P. falciparum infection and maternofetal antibody transfer in malaria-endemic settings of varying transmission
Identifieur interne : 002999 ( Pmc/Corpus ); précédent : 002998; suivant : 002A00P. falciparum infection and maternofetal antibody transfer in malaria-endemic settings of varying transmission
Auteurs : Alistair R. D. Mclean ; Danielle Stanisic ; Rose Mcgready ; Kesinee Chotivanich ; Caroline Clapham ; Francesca Baiwog ; Mupawjay Pimanpanarak ; Peter Siba ; Ivo Mueller ; Christopher L. King ; François Nosten ; James G. Beeson ; Stephen Rogerson ; Julie A. Simpson ; Freya J. I. FowkesSource :
- PLoS ONE [ 1932-6203 ] ; 2017.
Abstract
During pregnancy, immunoglobulin G (IgG) is transferred from the mother to the fetus, providing protection from disease in early infancy.
Mother-cord paired serum samples collected at delivery from Papua New Guinea (PNG) and the Thailand-Myanmar Border Area (TMBA) were tested for IgG1 and IgG3 to four
Maternofetal antibody transfer efficiency of IgG1 and IgG3 was lower in PNG compared to TMBA (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.88 to 0.09, median of -0.20 log2 units). Placental
Primigravid women may be at risk of impaired maternofetal antibody transport with placental
Url:
DOI: 10.1371/journal.pone.0186577
PubMed: 29028827
PubMed Central: 5640245
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PMC:5640245Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>P</italic>. <italic>falciparum</italic> infection and maternofetal antibody transfer in malaria-endemic settings of varying transmission</title><author><name sortKey="Mclean, Alistair R D" sort="Mclean, Alistair R D" uniqKey="Mclean A" first="Alistair R. D." last="Mclean">Alistair R. D. Mclean</name><affiliation><nlm:aff id="aff001"><addr-line>Burnet Institute, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Myanmar Oxford Clinical Research Unit, Yangon, Myanmar</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stanisic, Danielle" sort="Stanisic, Danielle" uniqKey="Stanisic D" first="Danielle" last="Stanisic">Danielle Stanisic</name><affiliation><nlm:aff id="aff004"><addr-line>Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mcgready, Rose" sort="Mcgready, Rose" uniqKey="Mcgready R" first="Rose" last="Mcgready">Rose Mcgready</name><affiliation><nlm:aff id="aff005"><addr-line>Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chotivanich, Kesinee" sort="Chotivanich, Kesinee" uniqKey="Chotivanich K" first="Kesinee" last="Chotivanich">Kesinee Chotivanich</name><affiliation><nlm:aff id="aff007"><addr-line>Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Clapham, Caroline" sort="Clapham, Caroline" uniqKey="Clapham C" first="Caroline" last="Clapham">Caroline Clapham</name><affiliation><nlm:aff id="aff008"><addr-line>Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Baiwog, Francesca" sort="Baiwog, Francesca" uniqKey="Baiwog F" first="Francesca" last="Baiwog">Francesca Baiwog</name><affiliation><nlm:aff id="aff008"><addr-line>Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pimanpanarak, Mupawjay" sort="Pimanpanarak, Mupawjay" uniqKey="Pimanpanarak M" first="Mupawjay" last="Pimanpanarak">Mupawjay Pimanpanarak</name><affiliation><nlm:aff id="aff005"><addr-line>Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Siba, Peter" sort="Siba, Peter" uniqKey="Siba P" first="Peter" last="Siba">Peter Siba</name><affiliation><nlm:aff id="aff008"><addr-line>Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mueller, Ivo" sort="Mueller, Ivo" uniqKey="Mueller I" first="Ivo" last="Mueller">Ivo Mueller</name><affiliation><nlm:aff id="aff009"><addr-line>Population Health & Immunity Division, WEHI, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff010"><addr-line>Malaria: Parasites & Hosts Unit, Institut Pasteur, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff011"><addr-line>Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="King, Christopher L" sort="King, Christopher L" uniqKey="King C" first="Christopher L." last="King">Christopher L. King</name><affiliation><nlm:aff id="aff012"><addr-line>Center for Global Health and Diseases, Case Western Reserve University, and Veterans Affairs Medical Center, Cleveland, OH, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nosten, Francois" sort="Nosten, Francois" uniqKey="Nosten F" first="François" last="Nosten">François Nosten</name><affiliation><nlm:aff id="aff005"><addr-line>Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Beeson, James G" sort="Beeson, James G" uniqKey="Beeson J" first="James G." last="Beeson">James G. Beeson</name><affiliation><nlm:aff id="aff001"><addr-line>Burnet Institute, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff013"><addr-line>Department of Medicine, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff014"><addr-line>Department of Microbiology and Central Clinical School, Monash University, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rogerson, Stephen" sort="Rogerson, Stephen" uniqKey="Rogerson S" first="Stephen" last="Rogerson">Stephen Rogerson</name><affiliation><nlm:aff id="aff013"><addr-line>Department of Medicine, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Simpson, Julie A" sort="Simpson, Julie A" uniqKey="Simpson J" first="Julie A." last="Simpson">Julie A. Simpson</name><affiliation><nlm:aff id="aff002"><addr-line>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fowkes, Freya J I" sort="Fowkes, Freya J I" uniqKey="Fowkes F" first="Freya J. I." last="Fowkes">Freya J. I. Fowkes</name><affiliation><nlm:aff id="aff001"><addr-line>Burnet Institute, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff015"><addr-line>Department of Epidemiology and Preventative Medicine, Monash University, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29028827</idno><idno type="pmc">5640245</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640245</idno><idno type="RBID">PMC:5640245</idno><idno type="doi">10.1371/journal.pone.0186577</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">002999</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002999</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>P</italic>. <italic>falciparum</italic> infection and maternofetal antibody transfer in malaria-endemic settings of varying transmission</title><author><name sortKey="Mclean, Alistair R D" sort="Mclean, Alistair R D" uniqKey="Mclean A" first="Alistair R. D." last="Mclean">Alistair R. D. Mclean</name><affiliation><nlm:aff id="aff001"><addr-line>Burnet Institute, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Myanmar Oxford Clinical Research Unit, Yangon, Myanmar</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stanisic, Danielle" sort="Stanisic, Danielle" uniqKey="Stanisic D" first="Danielle" last="Stanisic">Danielle Stanisic</name><affiliation><nlm:aff id="aff004"><addr-line>Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mcgready, Rose" sort="Mcgready, Rose" uniqKey="Mcgready R" first="Rose" last="Mcgready">Rose Mcgready</name><affiliation><nlm:aff id="aff005"><addr-line>Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chotivanich, Kesinee" sort="Chotivanich, Kesinee" uniqKey="Chotivanich K" first="Kesinee" last="Chotivanich">Kesinee Chotivanich</name><affiliation><nlm:aff id="aff007"><addr-line>Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Clapham, Caroline" sort="Clapham, Caroline" uniqKey="Clapham C" first="Caroline" last="Clapham">Caroline Clapham</name><affiliation><nlm:aff id="aff008"><addr-line>Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Baiwog, Francesca" sort="Baiwog, Francesca" uniqKey="Baiwog F" first="Francesca" last="Baiwog">Francesca Baiwog</name><affiliation><nlm:aff id="aff008"><addr-line>Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pimanpanarak, Mupawjay" sort="Pimanpanarak, Mupawjay" uniqKey="Pimanpanarak M" first="Mupawjay" last="Pimanpanarak">Mupawjay Pimanpanarak</name><affiliation><nlm:aff id="aff005"><addr-line>Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Siba, Peter" sort="Siba, Peter" uniqKey="Siba P" first="Peter" last="Siba">Peter Siba</name><affiliation><nlm:aff id="aff008"><addr-line>Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mueller, Ivo" sort="Mueller, Ivo" uniqKey="Mueller I" first="Ivo" last="Mueller">Ivo Mueller</name><affiliation><nlm:aff id="aff009"><addr-line>Population Health & Immunity Division, WEHI, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff010"><addr-line>Malaria: Parasites & Hosts Unit, Institut Pasteur, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff011"><addr-line>Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="King, Christopher L" sort="King, Christopher L" uniqKey="King C" first="Christopher L." last="King">Christopher L. King</name><affiliation><nlm:aff id="aff012"><addr-line>Center for Global Health and Diseases, Case Western Reserve University, and Veterans Affairs Medical Center, Cleveland, OH, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nosten, Francois" sort="Nosten, Francois" uniqKey="Nosten F" first="François" last="Nosten">François Nosten</name><affiliation><nlm:aff id="aff005"><addr-line>Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff006"><addr-line>Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Beeson, James G" sort="Beeson, James G" uniqKey="Beeson J" first="James G." last="Beeson">James G. Beeson</name><affiliation><nlm:aff id="aff001"><addr-line>Burnet Institute, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff013"><addr-line>Department of Medicine, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff014"><addr-line>Department of Microbiology and Central Clinical School, Monash University, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rogerson, Stephen" sort="Rogerson, Stephen" uniqKey="Rogerson S" first="Stephen" last="Rogerson">Stephen Rogerson</name><affiliation><nlm:aff id="aff013"><addr-line>Department of Medicine, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Simpson, Julie A" sort="Simpson, Julie A" uniqKey="Simpson J" first="Julie A." last="Simpson">Julie A. Simpson</name><affiliation><nlm:aff id="aff002"><addr-line>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fowkes, Freya J I" sort="Fowkes, Freya J I" uniqKey="Fowkes F" first="Freya J. I." last="Fowkes">Freya J. I. Fowkes</name><affiliation><nlm:aff id="aff001"><addr-line>Burnet Institute, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff015"><addr-line>Department of Epidemiology and Preventative Medicine, Monash University, Melbourne, Victoria, Australia</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Introduction</title><p>During pregnancy, immunoglobulin G (IgG) is transferred from the mother to the fetus, providing protection from disease in early infancy. <italic>Plasmodium falciparum</italic> infections may reduce maternofetal antibody transfer efficiency, but mechanisms remain unclear.