{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T19:49:10Z","timestamp":1774381750472,"version":"3.50.1"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD080385"],"award-info":[{"award-number":["R01HD080385"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["1R01HD074558"],"award-info":[{"award-number":["1R01HD074558"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000061","name":"Fogarty International Center","doi-asserted-by":"publisher","award":["#5R25TW009340"],"award-info":[{"award-number":["#5R25TW009340"]}],"id":[{"id":"10.13039\/100000061","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DELTAS Africa Initiative","award":["# DEL-15-006"],"award-info":[{"award-number":["# DEL-15-006"]}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["# 107752\/Z\/15\/Z"],"award-info":[{"award-number":["# 107752\/Z\/15\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Mechanisms underlying an association between human immunodeficiency virus (HIV) or antiretroviral therapy (ART) during pregnancy with risk of preterm delivery (PTD) and small-for-gestational-age (SGA) remain unclear. We explored the association between cellular immune activation and PTD or SGA in women with HIV initiating ART during or before pregnancy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Women with HIV enrolled at median 15 weeks\u2019 gestation, were analyzed for immune markers, and matched on ART initiation timing (15 women initiated pre- and 15 during pregnancy). There were 30 PTD (delivery &amp;lt;37 weeks), 30 SGA (weight for age \u226410th percentile) cases, and 30 controls (term, weight for gestational age &amp;gt;25th percentile) as outcomes. Lymphocytes, monocytes, and dendritic cell populations and their activation status or functionality were enumerated by flow cytometry.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>PTD cases initiating ART in pregnancy showed decreased CD8+ T cell, monocyte, and dendritic cell activation; increased classical (CD14+CD16\u2013) and intermediate (CD14+CD16+) monocyte frequencies; and decreased inflammatory monocytes (CD14dimCD16+) compared with SGA cases and term controls (all P\u2005&amp;lt;\u2005.05). Allowing for baseline viral load, the immune markers remained significantly associated with PTD but only in women initiating ART in pregnancy. Lower monocyte activation was predictive of PTD. TLR ligand-induced interferon-\u03b1 and macrophage inflammatory protein-1\u03b2 levels in monocytes were significantly lower in PTD women initiating ART in pregnancy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Low immune activation, skewing toward anti-inflammatory monocytes, and lower monocyte cytokine production in response to TLR ligand stimulation were associated with PTD but not SGA among women initiating ART in, but not before, pregnancy, suggesting immune anergy to microbial stimulation as a possible underlying mechanism for PTD in women initiating ART in pregnancy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciab151","type":"journal-article","created":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T20:26:43Z","timestamp":1613420803000},"page":"2205-2216","source":"Crossref","is-referenced-by-count":5,"title":["Low Immune Activation in Early Pregnancy Is Associated With Preterm But Not Small-for-gestational-age Delivery in Women Infected With Human Immunodeficiency Virus Initiating Antiretroviral Therapy in Pregnancy: A Prematurity Immunology in HIV-infected Mothers and their Infants Study (PIMS) Case-control Study in Cape Town, South Africa"],"prefix":"10.1093","volume":"73","author":[{"given":"Nontlantla","family":"Mdletshe","sequence":"first","affiliation":[{"name":"HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Thobakgale","sequence":"additional","affiliation":[{"name":"HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa"},{"name":"School of Pathology, National Institute for Communicable Diseases and the University of the Witwatersrand, Johannesburg, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thokozile R","family":"Malaba","sequence":"additional","affiliation":[{"name":"Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hlengiwe","family":"Madlala","sequence":"additional","affiliation":[{"name":"Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Landon","family":"Myer","sequence":"additional","affiliation":[{"name":"Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel M","family":"Muema","sequence":"additional","affiliation":[{"name":"Africa Health Research Institute, Durban, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Polycarp","family":"Mogeni","sequence":"additional","affiliation":[{"name":"Africa Health Research Institute, Durban, South Africa"},{"name":"School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa"},{"name":"KwaZulu-Natal Innovation and Sequencing Platform, University of KwaZulu-Natal, Durban, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clive M","family":"Gray","sequence":"additional","affiliation":[{"name":"Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Altfeld","sequence":"additional","affiliation":[{"name":"Department of Viral Immunology, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie-Louise","family":"Newell","sequence":"additional","affiliation":[{"name":"School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom"},{"name":"School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thumbi","family":"Ndung\u2019u","sequence":"additional","affiliation":[{"name":"HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa"},{"name":"Africa