-type="bibr" rid="R22">22</xref>]. As described above, in vivo efficacy studies conducted at sentinel sites near our study site revealed a high efficacy of SP in young children [<xref ref-type="bibr" rid="R14">14</xref>], with gradually rising treatment failure rates toward the study's end [<xref ref-type="bibr" rid="R15">15</xref>]. Although in vivo efficacy testing has not been done in pregnant women in Zambia, the high efficacy of SP in 2002 and 2003 in sentinel districts near the study site makes it unlikely that SP resistance was an issue. Moreover, adults are likely to have underlying partial immunity and therefore respond better than children in a setting of rising SP resistance. Regardless, SP was highly efficacious in eliminating peripheral parasitemia and reducing the risk of placental infection in both study regimens.</p>
<p>Of the 456 women enrolled, only 1 had a serious adverse reaction attributed to SP. This unfortunate woman developed fatal Stevens-Johnson syndrome ∼3 weeks after her first SP treatment. Prolonged delays from the time of treatment to the development of a severe reaction are unusual but have been reported [<xref ref-type="bibr" rid="R23">23</xref>–<xref ref-type="bibr" rid="R25">25</xref>], including fatal reactions in patients with AIDS receiving sulfonamides to prevent opportunistic infections [<xref ref-type="bibr" rid="R26">26</xref>, <xref ref-type="bibr" rid="R27">27</xref>]. A recent review estimated a risk of severe adverse reactions to intermittent SP (monthly or less often) of 0%–6.3% [<xref ref-type="bibr" rid="R28">28</xref>]. Passive surveillance for severe adverse events associated with SP and trimethoprim-sulfamethoxazole in Malawi found that life-threatening reactions (including Stevens-Johnson syndrome) occurred infrequently [<xref ref-type="bibr" rid="R29">29</xref>]. Rates were highest in HIV-positive adults (4.9/100,000 SP exposures). Fatal adverse reactions to SP were estimated to be 0.11 deaths/100,000 SP exposures. Although this is reassuring, the fatal reaction associated with SP in the present study highlights the importance of careful monitoring for serious reactions when SP is used for IPTp.</p>
<p>In conclusion, in contrast to prior studies of I-IPTp performed in sites with more intense malaria transmission [<xref ref-type="bibr" rid="R12">12</xref>, <xref ref-type="bibr" rid="R19">19</xref>], we found no convincing evidence that I-IPTp was superior to S-IPTp in an area of relatively mild malaria transmission. However, as described in the accompanying article [<xref ref-type="bibr" rid="R19">19</xref>], single-dose SP IPTp is inferior to ⩾2 doses for the prevention of maternal anemia, LBW, and prematurity. In addition, inadvertent underdosing is a potential vulnerability of standard-dose SP IPTp. From the efficacy standpoint, even though our study did not show a clear advantage of a monthly dosing schedule, factors related to effectiveness, such as the greater simplicity of monthly dosing at a programmatic level, argue in favor of a more intensive schedule.</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>We thank Dr. Carlos Abramowsky of Emory University for performing quality control on the histological samples and the National Malaria Control Center parasitologists in Lusaka for quality control on the malaria blood smears. We also thank Dr. Michael Macdonald and Ms. Christine Ayash for their assistance throughout the study with logistics.</p>
</ack>
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<caption><p>Study profile. I-IPTp, intensive monthly sulfadoxine-pyrimethamine intermittent preventive treatment during pregnancy; S-IPTp, standard 2-dose sulfadoxine-pyrimethamine intermittent preventive treatment during pregnancy.</p></caption>
<graphic mimetype="image" xlink:href="196-11-1585-fig001.tif"></graphic>
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<fig id="F2" position="float">
<label>Figure 2.</label>
<caption><p>Proportion of women with baseline parasitemia, by enrollment date</p></caption>
<graphic mimetype="image" xlink:href="196-11-1585-fig002.tif"></graphic>
</fig>
<fig id="F3" position="float">
<label>Figure 3.</label>