</p></sec><sec id="sec002"><title>Methods</title><p>Mother-cord paired serum samples collected at delivery from Papua New Guinea (PNG) and the Thailand-Myanmar Border Area (TMBA) were tested for IgG1 and IgG3 to four <italic>P</italic>. <italic>falciparum</italic> antigens and measles antigen, as well as total serum IgG. Multivariable linear regression was conducted to assess the association of peripheral <italic>P</italic>. <italic>falciparum</italic> infection during pregnancy or placental <italic>P</italic>. <italic>falciparum</italic> infection assessed at delivery with maternofetal antibody transfer efficiency. Path analysis assessed the extent to which associations between <italic>P</italic>. <italic>falciparum</italic> infection and antibody transfer were mediated by gestational age at delivery or levels of maternal total serum IgG.</p></sec><sec id="sec003"><title>Results</title><p>Maternofetal antibody transfer efficiency of IgG1 and IgG3 was lower in PNG compared to TMBA (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.88 to 0.09, median of -0.20 log<sub>2</sub> units). Placental <italic>P</italic>. <italic>falciparum</italic> infections were associated with substantially lower maternofetal antibody transfer efficiency in PNG primigravid women (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.62 to -0.10, median of -0.36 log<sub>2</sub> units), but not multigravid women. The lower antibody transfer efficiency amongst primigravid women with placental infection was only partially mediated by gestational age at delivery (proportion indirect effect ranged from 0% to 18%), whereas no mediation effects of maternal total serum IgG were observed.</p></sec><sec id="sec004"><title>Discussion</title><p>Primigravid women may be at risk of impaired maternofetal antibody transport with placental <italic>P</italic>. <italic>falciparum</italic> infection. Direct effects of <italic>P</italic>. <italic>falciparum</italic> on the placenta, rather than earlier gestational age and elevated serum IgG, are likely responsible for the majority of the reduction in maternofetal antibody transfer efficiency with placental infection.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Chu, Hy" uniqKey="Chu H">HY Chu</name></author><author><name sortKey="Englund, Ja" uniqKey="Englund J">JA Englund</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bruce Chwatt, Lj" uniqKey="Bruce Chwatt L">LJ Bruce-Chwatt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Garnham, Pc" uniqKey="Garnham P">PC Garnham</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sehgal, Vm" uniqKey="Sehgal V">VM Sehgal</name></author><author><name sortKey="Siddjiqui, Wa" uniqKey="Siddjiqui W">WA 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29028827</article-id><article-id pub-id-type="pmc">5640245</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0186577</article-id><article-id pub-id-type="publisher-id">PONE-D-17-23595</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Parasitology</subject><subj-group><subject>Parasite Groups</subject><subj-group><subject>Apicomplexa</subject><subj-group><subject>Plasmodium</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Immune Physiology</subject><subj-group><subject>Antibodies</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Immune Physiology</subject><subj-group><subject>Antibodies</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Antibodies</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Antibodies</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Immune System Proteins</subject><subj-group><subject>Antibodies</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Parasitic Diseases</subject><subj-group><subject>Malaria</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Tropical Diseases</subject><subj-group><subject>Malaria</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Parasitic Diseases</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Eukaryota</subject><subj-group><subject>Protozoans</subject><subj-group><subject>Parasitic Protozoans</subject><subj-group><subject>Malarial Parasites</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pulmonology</subject><subj-group><subject>Respiratory Infections</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Infectious Diseases</subject><subj-group><subject>Viral Diseases</subject><subj-group><subject>Measles</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Developmental Biology</subject><subj-group><subject>Embryology</subject><subj-group><subject>Placenta</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Reproductive System</subject><subj-group><subject>Placenta</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Reproductive System</subject><subj-group><subject>Placenta</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title><italic>P</italic>. <italic>falciparum</italic> infection and maternofetal antibody transfer in malaria-endemic settings of varying transmission</article-title><alt-title alt-title-type="running-head"><italic>P</italic>. <italic>falciparum</italic> infection and maternofetal antibody transfer</alt-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-3449-7142</contrib-id><name><surname>McLean</surname><given-names>Alistair R. D.</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stanisic</surname><given-names>Danielle</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>McGready</surname><given-names>Rose</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff005"><sup>5</sup></xref><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chotivanich</surname><given-names>Kesinee</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Clapham</surname><given-names>Caroline</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff008"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Baiwog</surname><given-names>Francesca</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff008"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pimanpanarak</surname><given-names>Mupawjay</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Siba</surname><given-names>Peter</given-names></name><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff008"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mueller</surname><given-names>Ivo</given-names></name><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff009"><sup>9</sup></xref><xref ref-type="aff" rid="aff010"><sup>10</sup></xref><xref ref-type="aff" rid="aff011"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>King</surname><given-names>Christopher L.</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff012"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nosten</surname><given-names>François</given-names></name><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff005"><sup>5</sup></xref><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Beeson</surname><given-names>James G.</given-names></name><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff013"><sup>13</sup></xref><xref ref-type="aff" rid="aff014"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rogerson</surname><given-names>Stephen</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff013"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Simpson</surname><given-names>Julie A.</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fowkes</surname><given-names>Freya J. I.</given-names></name><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff015"><sup>15</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Burnet Institute, Melbourne, Victoria, Australia</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Myanmar Oxford Clinical Research Unit, Yangon, Myanmar</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland, Australia</addr-line></aff><aff id="aff005"><label>5</label><addr-line>Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</addr-line></aff><aff id="aff006"><label>6</label><addr-line>Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom</addr-line></aff><aff id="aff007"><label>7</label><addr-line>Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand</addr-line></aff><aff id="aff008"><label>8</label><addr-line>Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea</addr-line></aff><aff id="aff009"><label>9</label><addr-line>Population Health & Immunity Division, WEHI, Parkville, Victoria, Australia</addr-line></aff><aff id="aff010"><label>10</label><addr-line>Malaria: Parasites & Hosts Unit, Institut Pasteur, Paris, France</addr-line></aff><aff id="aff011"><label>11</label><addr-line>Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia</addr-line></aff><aff id="aff012"><label>12</label><addr-line>Center for Global Health and Diseases, Case Western Reserve University, and Veterans Affairs Medical Center, Cleveland, OH, United States of America</addr-line></aff><aff id="aff013"><label>13</label><addr-line>Department of Medicine, University of Melbourne, Melbourne, Australia</addr-line></aff><aff id="aff014"><label>14</label><addr-line>Department of Microbiology and Central Clinical School, Monash University, Melbourne, Victoria, Australia</addr-line></aff><aff id="aff015"><label>15</label><addr-line>Department of Epidemiology and Preventative Medicine, Monash University, Melbourne, Victoria, Australia</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Braga</surname><given-names>Érika Martins</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Universidade Federal de Minas Gerais, BRAZIL</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><corresp id="cor001">* E-mail: <email>freya.fowkes@burnet.edu.au</email></corresp></author-notes><pub-date pub-type="epub"><day>13</day><month>10</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>12</volume><issue>10</issue><elocation-id>e0186577</elocation-id><history><date date-type="received"><day>21</day><month>6</month><year>2017</year></date><date date-type="accepted"><day>3</day><month>10</month><year>2017</year></date></history><permissions><copyright-statement>© 2017 McLean et al</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>McLean et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0186577.pdf"></self-uri><abstract><sec id="sec001"><title>Introduction</title><p>During pregnancy, immunoglobulin G (IgG) is transferred from the mother to the fetus, providing protection from disease in early infancy. <italic>Plasmodium falciparum</italic> infections may reduce maternofetal antibody transfer efficiency, but mechanisms remain unclear.