Health Research Institute, Durban, South Africa"},{"name":"Max Planck Institute for Infection Biology, Berlin, Germany"},{"name":"Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA"},{"name":"Division of Infection and Immunity, University College London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"2021121701521036700_CIT0001","doi-asserted-by":"crossref","first-page":"S208","DOI":"10.1097\/QAI.0b013e3182986f55","article-title":"Can we achieve an AIDS-free generation? Perspectives on the global campaign to eliminate new pediatric HIV infections","volume":"63 Suppl 2","author":"Abrams","year":"2013","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2021121701521036700_CIT0002","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1097\/QAI.0b013e31802ea4b0","article-title":"Pregnancy outcomes in HIV-infected and uninfected women in rural and urban South Africa","volume":"44","author":"Rollins","year":"2007","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2021121701521036700_CIT0003","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1093\/infdis\/jis553","article-title":"Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana","volume":"206","author":"Chen","year":"2012","journal-title":"J Infect Dis"},{"key":"2021121701521036700_CIT0004","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1016\/j.ajog.2004.06.092","article-title":"Induction of premature labor and delivery by allergic reaction and prevention by histamine H1 receptor antagonist","volume":"191","author":"Bytautiene","year":"2004","journal-title":"Am J Obstet Gynecol"},{"key":"2021121701521036700_CIT0005","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1097\/00002030-200411190-00019","article-title":"Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe","volume":"18","author":"Thorne","year":"2004","journal-title":"AIDS"},{"key":"2021121701521036700_CIT0006","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1111\/j.1471-0528.2010.02689.x","article-title":"Antiretroviral therapy and preterm delivery\u2014a pooled analysis of data from the United States and Europe","volume":"117","author":"Townsend","year":"2010","journal-title":"BJOG"},{"key":"2021121701521036700_CIT0007","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1097\/QAD.0b013e32830b8ab9","article-title":"Antiretroviral therapy in pregnant women with advanced HIV disease and pregnancy outcomes in Abidjan, C\u00f4te d\u2019Ivoire","volume":"22","author":"Ekouevi","year":"2008","journal-title":"AIDS"},{"key":"2021121701521036700_CIT0008","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1056\/NEJMoa1511691","article-title":"Benefits and risks of antiretroviral therapy for perinatal HIV prevention","volume":"375","author":"Fowler","year":"2016","journal-title":"N Engl J Med"},{"key":"2021121701521036700_CIT0009","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S1473-3099(10)70288-7","article-title":"Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial","volume":"11","author":"de Vincenzi","year":"2011","journal-title":"Lancet Infect Dis"},{"key":"2021121701521036700_CIT0010","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1093\/infdis\/jir307","article-title":"Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy","volume":"204","author":"Powis","year":"2011","journal-title":"J Infect Dis"},{"key":"2021121701521036700_CIT0011","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1097\/QAI.0000000000002072","article-title":"Risk factors for adverse birth outcomes in the PROMISE 1077BF\/1077FF Trial","volume":"81","author":"Sebikari","year":"2019","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2021121701521036700_CIT0012","author":"WHO","year":"2015"},{"key":"2021121701521036700_CIT0013","author":"SANAC","year":"2017"},{"key":"2021121701521036700_CIT0014","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1093\/infdis\/jis581","article-title":"Antiretrovirals in pregnancy: a note of caution","volume":"206","author":"Watts","year":"2012","journal-title":"J Infect Dis"},{"key":"2021121701521036700_CIT0015","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0165-0378(97)00018-1","article-title":"Immunologic activation during pregnancy: serial measurement of lymphocyte phenotype and serum activation molecules in HIV-infected and uninfected women","volume":"33","author":"Mikyas","year":"1997","journal-title":"J Reprod Immunol"},{"key":"2021121701521036700_CIT0016","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/molehr\/gap054","article-title":"Leukocytes are primed in peripheral blood for activation during term and preterm labour","volume":"15","author":"Yuan","year":"2009","journal-title":"Mol Hum Reprod"},{"key":"2021121701521036700_CIT0017","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.3389\/fimmu.2017.01138","article-title":"Changes in T cell and dendritic cell phenotype from mid to late pregnancy are indicative of a shift from immune tolerance to immune activation","volume":"8","author":"Shah","year":"2017","journal-title":"Front Immunol"},{"key":"2021121701521036700_CIT0018","doi-asserted-by":"crossref","first-page":"e96723","DOI":"10.1371\/journal.pone.0096723","article-title":"Normal human pregnancy results in maternal immune activation in the periphery and at the uteroplacental