<caption><p>Proportion of women with placental malaria (acute and recent [C1 +C2]), by delivery date</p></caption>
<graphic mimetype="image" xlink:href="196-11-1585-fig003.tif"></graphic>
</fig>
<fig id="T1" position="float">
<label>Table 1.</label>
<caption><p>Pathological criteria used for staging of placental malaria.</p></caption>
<graphic mimetype="image" xlink:href="196-11-1585-tbl001.tif"></graphic>
</fig>
<fig id="T2" position="float">
<label>Table 2.</label>
<caption><p>Baseline characteristics.</p></caption>
<graphic mimetype="image" xlink:href="196-11-1585-tbl002.tif"></graphic>
</fig>
<fig id="T3" position="float">
<label>Table 3.</label>
<caption><p>Delivery outcomes and anemia by treatment group.</p></caption>
<graphic mimetype="image" xlink:href="196-11-1585-tbl003.tif"></graphic>
</fig>
<fig id="T4" position="float">
<label>Table 4.</label>
<caption><p>Primary outcomes (placental and maternal peripheral parasitemia) by treatment group, stratified by gravidity.</p></caption>
<graphic mimetype="image" xlink:href="196-11-1585-tbl004.tif"></graphic>
</fig>
<fig id="T5" position="float">
<label>Table 5.</label>
<caption><p>Secondary outcomes (maternal anemia and birth outcomes) by treatment group, stratified by gravidity.</p></caption>
<graphic mimetype="image" xlink:href="196-11-1585-tbl005.tif"></graphic>
</fig>
</sec>
<fn-group>
<fn fn-type="other">
<p>Potential conflicts of interest: none reported.</p>
</fn>
<fn fn-type="financial-disclosure">
<p>Financial support: Cooperative agreement S1954–21/21 between the Association of Schools of Public Health and the Centers for Disease Control and Prevention (Zambia Boston University Malaria Project); National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant K23-AI062208–03 to C.J.G.).</p>
</fn>
<fn fn-type="presented-at">
<p>Presented in part: 54th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Washington, DC, 11–15 December 2005 (abstract 54).</p>
</fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Two-Dose versus Monthly Intermittent Preventive Treatment of Malaria with Sulfadoxine-Pyrimethamine in HIV-Seropositive Pregnant Zambian Women</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Two-Dose versus Monthly Intermittent Preventive Treatment of Malaria with Sulfadoxine-Pyrimethamine in HIV-Seropositive Pregnant Zambian Women</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="termsOfAddress">Dr.</namePart><namePart type="given">Davidson H.</namePart><namePart type="family">Hamer</namePart><affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</affiliation><affiliation>E-mail: dhamer@bu.edu</affiliation><affiliation>Reprints or correspondence: Dr. Davidson H. Hamer Center for International Health and Development Boston University School of Public Health 5th Fl. 85 E. Concord St. Boston MA 02118</affiliation><affiliation>E-mail: dhamer@bu.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Victor</namePart><namePart type="family">Mwanakasale</namePart><affiliation>Tropical Diseases Research Centre, Ndola</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William B.</namePart><namePart type="family">MacLeod</namePart><affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Victor</namePart><namePart type="family">Chalwe</namePart><affiliation>Tropical Diseases Research Centre, Ndola</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Doreen</namePart><namePart type="family">Mukwamataba</namePart><affiliation>Tropical Diseases Research Centre, Ndola</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Davies</namePart><namePart type="family">Champo</namePart><affiliation>Tropical Diseases Research Centre, Ndola</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lawrence</namePart><namePart type="family">Mwananyanda</namePart><affiliation>Tropical Diseases Research Centre, Ndola</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Roma</namePart><namePart type="family">Chilengi</namePart><affiliation>Africa Malaria Network Trust, Dar es Salaam, Tanzania</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lwambwa</namePart><namePart type="family">Mubikayi</namePart><affiliation>Ndola Central Hospital, Ndola</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chikuli Kabika</namePart><namePart type="family">Mulele</namePart><affiliation>Mines Hospital, Kitwe, Zambia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Modest</namePart><namePart type="family">Mulenga</namePart><affiliation>Tropical Diseases Research Centre, Ndola</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Donald M.