</p></sec><sec id="sec002"><title>Methods</title><p>Mother-cord paired serum samples collected at delivery from Papua New Guinea (PNG) and the Thailand-Myanmar Border Area (TMBA) were tested for IgG1 and IgG3 to four <italic>P</italic>. <italic>falciparum</italic> antigens and measles antigen, as well as total serum IgG. Multivariable linear regression was conducted to assess the association of peripheral <italic>P</italic>. <italic>falciparum</italic> infection during pregnancy or placental <italic>P</italic>. <italic>falciparum</italic> infection assessed at delivery with maternofetal antibody transfer efficiency. Path analysis assessed the extent to which associations between <italic>P</italic>. <italic>falciparum</italic> infection and antibody transfer were mediated by gestational age at delivery or levels of maternal total serum IgG.</p></sec><sec id="sec003"><title>Results</title><p>Maternofetal antibody transfer efficiency of IgG1 and IgG3 was lower in PNG compared to TMBA (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.88 to 0.09, median of -0.20 log<sub>2</sub> units). Placental <italic>P</italic>. <italic>falciparum</italic> infections were associated with substantially lower maternofetal antibody transfer efficiency in PNG primigravid women (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.62 to -0.10, median of -0.36 log<sub>2</sub> units), but not multigravid women. The lower antibody transfer efficiency amongst primigravid women with placental infection was only partially mediated by gestational age at delivery (proportion indirect effect ranged from 0% to 18%), whereas no mediation effects of maternal total serum IgG were observed.</p></sec><sec id="sec004"><title>Discussion</title><p>Primigravid women may be at risk of impaired maternofetal antibody transport with placental <italic>P</italic>. <italic>falciparum</italic> infection. Direct effects of <italic>P</italic>. <italic>falciparum</italic> on the placenta, rather than earlier gestational age and elevated serum IgG, are likely responsible for the majority of the reduction in maternofetal antibody transfer efficiency with placental infection.</p></sec></abstract><funding-group><funding-statement>This work was supported by the National Health and Medical Research Council of Australia (project grant and training award to Freya J. I. Fowkes; Infrastructure for Research Institutes Support Scheme grant, Senior Research Fellowship and Program Grant to JGB and IM, NHMRC Independent Research Institutes Infrastructure Support to the Burnet Institute and WEHI), Australian Research Council (Future Fellowship to Freya J. I. Fowkes), and Victorian State Government Operational Infrastructure Support grant to the Burnet Institute. Alistair R. D. McLean is supported by an Australian Postgraduate Award. Shoklo Malaria Research Unit is part of the Mahidol Oxford University Tropical Medicine Research Unit supported by the Wellcome Trust of Great Britain. The Christophe and Rodolphe Mérieux Foundation supported the study through a prize (2008) to François Nosten. No individuals employed or contracted by the funders (other than the named authors) played any role in: study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><fig-count count="5"></fig-count><table-count count="2"></table-count><page-count count="18"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data is within the paper and its Supporting Information files.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data is within the paper and its Supporting Information files.</p></notes></front><body><sec sec-type="intro" id="sec005"><title>Introduction</title><p>During pregnancy, immunoglobulin G (IgG) antibodies are transferred from mother to fetus. Maternally-derived antibodies provide the neonate with a pre-existing level of passive immunity to help protect from infection and disease. Vaccination of pregnant women can help protect infants against infectious diseases including influenza, tetanus and whooping cough [<xref rid="pone.0186577.ref001" ref-type="bibr">1</xref>]. These strategies rely on adequate maternofetal antibody transfer, but the factors that influence maternofetal antibody transfer are not fully understood. Clinical malaria caused by <italic>Plasmodium falciparum</italic> infection is uncommon during the first six months of life and, when <italic>P</italic>. <italic>falciparum</italic> infections are detected, they tend to be asymptomatic and are of lower parasite density than infections in older infants [<xref rid="pone.0186577.ref002" ref-type="bibr">2</xref>,<xref rid="pone.0186577.ref003" ref-type="bibr">3</xref>,<xref rid="pone.0186577.ref004" ref-type="bibr">4</xref>,<xref rid="pone.0186577.ref005" ref-type="bibr">5</xref>]. Protection against malaria during early infancy has been attributed to many factors [<xref rid="pone.0186577.ref006" ref-type="bibr">6</xref>] including the presence of maternal antibodies in the infant [<xref rid="pone.0186577.ref007" ref-type="bibr">7</xref>], though the relative contribution of maternal antibodies in mediating protection is unclear [<xref rid="pone.0186577.ref008" ref-type="bibr">8</xref>,<xref rid="pone.0186577.ref009" ref-type="bibr">9</xref>].</p><p>The humoral immune response is an important component of naturally acquired immunity to malaria and antibodies targeting blood-stage antigens (expressed by merozoites and infected erythrocytes) suppress high parasite densities and progression to symptomatic disease [<xref rid="pone.0186577.ref010" ref-type="bibr">10</xref>]. In malaria endemic areas, individuals develop naturally acquired immunity to <italic>P</italic>. <italic>falciparum</italic> infections with age, following repeated infections [<xref rid="pone.0186577.ref010" ref-type="bibr">10</xref>]. Breadth, magnitude and quality of antibody responses are critical, with antibody responses to a broad repertoire of antigenic targets associated with protection against symptomatic malaria in children [<xref rid="pone.0186577.ref011" ref-type="bibr">11</xref>,<xref rid="pone.0186577.ref012" ref-type="bibr">12</xref>,<xref rid="pone.0186577.ref013" ref-type="bibr">13</xref>,<xref rid="pone.0186577.ref014" ref-type="bibr">14</xref>]. Women who would otherwise be relatively immune to clinical <italic>P</italic>. <italic>falciparum</italic> malaria are again susceptible to malaria during pregnancy due in part to changes in immune function as well as the appearance of the placenta, a site of sequestration for <italic>P</italic>. <italic>falciparum</italic> variants that express <italic>Pf</italic>VAR2CSA on the erythrocyte surface [<xref rid="pone.0186577.ref015" ref-type="bibr">15</xref>]. The predominant antibody isotypes produced in response to malarial antigens are IgG1 and IgG3 [<xref rid="pone.0186577.ref012" ref-type="bibr">12</xref>,<xref rid="pone.0186577.ref016" ref-type="bibr">16</xref>,<xref rid="pone.0186577.ref017" ref-type="bibr">17</xref>,<xref rid="pone.0186577.ref018" ref-type="bibr">18</xref>], which are known to mediate complement deposition and opsonic phagocytosis, mechanisms that have been linked with protective immunity [<xref rid="pone.0186577.ref019" ref-type="bibr">19</xref>,<xref rid="pone.0186577.ref020" ref-type="bibr">20</xref>,<xref rid="pone.0186577.ref021" ref-type="bibr">21</xref>].</p><p>Several factors are known or suspected to influence the rate of maternofetal antibody transfer including total maternal IgG [<xref rid="pone.0186577.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0186577.ref023" ref-type="bibr">23</xref>,<xref rid="pone.0186577.ref024" ref-type="bibr">24</xref>,<xref rid="pone.0186577.ref025" ref-type="bibr">25</xref>], gestational age at delivery [<xref rid="pone.0186577.ref025" ref-type="bibr">25</xref>,<xref rid="pone.0186577.ref026" ref-type="bibr">26</xref>,<xref rid="pone.0186577.ref027" ref-type="bibr">27</xref>,<xref rid="pone.0186577.ref028" ref-type="bibr">28</xref>,<xref rid="pone.0186577.ref029" ref-type="bibr">29</xref>], IgG subclass composition [<xref rid="pone.0186577.ref028" ref-type="bibr">28</xref>,<xref rid="pone.0186577.ref030" ref-type="bibr">30</xref>], HIV infection [<xref rid="pone.0186577.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0186577.ref029" ref-type="bibr">29</xref>,<xref rid="pone.0186577.ref031" ref-type="bibr">31</xref>,<xref rid="pone.0186577.ref032" ref-type="bibr">32</xref>] and <italic>P</italic>. <italic>falciparum</italic> infection [<xref rid="pone.0186577.