{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T10:56:16Z","timestamp":1762253776361,"version":"3.41.2"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T00:00:00Z","timestamp":1619740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Fetal anemia is common in malaria-endemic areas and a risk factor for anemia as well as mortality during infancy. Placental malaria (PM) and red cell abnormalities have been proposed as possible etiologies, but the relationship between PM and fetal anemia has varied in earlier studies, and the role of red cell abnormalities has not been studied in malaria-endemic areas. In a Tanzanian birth cohort study designed to elucidate the pathogenesis of severe malaria in young infants, we performed a cross-sectional analysis of risk factors for fetal anemia. We determined PM status, newborn red cell abnormalities, and maternal and cord blood levels of iron regulatory proteins, erythropoietin (EPO), cytokines and cytokine receptors. We examined the relationship between these factors and fetal anemia. Fetal anemia was present in 46.2% of the neonates but was not related to PM. Maternal iron deficiency was common (81.6%), most frequent in multigravidae, and interacted with parity to modify risk of fetal anemia, but it was not directly related to risk. Among offspring of iron-deficient women, the odds of fetal anemia increased with fetal \u03b1<jats:sup>+<\/jats:sup>-thalassemia, as well as these patterns of cord blood cytokines: increased cord IL-6, decreased TNF-RI, and decreased sTfR. The EPO response to fetal anemia was low or absent and EPO levels were significantly decreased in newborns with the most severe anemia. This study from an area of high malaria transmission provides evidence that 1) fetal \u03b1<jats:sup>+<\/jats:sup>-thalassemia and cytokine balance, but not PM at delivery, are related to fetal anemia; 2) maternal iron deficiency increases the risk that other factors may cause fetal anemia; and 3) fetal anemia has a multifactorial etiology that may require a variety of interventions, although measures that reduce maternal iron deficiency may be generally beneficial.<\/jats:p>","DOI":"10.3389\/fimmu.2021.624136","type":"journal-article","created":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T06:41:11Z","timestamp":1619764871000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Fetal Cytokine Balance, Erythropoietin and Thalassemia but Not Placental Malaria Contribute to Fetal Anemia Risk in Tanzania"],"prefix":"10.3389","volume":"12","author":[{"given":"Edward R.","family":"Kabyemela","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Fried","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan D.","family":"Kurtis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gwamaka","family":"Moses","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Patrick","family":"Gorres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atis","family":"Muehlenbachs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick E.","family":"Duffy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/00006250-199203000-00013","article-title":"The severely anemic and hydropic isoimmune fetus: changes in fetal hematocrit associated with intrauterine death","volume":"79","author":"Radunovic","year":"1992","journal-title":"Obstet Gynecol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2001.116690","article-title":"The severity of immune fetal hydrops is predictive of fetal outcome after intrauterine treatment","volume":"185","author":"van Kamp","year":"2001","journal-title":"Am J Obstet Gynecol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"69","DOI":"10.4314\/mmj.v21i2.44553","article-title":"Low birth weight and fetal anaemia as risk factors for infant morbidity in rural Malawi","volume":"21","author":"Kalanda","year":"2009","journal-title":"Malawi Med J"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/fn.86.3.F182","article-title":"Changes in haemoglobin levels in infants in Malawi: effect of low birth weight and fetal anaemia","volume":"86","author":"le Cessie","year":"2002","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1086\/518441","article-title":"HIV, malaria, and infant anemia as risk factors for postneonatal infant mortality among HIV-seropositive women in Kisumu, Kenya","volume":"196","author":"van Eijk","year":"2007","journal-title":"J Infect Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1080\/02724936.1992.11747589","article-title":"Fetal anaemia in malarious areas: its causes and significance","volume":"12","author":"Brabin","year":"1992","journal-title":"Ann Trop Paediatr"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1179\/027249304225019136","article-title":"Risk factors for fetal anaemia in a malarious area of Malawi","volume":"24","author":"Brabin","year":"2004","journal-title":"Ann Trop Paediatr"},{"key":"B8","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1186\/1756-0500-6-350","article-title":"Predictors of fetal anemia and cord blood malaria parasitemia among newborns of HIV-positive mothers","volume":"6","author":"Laar","year":"2013","journal-title":"BMC Res Notes"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis597","article-title":"The effects of malaria and intermittent preventive treatment during pregnancy on fetal anemia in Malawi","volume":"55","author":"Rogawski","year":"2012","journal-title":"Clin Infect Dis"},{"key":"B10","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/1475-2875-4-39","article-title":"Malaria during pregnancy and foetal haematological status in Blantyre, Malawi","volume":"4","author":"Abrams","year":"2005","journal-title":"Malar J"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e2724","DOI":"10.1371\/journal.pntd.0002724","article-title":"The association of parasitic infections in pregnancy and maternal and fetal anemia: a cohort study in coastal Kenya","volume":"8","author":"McClure","year":"2014","journal-title":"PloS Negl Trop Dis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2011.10-0250","article-title":"Iron homeostasis in mother and child during placental malaria infection","volume":"84","author":"Van Santen","year":"2011","journal-title":"Am J Trop Med