interface","volume":"9","author":"Loewendorf","year":"2014","journal-title":"PLoS One"},{"key":"2021121701521036700_CIT0019","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1097\/00002030-199814000-00015","article-title":"Immunologic effects of combined protease inhibitor and reverse transcriptase inhibitor therapy in previously treated chronic HIV-1 infection","volume":"12","author":"Giorgi","year":"1998","journal-title":"AIDS"},{"key":"2021121701521036700_CIT0020","first-page":"904","article-title":"Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study","volume":"6","author":"Giorgi","year":"1993","journal-title":"J Acquir Immune Defic Syndr (1988)"},{"key":"2021121701521036700_CIT0021","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1093\/infdis\/jiu238","article-title":"Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection","volume":"210","author":"Hunt","year":"2014","journal-title":"J Infect Dis"},{"key":"2021121701521036700_CIT0022","first-page":"; 202:2585\u2013608","article-title":"Effector and activated T Cells iinduce preterm labor and birth that is prevented by treatment with progesterone","author":"Arenas-Hernandez","year":"2019","journal-title":"J Immunol"},{"key":"2021121701521036700_CIT0023","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/cei.12968","article-title":"In vivo activation of invariant natural killer T cells induces systemic and local alterations in T-cell subsets prior to preterm birth","volume":"189","author":"Gomez-Lopez","year":"2017","journal-title":"Clin Exp Immunol"},{"key":"2021121701521036700_CIT0024","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.4049\/jimmunol.1501962","article-title":"Invariant NKT cell activation induces late preterm birth that is attenuated by rosiglitazone","volume":"196","author":"St Louis","year":"2016","journal-title":"J Immunol"},{"key":"2021121701521036700_CIT0025","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1126\/science.1251816","article-title":"Preterm labor: one syndrome, many causes","volume":"345","author":"Romero","year":"2014","journal-title":"Science"},{"key":"2021121701521036700_CIT0026","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.placenta.2019.03.003","article-title":"The role of maternal T cell and macrophage activation in preterm birth: cause or consequence?","volume":"79","author":"Bonney","year":"2019","journal-title":"Placenta"},{"key":"2021121701521036700_CIT0027","doi-asserted-by":"crossref","first-page":"11246","DOI":"10.1038\/s41598-019-47756-7","article-title":"Predictive value of cervical cytokine, antimicrobial and microflora levels for pre-term birth in high-risk women","volume":"9","author":"Manning","year":"2019","journal-title":"Sci Rep"},{"key":"2021121701521036700_CIT0028","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3389\/fmed.2018.00181","article-title":"The vaginal microenvironment: the physiologic role of lactobacilli","volume":"5","author":"Amabebe","year":"2018","journal-title":"Front Med (Lausanne)"},{"key":"2021121701521036700_CIT0029","article-title":"Cohort profile: prematurity immunology in HIV-infected mothers and their infants study (PIMS)","author":"Malaba","year":"2020","journal-title":"medRxiv"},{"key":"2021121701521036700_CIT0030","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.siny.2006.05.001","article-title":"Inflammation in preterm and term labour and delivery","volume":"11","author":"Romero","year":"2006","journal-title":"Semin Fetal Neonatal Med"},{"key":"2021121701521036700_CIT0031","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1189\/jlb.3MR0615-272RR","article-title":"Inflammation and preterm birth","volume":"99","author":"Cappelletti","year":"2016","journal-title":"J Leukoc Biol"},{"key":"2021121701521036700_CIT0032","doi-asserted-by":"crossref","first-page":"993","DOI":"10.3389\/fimmu.2018.00993","article-title":"Meta-analysis of maternal and fetal transcriptomic data elucidates the role of adaptive and innate immunity in preterm birth","volume":"9","author":"Vora","year":"2018","journal-title":"Front Immunol"},{"key":"2021121701521036700_CIT0033","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.3389\/fimmu.2017.01266","article-title":"Preterm birth affects the risk of developing immune-mediated diseases","volume":"8","author":"Goedicke-Fritz","year":"2017","journal-title":"Front Immunol"},{"key":"2021121701521036700_CIT0034","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1086\/657143","article-title":"Profound lack of interleukin (IL)-12\/IL-23p40 in neonates born early in gestation is associated with an increased risk of sepsis","volume":"202","author":"Lavoie","year":"2010","journal-title":"J Infect Dis"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciab151\/37408740\/ciab151.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/73\/12\/2205\/41794000\/ciab151.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/73\/12\/2205\/41794000\/ciab151.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T01:54:51Z","timestamp":1639706091000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/73\/12\/2205\/6144975"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,19]]},"references-count":34,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,2,19]]},"published-print":{"date-parts":[[2021,12,16]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciab151","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,15]]},"published":{"date-parts":[[2021,2,19]]}}}