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0186577.ref023" ref-type="bibr">23</xref>,<xref rid="pone.0186577.ref025" ref-type="bibr">25</xref>,<xref rid="pone.0186577.ref031" ref-type="bibr">31</xref>,<xref rid="pone.0186577.ref033" ref-type="bibr">33</xref>,<xref rid="pone.0186577.ref034" ref-type="bibr">34</xref>]. Infections with <italic>P</italic>. <italic>falciparum</italic> during pregnancy have been associated with earlier gestational age at delivery and increased maternal sera total IgG in some populations [<xref rid="pone.0186577.ref023" ref-type="bibr">23</xref>,<xref rid="pone.0186577.ref034" ref-type="bibr">34</xref>,<xref rid="pone.0186577.ref035" ref-type="bibr">35</xref>]; both preterm birth and increased total maternal IgG have been associated with reduced transport efficiency [<xref rid="pone.0186577.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0186577.ref023" ref-type="bibr">23</xref>,<xref rid="pone.0186577.ref024" ref-type="bibr">24</xref>,<xref rid="pone.0186577.ref026" ref-type="bibr">26</xref>,<xref rid="pone.0186577.ref027" ref-type="bibr">27</xref>,<xref rid="pone.0186577.ref028" ref-type="bibr">28</xref>,<xref rid="pone.0186577.ref030" ref-type="bibr">30</xref>]. Placental <italic>P</italic>. <italic>falciparum</italic> infection may also impact maternofetal antibody transfer efficiency directly through the induction of pathological changes in the placenta including inflammation, deposition of pigment in fibrin or inflammatory cells, syncytial knotting and thickening of the trophoblastic basement membrane [<xref rid="pone.0186577.ref036" ref-type="bibr">36</xref>,<xref rid="pone.0186577.ref037" ref-type="bibr">37</xref>,<xref rid="pone.0186577.ref038" ref-type="bibr">38</xref>,<xref rid="pone.0186577.ref039" ref-type="bibr">39</xref>,<xref rid="pone.0186577.ref040" ref-type="bibr">40</xref>].</p><p>Studies investigating the relationship between placental <italic>P</italic>. <italic>falciparum</italic> infection and maternofetal antibody transfer efficiency of IgG (specific for tetanus [<xref rid="pone.0186577.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0186577.ref032" ref-type="bibr">32</xref>,<xref rid="pone.0186577.ref033" ref-type="bibr">33</xref>], measles [<xref rid="pone.0186577.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0186577.ref029" ref-type="bibr">29</xref>,<xref rid="pone.0186577.ref034" ref-type="bibr">34</xref>], respiratory syncytial virus [<xref rid="pone.0186577.ref023" ref-type="bibr">23</xref>,<xref rid="pone.0186577.ref024" ref-type="bibr">24</xref>] and malaria [<xref rid="pone.0186577.ref025" ref-type="bibr">25</xref>] antigens) have reported mixed results. Of the nine studies that have investigated associations between placental <italic>P</italic>. <italic>falciparum</italic> infection and maternofetal antibody transfer, three have found placental infection is associated with reduced antibody transfer efficiency for all antibodies investigated [<xref rid="pone.0186577.ref032" ref-type="bibr">32</xref>,<xref rid="pone.0186577.ref033" ref-type="bibr">33</xref>,<xref rid="pone.0186577.ref034" ref-type="bibr">34</xref>], four have noted reductions in transfer efficiency for some antibodies but not others [<xref rid="pone.0186577.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0186577.ref023" ref-type="bibr">23</xref>,<xref rid="pone.0186577.ref025" ref-type="bibr">25</xref>,<xref rid="pone.0186577.ref031" ref-type="bibr">31</xref>], while two have reported no association [<xref rid="pone.0186577.ref024" ref-type="bibr">24</xref>,<xref rid="pone.0186577.ref029" ref-type="bibr">29</xref>]. Only one study has investigated the effect of <italic>P</italic>. <italic>falciparum</italic> infection on malaria-specific IgG, IgG1 and IgG3, reporting significantly lower maternofetal antibody transfer efficiency in women with any detectable <italic>P</italic>. <italic>falciparum</italic> infection at delivery of antibodies specific for some antigens, but not others [<xref rid="pone.0186577.ref031" ref-type="bibr">31</xref>]. Discrepancies in the above findings may be due to differences in antibodies studied, definitions of <italic>P</italic>. <italic>falciparum</italic> infection, transmission intensity, antimalarial treatment, location and statistical approaches.</p><p>To date, no study has directly reported associations between maternal <italic>P</italic>. <italic>falciparum</italic> infections detected in the periphery and antibody transfer efficiency. The relative contribution of gestational age at delivery and maternal sera IgG to associations between <italic>P</italic>. <italic>falciparum</italic> infection and reduced maternofetal transfer efficiency are yet to be elucidated. To address these gaps in the literature we sought to assess the effect of maternal <italic>P</italic>. <italic>falciparum</italic> infection during pregnancy and placental <italic>P</italic>. <italic>falciparum</italic> infection on maternofetal transfer efficiency of IgG1 and IgG3 against several malaria antigens and a non-malaria antigen (measles) in an area of high <italic>P</italic>. <italic>falciparum</italic> endemicity in Papua New Guinea (PNG), and an area of low <italic>P</italic>. <italic>falciparum</italic> endemicity at the Thailand-Myanmar Border Area (TMBA). We also investigated the extent to which any associations between <italic>P</italic>. <italic>falciparum</italic> infection and maternofetal transfer efficiency are explained through associations between <italic>P</italic>. <italic>falciparum</italic> infection and early gestational age at delivery or increased maternal sera IgG.</p></sec><sec sec-type="materials|methods" id="sec006"><title>Materials and methods</title><sec id="sec007"><title>Study population–Alexishafen, Papua New Guinea</title><p>Women attending prenatal care at Alexishafen Health Centre, Madang Province, Papua New Guinea (PNG) between August 2005 and September 2007 were recruited into a longitudinal study of malaria and pregnancy following voluntary informed consent [<xref rid="pone.0186577.ref041" ref-type="bibr">41</xref>]. Peripheral blood (5ml) was obtained from women at enrolment, delivery and any additional antenatal clinic visits. At delivery a placental biopsy and 10ml of cord blood were collected. Clinical and demographic data were obtained at enrolment and delivery visits. Presence of microscopic parasitaemia was determined from blood smears by two independent microscopists. A subset of 204 participants with available delivery and cord samples were included in the present study. The study was approved by The Medical Research Advisory Council of Papua New Guinea (MRAC 05/05) and the Human Research Ethics Committee of Melbourne Health, Australia (06/06).</p></sec><sec id="sec008"><title>Study population—Shoklo Malaria Research Unit, Thailand-Myanmar Border Area</title><p>Women attending antenatal clinics of the Shoklo Malaria Research Unit, Thailand-Myanmar Border Area (TMBA), between November 1998 and January 2000 were invited to participate in a chloroquine prophylaxis randomized controlled trial for prevention of <italic>P</italic>. <italic>vivax</italic> [<xref rid="pone.0186577.ref042" ref-type="bibr">42</xref>]. <italic>P</italic>. <italic>falciparum</italic> episodes were similar in the chloroquine prophylaxis and placebo groups [<xref rid="pone.0186577.ref042" ref-type="bibr">42</xref>]. A total of 118 peripheral maternal blood and paired cord blood samples were utilised from a subset of pregnant women at delivery included in a previously reported study of malaria immunity [<xref rid="pone.0186577.ref043" ref-type="bibr">43</xref>]. At the Shoklo Malaria Research Unit, women are invited to attend an ANC as soon as they become aware of their pregnancy and were then encouraged to attend weekly thereafter.</p></sec><sec id="sec009"><title>Method of gestational age assessment</title><p>Gestational age was estimated from Ballard scores [<xref rid="pone.0186577.ref044" ref-type="bibr">44</xref>] in PNG, and in TMBA either the Dubowitz method [<xref rid="pone.0186577.ref045" ref-type="bibr">45</xref>] or a calculation based on fundal height [<xref rid="pone.0186577.ref046" ref-type="bibr">46</xref>], which performed well compared to ultrasound in term newborns [<xref rid="pone.0186577.ref047" ref-type="bibr">47</xref>]. Studies conducted in resource-limited settings suggest that Ballard and Dubowitz methods give comparable estimates of gestational age [<xref rid="pone.0186577.ref048" ref-type="bibr">48</xref>,<xref rid="pone.0186577.ref049" ref-type="bibr">49</xref>], however there was no attempt to quality control gestational age assessment between sites. Ballard scores and the Dubowitz method both fall short of estimation of gestational age by early ultrasound assessment [<xref rid="pone.0186577.ref050" ref-type="bibr">50</xref>].</p></sec><sec id="sec010"><title><italic>P</italic>. <italic>falciparum</italic> exposures</title><p>In PNG, maternal <italic>P</italic>. <italic>falciparum</italic> peripheral infection during pregnancy was defined as any light microscopy detected infection in peripheral blood at any point during pregnancy. Women with <italic>P</italic>. <italic>falciparum</italic> infections detected were treated with curative doses of chloroquine and sulphadoxine pyrimethamine and all women were given unsupervised prophylaxis [<xref rid="pone.0186577.ref041" ref-type="bibr">41</xref>].</p><p>In TMBA, maternal <italic>P</italic>. <italic>falciparum</italic> peripheral infection during pregnancy was defined as any light microscopy detected infection in peripheral blood at any point during pregnancy. All women who attend TMBA ANCs were screened weekly for the presence of <italic>P</italic>. <italic>falciparum</italic> by light microscopy. When infections were detected they were treated immediately. For <italic>P</italic>. <italic>falciparum</italic> or mixed infections, a first infection was treated with quinine or artesunate and all women were given weekly chloroquine prophylaxis [<xref rid="pone.0186577.ref042" ref-type="bibr">42</xref>].</p></sec><sec id="sec011"><title>Placental histology</title><p>In PNG only, placental histology was performed as described by Rogerson et al [<xref rid="pone.0186577.ref037" ref-type="bibr">37</xref>]. We compared the presence of any parasitaemia in the placenta (pathology class 1–3) to no parasites (pathology class 4–5). As a secondary analysis we compared the presence of parasites and monocytes with malaria pigment in the placenta (pathology class 2) to parasites without malaria pigment-containing monocytes (pathology class 1 and 3) and to no parasites (pathology class 4–5).