</namePart><namePart type="family">Thea</namePart><affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher J.</namePart><namePart type="family">Gill</namePart><affiliation>Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2007-12-01</dateIssued><copyrightDate encoding="w3cdtf">2007</copyrightDate></originInfo><abstract>Background. Intermittent preventive treatment of malaria during pregnancy (IPTp) reduces placental infection, maternal anemia, and low birth weight (LBW). However, the optimal dosing regimen in settings in which human immunodeficiency virus (HIV) is highly prevalent among pregnant women remains controversial. Methods. We conducted a randomized, double-blind, placebo-controlled study of IPTp comparing the standard 2-dose sulfadoxine-pyrimethamine (SP) regimen with monthly IPTp among a cohort of HIV-positive pregnant Zambian women. Primary outcomes included placental malaria (by smear and histology) and maternal peripheral parasitemia at delivery. Results. There were no differences between monthly IPTp ( n= 224) and standard IPTp ( n = 232) in placental malaria by histopathology (26% vs. 29%; relative risk [RR], 0.90 [95% confidence interval {CI}, 0.64–1.26]) or placental parasitemia (2% vs. 4%; RR, 0.55 [95% CI, 0.17–1.79]). There also were no differences in maternal anemia, stillbirths, preterm delivery, LBW, or all-cause mortality of infants at 6 weeks. Conclusions. In an area of mesoendemicity in Zambia, monthly SP IPTp was not more efficacious than the standard 2-dose regimen for the prevention of placental malaria or adverse birth outcomes. IPTp policy recommendations need to take into account local malaria transmission patterns and the prevalence of HIV. Trial registration. ClinicalTrials.gov identifier: NCT00270530.</abstract><relatedItem type="host"><titleInfo><title>The Journal of Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>The Journal of Infectious Diseases</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><subject><topic>Parasites</topic></subject><subject><topic>Major Article</topic></subject><subject><topic>Global Theme Issue: Poverty and Human Development</topic></subject><identifier type="ISSN">0022-1899</identifier><identifier type="eISSN">1537-6613</identifier><identifier type="PublisherID">jid</identifier><identifier type="PublisherID-hwp">jinfdis</identifier><part><date>2007</date><detail type="volume"><caption>vol.</caption><number>196</number></detail><detail type="issue"><caption>no.</caption><number>11</number></detail><extent unit="pages"><start>1585</start><end>1594</end></extent></part></relatedItem><identifier type="istex">9157C299F1F09A7EF956996ADF8BA3226A6AF2DB</identifier><identifier type="DOI">10.1086/522142</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2007 by the Infectious Diseases Society of America</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</recordContentSource><recordOrigin>© 2007 by the Infectious Diseases Society of America</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/document/9157C299F1F09A7EF956996ADF8BA3226A6AF2DB/metadata/json</uri></json:item></metadata><covers><json:item><extension>tiff</extension><original>true</original><mimetype>image/tiff</mimetype><uri>https://api.istex.fr/document/9157C299F1F09A7EF956996ADF8BA3226A6AF2DB/covers/tiff</uri></json:item><json:item><extension>html</extension><original>true</original><mimetype>text/html</mimetype><uri>https://api.istex.fr/document/9157C299F1F09A7EF956996ADF8BA3226A6AF2DB/covers/html</uri></json:item></covers><annexes><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/document/9157C299F1F09A7EF956996ADF8BA3226A6AF2DB/annexes/jpeg</uri></json:item><json:item><extension>gif</extension><original>true</original><mimetype>image/gif</mimetype><uri>https://api.istex.fr/document/9157C299F1F09A7EF956996ADF8BA3226A6AF2DB/annexes/gif</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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