</p></sec><sec id="sec012"><title>Antibody determination at delivery</title><p>We measured total serum IgG; IgG1 and IgG3 antibodies to measles antigen (MEV-007—PROSPECbio, Rehovot, Israel) and four <italic>P</italic>. <italic>falciparum</italic> antigens (<italic>Pf</italic>EBA175<sub>RII</sub> (3D7, amino acid position 146–713), <italic>Pf</italic>MSP2 (3D7, amino acid position 19–249), <italic>Pf</italic>AMA-1 (3D7, amino acid position 25–545) and <italic>Pf</italic>DBL5 (7G8, amino acid position 2003–2270)). We did not assess IgG2 or IgG4 levels, as these isotypes have previously been found to be present at very low levels against the <italic>P</italic>. <italic>falciparum</italic> antigens assessed [<xref rid="pone.0186577.ref012" ref-type="bibr">12</xref>,<xref rid="pone.0186577.ref017" ref-type="bibr">17</xref>,<xref rid="pone.0186577.ref018" ref-type="bibr">18</xref>], precluding a reliable assessment of maternofetal antibody transfer. Antibodies to these <italic>P</italic>. <italic>falciparum</italic> merozoite antigens are thought to be protective [<xref rid="pone.0186577.ref051" ref-type="bibr">51</xref>,<xref rid="pone.0186577.ref052" ref-type="bibr">52</xref>]. One of these <italic>P</italic>. <italic>falciparum</italic> antigens is known to induce IgG1 dominant responses (<italic>Pf</italic>AMA-1) and another is known to induce IgG3 dominant responses (<italic>Pf</italic>MSP2) [<xref rid="pone.0186577.ref018" ref-type="bibr">18</xref>,<xref rid="pone.0186577.ref053" ref-type="bibr">53</xref>]. Antibodies were measured using an enzyme-linked immunosorbent assay (ELISA) as described previously [<xref rid="pone.0186577.ref043" ref-type="bibr">43</xref>]. <italic>P</italic>. <italic>falciparum</italic> antigens were coated at 0.5 μg/ml, measles antigen at 1 μg/ml and goat anti-human-kappa at 1/1000. Horeseradish peroxidase (HRP)-conjugated goat anti-human IgG (Sigma), mouse anti-human IgG1 (Invitrogen) and mouse anti-human IgG3 (Invitrogen) were used as the secondary antibody (at 1/1000) in the total serum IgG, specific IgG1 and specific IgG3 assays respectively. The tertiary antibody (at 1/1000) for specific IgG1 and IgG3 assays was HRP-conjugated goat anti-mouse IgG (Merck Millipore). Assay output was related to a standard curve of pooled sera using a four-parameter logistic nonlinear regression model. TMBA samples had substantially lower levels of malaria-specific antibodies than PNG samples, so immunoassays against <italic>P</italic>. <italic>falciparum</italic> antigens were run at multiple concentrations of sera (sera dilutions are provided in <xref ref-type="supplementary-material" rid="pone.0186577.s001">S1 Table</xref>, range 1/100-1/20,000 for <italic>P</italic>. <italic>falciparum</italic> antigens). When assay reactivity from a sample was too high to reliably interpolate from the standard curve, then it was rerun at a lower sera concentration. The highest reactivity in an assay was set to 100 arbitrary units (AU). All wash steps were performed using PBS with 0.05% Tween and completed using an automated plate washer within a robotic platform (Perkin Elmer, Waltham, USA). Serum addition was performed using a robotic platform (Perkin Elmer, Waltham, USA). A sample was considered to be seropositive (or in the case of total IgG: elevated) if the AU for that sample was above the mean + 3 standard deviations of those for 15 non-exposed Melbourne blood donors.</p></sec><sec id="sec013"><title>Statistical analysis</title><p>All statistical analyses were performed using Stata Version 13.1 (StataCorp, College Station, TX, USA). Correlations between cord and maternal antibodies were assessed using Spearman’s rank correlation coefficients. Wilcoxon rank-sum tests were used to assess differences in antibody levels between populations. Women who were seronegative for an antibody were not assessed for their ability to transfer that antibody. To assess the impact of study site on antibody transfer, multivariable linear regression of log<sub>2</sub> cord antibody levels was performed with log<sub>2</sub> maternal levels at delivery and study site as covariates, and further adjustment for the potential confounders, gravidity (primigravid/multigravid) and estimated gestational age at delivery (weeks). <italic>P</italic>. <italic>vivax</italic> infection was not included in the model.</p><p>To assess the impact of <italic>P</italic>. <italic>falciparum</italic> infection during pregnancy on cord antibody levels, all analyses were performed separately for each study site, as inherent differences in study design meant that the screening, treatment and recording of infections could not be considered equivalent for the two study sites. Multivariable linear regression was performed assessing the association of infection with log<sub>2</sub> cord antibody levels after adjustment for log<sub>2</sub> maternal antibody levels and gravidity (primigravid/multigravid). Effect modification by gravidity of the association between infection and cord antibody levels was assessed though the fitting of interaction terms between gravidity (primigravid/multigravid) and infection. Three different infection variables were used in the models: peripheral <italic>P</italic>. <italic>falciparum</italic> infection at any time during pregnancy (yes/no); placental histology (parasites/no parasites); placental histology (parasites and monocytes containing malaria pigment/parasites without monocytes containing malaria pigment/no parasites). Placental histology data were only recorded in the PNG study.</p><p>Where associations were observed between infection and maternofetal antibody transfer efficiency, path analysis was then conducted to investigate potential mediation of the relationship between infection and cord antibody levels through gestational age at delivery and maternal serum IgG. The proportion of the total effect due to an indirect association via gestation age at delivery or maternal serum IgG was then estimated.</p></sec></sec><sec sec-type="results" id="sec014"><title>Results</title><sec id="sec015"><title>Study populations</title><p>IgG1 and IgG3 levels were determined for 204 maternal/cord pairs from Alexishafen, Papua New Guinea (PNG) and 118 pairs from the Thailand-Myanmar Border Area (TMBA). Gravidity and gestational age at delivery were higher in TMBA women relative to PNG women (<xref ref-type="table" rid="pone.0186577.t001">Table 1</xref>). <italic>P</italic>. <italic>falciparum</italic> antibody seroprevalence, the proportion with detectable <italic>P</italic>. <italic>falciparum</italic> infections and the proportion with elevated serum IgG were lower in TMBA women relative to PNG women (<xref ref-type="table" rid="pone.0186577.t001">Table 1</xref>).</p><table-wrap id="pone.0186577.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0186577.t001</object-id><label>Table 1</label><caption><title>Distribution of maternal characteristics by study site.</title></caption><alternatives><graphic id="pone.0186577.t001g" xlink:href="pone.0186577.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th align="center" rowspan="1" colspan="1">Alexishafen, Papua<break></break>New Guinea<break></break>(n = 204)</th><th align="center" rowspan="1" colspan="1">TMBA, Thailand<break></break>(n = 118)</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>Maternal characteristics</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Age (years)</td><td align="left" rowspan="1" colspan="1">24 (21,28), [<xref rid="pone.0186577.ref016" ref-type="bibr">16</xref>–<xref rid="pone.0186577.ref049" ref-type="bibr">49</xref>]</td><td align="left" rowspan="1" colspan="1">25 (21–32), [<xref rid="pone.0186577.ref015" ref-type="bibr">15</xref>–<xref rid="pone.0186577.ref042" ref-type="bibr">42</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Gravidity</td><td align="left" rowspan="1" colspan="1">2 (1–4), [<xref rid="pone.0186577.ref001" ref-type="bibr">1</xref>–<xref rid="pone.0186577.ref010" ref-type="bibr">10</xref>]</td><td align="left" rowspan="1" colspan="1">3 (2–5), [<xref rid="pone.0186577.ref001" ref-type="bibr">1</xref>–<xref rid="pone.0186577.ref013" ref-type="bibr">13</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">Gestational age at delivery (weeks)<xref ref-type="table-fn" rid="t001fn002"><sup>a</sup></xref></td><td align="left" rowspan="1" colspan="1">38 (37–40), [<xref rid="pone.0186577.ref028" ref-type="bibr">28</xref>–<xref rid="pone.0186577.ref042" ref-type="bibr">42</xref>]</td><td align="left" rowspan="1" colspan="1">40 (40,41), [<xref rid="pone.0186577.ref031" ref-type="bibr">31</xref>–<xref rid="pone.0186577.ref042" ref-type="bibr">42</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold><italic>Plasmodium</italic> spp. infection</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>P</italic>. <italic>falciparum</italic> infection<xref ref-type="table-fn" rid="t001fn003"><sup>b</sup></xref></td><td align="left" rowspan="1" colspan="1">81 (40)</td><td align="left" rowspan="1" colspan="1">32 (27)</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>P</italic>. <italic>vivax</italic> infection<xref ref-type="table-fn" rid="t001fn003"><sup>b</sup></xref></td><td align="left" rowspan="1" colspan="1">12 (6)</td><td align="left" rowspan="1" colspan="1">32 (27)</td></tr><tr><td align="left" rowspan="1" colspan="1"><italic>P</italic>. <italic>falciparum</italic> placental histology</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> No parasites detected</td><td align="left" rowspan="1" colspan="1">92 (45)</td><td align="left" rowspan="1" colspan="1">Not determined</td></tr><tr><td align="left" rowspan="1" colspan="1"> Parasites detected</td><td align="left" rowspan="1" colspan="1">112 (55)</td><td align="left" rowspan="1" colspan="1">Not determined</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Antibody measures</bold></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Maternal seropositive</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>Pf</italic>EBA175<sub>RII</sub> IgG1</td><td align="left" rowspan="1" colspan="1">178 (87)</td><td align="left" rowspan="1" colspan="1">43 (36)</td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>Pf</italic>EBA175<sub>RII</sub> IgG3</td><td align="left" rowspan="1" colspan="1">199 (98)</td><td align="left" rowspan="1" colspan="1">114 (97)</td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>Pf</italic>AMA1 IgG1</td><td align="left" rowspan="1" colspan="1">197 (97)</td><td align="left" rowspan="1" colspan="1">106 (90)</td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>Pf</italic>AMA1 IgG3</td><td align="left" rowspan="1" colspan="1">189 (93)</td><td align="left" rowspan="1" colspan="1">91 (77)</td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>Pf</italic>MSP2 IgG1</td><td align="left" rowspan="1" colspan="1">199 (98)</td><td align="left" rowspan="1" colspan="1">95 (81)</td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>Pf</italic>MSP2 IgG3</td><td align="left" rowspan="1" colspan="1">204 (100)</td><td align="left" rowspan="1" colspan="1">106 (90)</td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>Pf</italic>DBL5 IgG1</td><td align="left" rowspan="1" colspan="1">119 (58)</td><td align="left" rowspan="1" colspan="1">34 (29)</td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>Pf</italic>DBL5 IgG3</td><td align="left" rowspan="1" colspan="1">123 (60)</td><td align="left" rowspan="1" colspan="1">74 (62)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Measles IgG1</td><td align="left" rowspan="1" colspan="1">195 (96)</td><td align="left" rowspan="1" colspan="1">113 (96)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Measles IgG3</td><td align="left" rowspan="1" colspan="1">204 (100)</td><td align="left" rowspan="1" colspan="1">117 (99)</td></tr><tr><td align="left" rowspan="1" colspan="1">Elevated serum IgG<xref ref-type="table-fn" rid="t001fn004"><sup>c</sup></xref></td><td align="left" rowspan="1" colspan="1">50 (25)</td><td align="left" rowspan="1" colspan="1">16 (14)</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>NB—Data presented as median (inter-quartile range), [minimum-maximum] or n (%). Abbreviations: TMBA = Thailand-Myanmar Border Area.</p></fn><fn id="t001fn002"><p><sup>a</sup> Estimated by Ballard scores in PNG, Dubowitz method in TMBA.</p></fn><fn id="t001fn003"><p><sup>b</sup> Infection detected by light microscopy (peripheral) at any point during pregnancy. 7 and 11 women experienced a <italic>P</italic>. <italic>falciparum</italic> infection and a <italic>P</italic>. <italic>vivax</italic> infection during pregnancy in Papua New Guinea and Thailand respectively.</p></fn><fn id="t001fn004"><p><sup>c</sup> Defined as a level of total IgG greater than the mean + three standard deviations of 15 Melbourne blood donors.</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec016"><title>Higher levels of malaria-specific IgG1 and IgG3 in maternal and cord sera from PNG than from TMBA</title><p>Maternal IgG1 and IgG3 levels were strongly correlated with cord IgG1 and IgG3 levels (Spearman’s ρ ranges from 0.78–0.96, <xref ref-type="supplementary-material" rid="pone.0186577.s005">S1 Fig</xref>). Maternal and cord IgG1 and IgG3 levels against <italic>P</italic>. <italic>falciparum</italic> antigens were higher in PNG samples, where malaria transmission is higher, than in TMBA samples (Figs <xref ref-type="fig" rid="pone.0186577.g001">1</xref> and <xref ref-type="fig" rid="pone.0186577.g002">2</xref>, p<0.0001 for all comparisons except <italic>Pf</italic>DBL5 IgG3 (p = 0.16 and p = 0.58 for maternal and cord levels respectively)). IgG1 and IgG3 levels were lower in the cord blood than in the maternal blood for the majority of antigens (Figs <xref ref-type="fig" rid="pone.0186577.g001">1C</xref> and <xref ref-type="fig" rid="pone.0186577.g002">2C</xref>). The cord:maternal ratio of antibodies against all antigens (<italic>P</italic>. <italic>falciparum</italic> and measles) was lower in PNG samples than TMBA samples (Figs <xref ref-type="fig" rid="pone.0186577.g001">1C</xref> and <xref ref-type="fig" rid="pone.0186577.g002">2C</xref>). The cord:maternal IgG1 ratio was higher than the IgG3 ratio for each antigen investigated within each study site (Figs <xref ref-type="fig" rid="pone.0186577.g001">1C</xref> and <xref ref-type="fig" rid="pone.0186577.g002">2C</xref>).</p><fig id="pone.0186577.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0186577.g001</object-id><label>Fig 1</label><caption><title>Maternal and cord IgG1 levels by study site.</title><p>(A) Maternal IgG1 levels (arbitrary units) by study site. (B) Cord IgG1 levels (arbitrary units) by study site. (C) Cord:maternal IgG1 ratio by study site.</p></caption><graphic xlink:href="pone.0186577.g001"></graphic></fig><fig id="pone.0186577.g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0186577.g002</object-id><label>Fig 2</label><caption><title>Maternal and cord IgG3 levels by study site.</title><p>(A) Maternal IgG3 levels (arbitrary units) by study site. (B) Cord IgG3 levels (arbitrary units) by study site. (C) Cord:maternal IgG3 ratio by study site.</p></caption><graphic xlink:href="pone.0186577.g002"></graphic></fig></sec><sec id="sec017"><title>Maternofetal transfer efficiency of IgG1 and IgG3 antibodies specific for malaria and measles was lower in PNG women relative to TMBA women</title><p>To investigate maternofetal antibody transfer efficiency, linear regression was performed, modelling cord antibody levels (log<sub>2</sub>(AU)) with maternal levels (log<sub>2</sub>(AU)) included as a covariate. Maternofetal transfer efficiency of IgG1 and IgG3 antibodies specific for <italic>P</italic>. <italic>falciparum</italic> antigens was reduced in PNG compared to TMBA (<xref ref-type="table" rid="pone.0186577.t002">Table 2</xref>) (estimate of adjusted mean difference of <italic>P</italic>. <italic>falciparum</italic> antibody levels in cord blood (log<sub>2</sub> units) for PNG versus TMBA ranged from -0.88 to 0.09 with a median value of -0.15). The largest magnitude of effect was observed in DBL5 IgG3. Maternofetal transfer efficiency of antibodies specific for measles was significantly lower in PNG relative to TMBA (-0.41 log<sub>2</sub> units (95% confidence interval (CI): -0.61, -0.21) and -0.26 (95% CI: -0.38, -0.14) for IgG1 and IgG3 respectively). Adjusting for gestational age at delivery and gravidity did not substantially alter the magnitude of associations observed (<xref ref-type="table" rid="pone.0186577.t002">Table 2</xref>).</p><table-wrap id="pone.0186577.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0186577.t002</object-id><label>Table 2</label><caption><title>Association of study site with maternofetal antibody transfer efficiency; estimated adjusted mean difference (95% confidence intervals) and p-values are presented.</title></caption><alternatives><graphic id="pone.0186577.t002g" xlink:href="pone.0186577.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1"><italic>Pf</italic>EBA175<sub>RII</sub>−IgG1</th><th align="left" rowspan="1" colspan="1"><italic>Pf</italic>EBA175<sub>RII</sub>−IgG3</th><th align="left" rowspan="1" colspan="1"><italic>Pf</italic>AMA-1 –IgG1</th><th align="left" rowspan="1" colspan="1"><italic>Pf</italic>AMA-1 –IgG3</th><th align="left" rowspan="1" colspan="1"><italic>Pf</italic>MSP2 –IgG1</th><th align="left" rowspan="1" colspan="1"><italic>Pf</italic>MSP2 –IgG3</th><th align="left" rowspan="1" colspan="1">PfDBL5 –IgG1</th><th align="left" rowspan="1" colspan="1">PfDBL5 –IgG3</th><th align="left" rowspan="1" colspan="1">Measles–IgG1</th><th align="left" rowspan="1" colspan="1">Measles–IgG3</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1"><bold>Adjusted</bold><sup><bold>1</bold></sup></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">TMBA</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td></tr><tr><td align="left" rowspan="1" colspan="1">PNG</td><td align="left" rowspan="1" colspan="1">-0.24<break></break>(-0.57,0.09); 0.16</td><td align="left" rowspan="1" colspan="1">-0.07<break></break>(-0.26,0.14); 0.53</td><td align="left" rowspan="1" colspan="1">-0.06<break></break>(-0.40,0.29); 0.75</td><td align="left" rowspan="1" colspan="1">-0.16<break></break>(-0.47,0.14); 0.29</td><td align="left" rowspan="1" colspan="1">-0.13<break></break>(-0.34,0.08); 0.22</td><td align="left" rowspan="1" colspan="1">0.09<break></break>(-0.12,0.29); 0.40</td><td align="left" rowspan="1" colspan="1">-0.28<break></break>(-0.64,0.07); 0.12</td><td align="left" rowspan="1" colspan="1">-0.88<break></break>(-1.11,-0.65); <0.001</td><td align="left" rowspan="1" colspan="1">-0.41<break></break>(-0.61,-0.21); <0.001</td><td align="left" rowspan="1" colspan="1">-0.26<break></break>(-0.39,-0.14); <0.001</td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Adjusted</bold><sup><bold>2</bold></sup></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">TMBA</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td><td align="left" rowspan="1" colspan="1">Reference</td></tr><tr><td align="left" rowspan="1" colspan="1">PNG</td><td align="left" rowspan="1" colspan="1">-0.11<break></break>(-0.45,0.23); 0.52</td><td align="left" rowspan="1" colspan="1">0.07<break></break>(-0.15,0.28); 0.53</td><td align="left" rowspan="1" colspan="1">0.10<break></break>(-0.25,0.45); 0.56</td><td align="left" rowspan="1" colspan="1">-0.03<break></break>(-0.35,0.29); 0.85</td><td align="left" rowspan="1" colspan="1">-0.04<break></break>(-0.26,0.19); 0.75</td><td align="left" rowspan="1" colspan="1">0.17<break></break>(-0.05,0.39); 0.14</td><td align="left" rowspan="1" colspan="1">-0.14<break></break>(-0.52,0.25); 0.48</td><td align="left" rowspan="1" colspan="1">-0.79<break></break>(-1.05,-0.53); <0.001</td><td align="left" rowspan="1" colspan="1">-0.34<break></break>(-0.56,-0.12); 0.002</td><td align="left" rowspan="1" colspan="1">-0.24<break></break>(-0.37,-0.11); 0.001</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p>NB–Coefficients represent the differences in cord antibody levels by study site after adjustment for maternal antibody levels. Abbreviations: TMBA = Thailand-Myanmar Border Area; PNG = Papua New Guinea. 1 –Adjusted for log<sub>2</sub> maternal levels. 2—Adjusted for log<sub>2</sub> maternal levels, gravidity (primigravid/multigravid) and gestational age at delivery (weeks).</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec018"><title>Maternal <italic>P</italic>. <italic>falciparum</italic> infection, detected peripherally, was not associated with antibody transfer efficiency in either study site</title><p>At PNG and TMBA there was no consistent association between peripheral <italic>P</italic>. <italic>falciparum</italic> infection and maternofetal IgG1 or IgG3 transfer efficiency (<xref ref-type="fig" rid="pone.0186577.g003">Fig 3</xref>, estimate of adjusted mean difference of antibody levels in cord blood (log<sub>2</sub>AU) for mothers with a peripheral <italic>P</italic>. <italic>falciparum</italic> infection versus those without a <italic>P</italic>. <italic>falciparum</italic> infection ranged from -0.15 to 0.21 with a median value of -0.05).</p><fig id="pone.0186577.g003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0186577.g003</object-id><label>Fig 3</label><caption><title>Association of maternal <italic>P</italic>. <italic>falciparum</italic> infection with maternofetal antibody transfer.</title><p>Estimates and 95% confidence intervals are presented of the mean difference in log<sub>2</sub> cord antibody levels after adjustment for log<sub>2</sub> maternal antibody levels and gravidity, for mothers with a <italic>P</italic>. <italic>falciparum</italic> infection during pregnancy compared to uninfected mothers. Dashed line at 0 indicates no difference in mean log<sub>2</sub> cord antibody levels. See <xref ref-type="supplementary-material" rid="pone.0186577.s002">S2 Table</xref> for a table version of this figure.</p></caption><graphic xlink:href="pone.0186577.g003"></graphic></fig></sec><sec id="sec019"><title>Placental <italic>P</italic>. <italic>falciparum</italic> infection was associated with lower antibody transfer efficiency in primigravid women, but not multigravid women</title><p>No data were available on the placental histology of TMBA women, but a study conducted in the Shoklo and Maela camps during the time of this study indicated a low estimated prevalence of <italic>P</italic>. <italic>falciparum</italic> placental histopathological changes when early detection and treatment of infection, routine in this population, was performed [<xref rid="pone.0186577.ref040" ref-type="bibr">40</xref>]. Placental histology data were available from the PNG study allowing us to investigate the impact of placental infection on maternofetal antibody transfer efficiency. The presence of placental <italic>P</italic>. <italic>falciparum</italic> was associated with reduced maternofetal IgG1 and IgG3 transfer efficiency in primigravid women (<xref ref-type="fig" rid="pone.0186577.g004">Fig 4A</xref>, <xref ref-type="supplementary-material" rid="pone.0186577.s003">S3 Table</xref>) (estimate of mean difference of antibody levels in cord blood (log<sub>2</sub> units) for mother-cord pairs with <italic>P</italic>. <italic>falciparum</italic> present in the placenta versus those without placental <italic>P</italic>. <italic>falciparum</italic> parasites present ranged from -0.62 to -0.10 with a median value of -0.36). There were no consistent associations between placental infection and maternofetal transfer efficiency in multigravid women (<xref ref-type="fig" rid="pone.0186577.g004">Fig 4B</xref>, <xref ref-type="supplementary-material" rid="pone.0186577.s003">S3 Table</xref>). In primigravid PNG women associations of placental infections with monocyte infiltrate were greater in magnitude than placental infections without monocyte infiltrate (<xref ref-type="supplementary-material" rid="pone.0186577.s006">S2 Fig</xref>).</p><fig id="pone.0186577.g004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0186577.g004</object-id><label>Fig 4</label><caption><title>Association of placental infection with maternofetal antibody transfer efficiency in primigravid and multigravid Papua New Guinea women.</title><p>Estimates and 95% confidence intervals are presented for the mean difference in log<sub>2</sub> cord antibody levels after adjustment for log<sub>2</sub> maternal antibody levels for <bold>(A)</bold> primigravid or <bold>(B)</bold> multigravid mothers with a <italic>P</italic>. <italic>falciparum</italic> placental infection compared to mothers with no placental infection. Dashed line at 0 indicates no difference in mean log<sub>2</sub> cord antibody levels. See <xref ref-type="supplementary-material" rid="pone.0186577.s003">S3 Table</xref> for a table version of this figure, including estimates for all women.</p></caption><graphic xlink:href="pone.0186577.g004"></graphic></fig></sec><sec id="sec020"><title>Placental <italic>P</italic>. <italic>falciparum</italic> infection was associated with lower antibody transfer efficiency in primigravid mothers primarily through mechanisms other than earlier gestational age at delivery or increased maternal IgG</title><p>Path analysis was performed to assess the proportion of the total effect of placental infection on maternofetal IgG1 and IgG3 transfer efficiency in PNG primigravid women mediated by gestational age and changes in total levels of maternal IgG. The negative effect of placental infection in primigravid women was not substantially mediated through induction of shorter gestational age at delivery (proportion of total effect attributable to gestational age mediation ranged from 0% to 18% with a median value of 5%, p ranged from 0.21 to 0.93 for indirect effects) (<xref ref-type="fig" rid="pone.0186577.g005">Fig 5</xref>, <xref ref-type="supplementary-material" rid="pone.0186577.s004">S4 Table</xref>). None of the effect appeared to be mediated through changes in total maternal serum IgG (p ranged from 0.63 to 0.87 for indirect effects).</p><fig id="pone.0186577.g005" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0186577.g005</object-id><label>Fig 5</label><caption><title>Path analysis model for cord PfAMA1 IgG1 levels and placental <italic>P</italic>. <italic>falciparum</italic> infection in primigravid women.</title><p>Estimated mean difference (95% CI) are presented. For other antibodies see <xref ref-type="supplementary-material" rid="pone.0186577.s004">S4 Table</xref>.</p></caption><graphic xlink:href="pone.0186577.g005"></graphic></fig></sec></sec><sec sec-type="conclusions" id="sec021"><title>Discussion</title><p>To date, there has been considerable uncertainty regarding the effects of <italic>P</italic>. <italic>falciparum</italic> infection during pregnancy on maternofetal antibody transfer efficiency, as well as the mechanisms by which infection may mediate impaired maternofetal antibody transfer. A great strength of this study was the inclusion of women from two separate study sites with differing <italic>P</italic>. <italic>falciparum</italic> endemicity and access to antenatal clinics. Importantly, antibody data were standardised to a reference sera pool curve, which enabled direct comparisons of antibody levels across the study populations. The assessment of measles antibodies, which were present at similar levels in both study sites and should not be boosted during a placental <italic>P</italic>. <italic>falciparum</italic> infection, strengthened the generalisibility of the findings. Although some studies have included the potential mediating effects of elevated serum IgG and shorter gestation as confounders [<xref rid="pone.0186577.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0186577.ref023" ref-type="bibr">23</xref>,<xref rid="pone.0186577.ref031" ref-type="bibr">31</xref>,<xref rid="pone.0186577.ref033" ref-type="bibr">33</xref>], this is the first study to investigate whether placental infection is mediated via these effects with path analysis. Malaria exposure during pregnancy was captured differently at each study site and therefore separate analyses had to be performed. The prevalence of HIV is very low (<1.5%) in these populations [<xref rid="pone.0186577.ref054" ref-type="bibr">54</xref>,<xref rid="pone.0186577.ref055" ref-type="bibr">55</xref>]) so HIV is unlikely to have a substantial effect on maternofetal transfer at the population level. The lack of placental histology data from the TMBA prevented an assessment of placental infection in that study site.</p><p>Maternofetal transfer efficiency of some antibodies was reduced in PNG compared to TMBA. Besides the direct effects of malaria, there are several factors that could account for this difference, including maternal genetic differences, gestational age at delivery and altered levels of total maternal IgG [<xref rid="pone.0186577.ref022" ref-type="bibr">22</xref>,<xref rid="pone.0186577.ref023" ref-type="bibr">23</xref>,<xref rid="pone.0186577.ref032" ref-type="bibr">32</xref>]. The median gestational age at delivery of PNG women was 2 weeks shorter than that observed at TMBA. However, differences in gestation cannot fully explain the difference we observed, given the persistence of an association between study site and maternofetal transfer efficiency of some antibodies even after controlling for gestational age at delivery. Very high levels of total maternal IgG are thought to saturate available receptors at the placenta, thereby reducing efficiency of transfer [<xref rid="pone.0186577.ref056" ref-type="bibr">56</xref>], however we did not observe an association between increased maternal IgG and decreased maternofetal transfer efficiency in either population in this study.</p><p>Greater maternofetal antibody transfer efficiency at TMBA relative to PNG may be due in part, to the prompt detection and treatment of <italic>P</italic>. <italic>falciparum</italic> infections at the TMBA site, preventing the persistence of long-term infections and thereby reducing the risk and consequences of placental infection. Women at TMBA were encouraged to attend antenatal clinics weekly, and were rapidly treated upon diagnosis, so the duration of any <italic>Plasmodium</italic> spp. infections during gestation is minimal and placental infections are rare [<xref rid="pone.0186577.ref040" ref-type="bibr">40</xref>]. In PNG, policy dictated weekly chloroquine prophylaxis, this was not monitored and so infections with <italic>P</italic>. <italic>falciparum</italic> may have persisted undetected. Malaria transmission was also substantially higher at the PNG site. At delivery, the majority of women presented with <italic>P</italic>. <italic>falciparum</italic> infected placentae in PNG, whereas at TMBA, placental infections are a rare outcome [<xref rid="pone.0186577.ref040" ref-type="bibr">40</xref>].</p><p>In primigravid PNG women we observed an association between the presence of <italic>P</italic>. <italic>falciparum</italic> parasites in the placenta and reduced maternofetal IgG1 and IgG3 transfer efficiency relative to uninfected women; no association was observed in multigravid PNG women. Primigravid women tend to have placental infections of greater parasite density and more commonly have associated placental inflammation than do multigravid women [<xref rid="pone.0186577.ref057" ref-type="bibr">57</xref>]. Multigravid women are not only to be less likely to present with placental infection, but also less likely to have impaired maternofetal antibody transfer when infected.</p><p>There are numerous mechanisms by which placental <italic>P</italic>. <italic>falciparum</italic> infection may reduce maternofetal antibody transfer efficiency. Placental <italic>P</italic>. <italic>falciparum</italic> infection is associated with a shorter gestational age [<xref rid="pone.0186577.ref035" ref-type="bibr">35</xref>] and shorter gestational age is associated with reduced maternofetal antibody transfer [<xref rid="pone.0186577.ref026" ref-type="bibr">26</xref>,<xref rid="pone.0186577.ref027" ref-type="bibr">27</xref>,<xref rid="pone.0186577.ref028" ref-type="bibr">28</xref>]. In our model, we found that gestational age explained a small proportion of the reduced maternofetal antibody transfer efficiency associated with placental infection. Placental infection has been associated with increased total maternal IgG in some other populations [<xref rid="pone.0186577.ref023" ref-type="bibr">23</xref>,<xref rid="pone.0186577.ref034" ref-type="bibr">34</xref>]; transfer efficiency can be reduced when maternal IgG levels are elevated [<xref rid="pone.0186577.ref056" ref-type="bibr">56</xref>]. However, amongst PNG women we did not observe a reduction in antibody transfer efficiency among those women with increased total serum IgG, as defined by levels greater than the mean plus three standard deviations of Melbourne control levels. The majority of the association between placental infection and reduced maternal transfer efficiency in primigravid PNG women was explained through mechanisms other than gestational age and maternal IgG in the present study. Our results indicate that a large proportion of the observed effect may be due to direct effects of placental infection. Given that placental infections with malaria-pigment containing monocytes tended to have even lower transfer efficiency than placental infections without monocytes, inflammation at the placenta is likely to be involved. Disruptions to the placental architecture that occur during placental infection [<xref rid="pone.0186577.ref036" ref-type="bibr">36</xref>,<xref rid="pone.0186577.ref058" ref-type="bibr">58</xref>,<xref rid="pone.0186577.ref059" ref-type="bibr">59</xref>,<xref rid="pone.0186577.ref060" ref-type="bibr">60</xref>] may have a negative impact on maternofetal transfer and receptor expression. Placental infection with inflammation seems to impair transplacental transport of glucose and amino acids via a reduction in expression of transport receptors [<xref rid="pone.0186577.ref061" ref-type="bibr">61</xref>,<xref rid="pone.0186577.ref062" ref-type="bibr">62</xref>]; if expression of placental immunoglobulin transport receptors were also reduced then this would explain some of the reduction in antibody transfer efficiency. As IgG1 outcompetes IgG3 for placental receptor binding [<xref rid="pone.0186577.ref063" ref-type="bibr">63</xref>], a reduction in transport receptors would likely have a greater impact on IgG1 transfer relative to IgG3 transfer. Further research is needed to elucidate the precise mechanisms by which placental infection with <italic>P</italic>. <italic>falciparum</italic> mediates reduced efficiency of maternofetal transfer, but our findings indicate direct effects of <italic>P</italic>. <italic>falciparum</italic> placental infection play a substantial role, emphasising the need for highly efficacious prevention in pregnancy.</p><p>Our study was subject to limitations. Our knowledge of infection status over the entire course of pregnancy was incomplete as the infection status of a woman was necessarily restricted to instances when they presented to antenatal care. Infection was detected via microscopy, so sub-microscopic infections were not captured. The infection status of cord blood was not determined in both study settings. Notably in the TMBA study we lacked placental histology data, limiting our analysis of placental histology exposures to pregnant women from PNG. We did not have data available on the outcomes of the children in their first year of life, precluding an assessment of the relationship between maternofetal antibody transfer and infant outcomes.</p><p>We have observed that placental <italic>P</italic>. <italic>falciparum</italic> infection was associated with reduced maternofetal antibody transfer efficiency in primigravid women and that only a small proportion of this association is mediated by gestational age. Adequate maternofetal transfer of antibodies is essential for maternal vaccination strategies to effectively protect infants; efforts to prevent and treat malaria in pregnancy should continue to be encouraged.</p></sec><sec sec-type="supplementary-material" id="sec022"><title>Supporting information</title><supplementary-material content-type="local-data" id="pone.0186577.s001"><label>S1 Table</label><caption><title>Assay sera dilutions.</title><p>(DOCX)</p></caption><media xlink:href="pone.0186577.s001.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0186577.s002"><label>S2 Table</label><caption><title>Effect of peripheral <italic>P</italic>. <italic>falciparum</italic> infection during pregnancy on log<sub>2</sub> cord levels after adjustment for log<sub>2</sub> maternal levels and gravidity; estimated adjusted mean difference (95% confidence intervals) and p-values are presented.</title><p>(DOCX)</p></caption><media xlink:href="pone.0186577.s002.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0186577.s003"><label>S3 Table</label><caption><title>Effect of placental infection on log<sub>2</sub> cord levels after adjustment for log<sub>2</sub> maternal levels in primigravid and multigravid women; estimated adjusted mean difference (95% confidence intervals) and p-values are presented.</title><p>(DOCX)</p></caption><media xlink:href="pone.0186577.s003.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0186577.s004"><label>S4 Table</label><caption><title>Proportion of total effect of placental infection mediated by gestational age at delivery in primigravid women.</title><p>(DOCX)</p></caption><media xlink:href="pone.0186577.s004.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0186577.s005"><label>S1 Fig</label><caption><title>Maternal and cord antibody levels are highly correlated.</title><p>Scatter plots of cord and maternal IgG1 and IgG3 levels against <italic>Pf</italic>EBA175RII, <italic>Pf</italic>AMA1, <italic>Pf</italic>MSP2, <italic>Pf</italic>DBL5 and Measles. Samples from Alexishafen, Papua New Guinea are denoted as green closed circles and from Shoklo Malaria Research Unit, Thailand-Myanmar Border Area as closed red circles. Spearman ρ values (IgG1 and IgG3): <italic>Pf</italic>EBA175RII (0.91,0.96); <italic>Pf</italic>AMA1 (0.89,0.95); <italic>Pf</italic>MSP2 (0.94,0.94); <italic>Pf</italic>DBL5 (0.79,0.78); Measles (0.87,0.86).</p><p>(TIF)</p></caption><media xlink:href="pone.0186577.s005.tif"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0186577.s006"><label>S2 Fig</label><caption><title>Association of placental infection (with and without monocyte infiltrate) with maternofetal antibody transfer efficiency in primigravid and multigravid Alexishafen women.</title><p>Estimates and 95% confidence intervals are presented for the mean difference in log<sub>2</sub> cord antibody levels after adjustment for log<sub>2</sub> maternal antibody levels for <bold>(A)</bold> primigravid or <bold>(B)</bold> multigravid mothers with a <italic>P</italic>. <italic>falciparum</italic> placental infection without monocyte infiltrate (orange triangles, n = 22 and n = 59 in primigravid and multigravida respectively) or a <italic>P</italic>. <italic>falciparum</italic> placental infection with monocyte infiltrate (blue triangles, n = 23 and n = 8 in primigravid and multigravida respectively) compared to mothers with placentas with no <italic>P</italic>. <italic>falciparum</italic> parasites present. Dashed line at y = 0 indicates no difference in mean log<sub>2</sub> cord antibody levels.</p><p>(TIF)</p></caption><media xlink:href="pone.0186577.s006.tif"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>We thank the staff of the Alexishafen Health Centre, PNG Institute of Medical Research and Shoklo Malaria Research Unit for their assistance with the study. We thank Joe Smith, Robin Anders, Damien Drew and Annie Mo for provision of antigens. We thank Sarah Charnaud and Kerryn Moore for assistance with analysis. 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