Hyg"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir376","article-title":"Intermittent treatment to prevent pregnancy malaria does not confer benefit in an area of widespread drug resistance","volume":"53","author":"Harrington","year":"2011","journal-title":"Clin Infect Dis"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/PL00008540","article-title":": Detection of congenital malaria by polymerase-chain-reaction methodology in Dar es Salaam, Tanzania","volume":"86","author":"Adachi","year":"2000","journal-title":"Parasitol Res"},{"key":"B15","article-title":"Inhibition of CFU-E colony formation in uremic patients with inflammatory disease: role of IFN-gamma and TNF-alpha","volume":"47","author":"Allen","year":"1999","journal-title":"J Investig Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1111\/j.1365-2141.1988.tb02440.x","article-title":"Tumour necrosis factor may contribute to the anaemia of malaria by causing dyserythropoiesis and erythrophagocytosis","volume":"70","author":"Clark","year":"1988","journal-title":"Br J Haematol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)09439-7","article-title":"Low plasma concentrations of interleukin 10 in severe malarial anaemia compared with cerebral and uncomplicated malaria","volume":"351","author":"Kurtzhals","year":"1998","journal-title":"Lancet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1086\/314548","article-title":"A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya","volume":"179","author":"Othoro","year":"1999","journal-title":"J Infect Dis"},{"key":"B19","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.160.5.2523","article-title":"Malaria elicits type 1 cytokines in the human placenta: IFN-gamma and TNF-alpha associated with pregnancy outcomes","volume":"160","author":"Fried","year":"1998","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1079\/PHN2004597","article-title":"Predictors of pregnancy and postpartum haemoglobin concentrations in low-income women","volume":"7","author":"Bodnar","year":"2004","journal-title":"Public Health Nutr"},{"key":"B21","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1159\/000010067","article-title":"The complexity of pregnancy anemia in Dar-es-Salaam","volume":"47","author":"Massawe","year":"1999","journal-title":"Gynecol Obstet Invest"},{"key":"B22","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.arcmed.2005.03.023","article-title":"Sub-optimal fetal iron acquisition under a maternal environment","volume":"36","author":"Jaime-Perez","year":"2005","journal-title":"Arch Med Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2006.06216.x","article-title":"Localisation of proteins of iron metabolism in the human placenta and liver","volume":"134","author":"Bastin","year":"2006","journal-title":"Br J Haematol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/35001596","article-title":": Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter","volume":"403","author":"Donovan","year":"2000","journal-title":"Nature"},{"key":"B25","article-title":"Cord blood erythropoietin in relation to different markers of fetal hypoxia","volume":"81","author":"Maier","year":"1993","journal-title":"Obstet Gynecol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/aogs.12553","article-title":"Amniotic fluid erythropoietin and neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks","volume":"94","author":"Seikku","year":"2015","journal-title":"Acta Obstet Gynecol Scand"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1097\/00006250-200004000-00016","article-title":"Maternal smoking and fetal erythropoietin levels","volume":"95","author":"Gruslin","year":"2000","journal-title":"Obstet Gynecol"},{"key":"B28","article-title":"Erythropoietin in human fetuses with immune hemolytic anemia and hydrops fetalis","volume":"82","author":"Moya","year":"1993","journal-title":"Obstet Gynecol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(89)90466-3","article-title":"Amniotic fluid erythropoietin predicts fetal distress in Rh-immunized pregnancies","volume":"160","author":"Voutilainen","year":"1989","journal-title":"Am J Obstet Gynecol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2220-1","article-title":"Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria","volume":"582","author":"Raj","year":"2020","journal-title":"Nature"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2019.06.084","article-title":"Impact of maternally derived antibodies to Plasmodium falciparum Schizont Egress Antigen-1 on the endogenous production of anti-PfSEA-1 in offspring","volume":"37","author":"Park","year":"2019","journal-title":"Vaccine"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0803657105","article-title":"Natural selection of FLT1 alleles and their association with malaria resistance in utero","volume":"105","author":"Muehlenbachs","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy728","article-title":": Maternally-derived Antibodies to Schizont Egress Antigen-1 and Protection of Infants From Severe Malaria","volume":"68","author":"Kurtis","year":"2019","journal-title":"Clin Infect Dis"},{"key":"B34","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/1475-2875-7-26","article-title":"Maternal peripheral blood level of IL-10 as a marker for inflammatory placental malaria","volume":"7","author":"Kabyemela","year":"2008","journal-title":"Malar J"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1086\/589512","article-title":"Decreased susceptibility to Plasmodium falciparum infection in pregnant women with iron deficiency","volume":"198","author":"Kabyemela","year":"2008","journal-title":"J Infect Dis"},{"key":"B36","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1186\/1475-2875-10-386","article-title":"Early and extensive CD55 loss from red blood cells supports a causal role in malarial anaemia","volume":"10","author":"Gwamaka","year":"2011","journal-title":"Malar J"},{"key":"B37","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1056\/NEJMc1407114","article-title":"Parasite burden and severity of malaria in Tanzanian children","volume":"371","author":"Goncalves","year":"2014","journal-title":"N Engl J Med"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e14","DOI":"10.1017\/gheg.2017.8","article-title":"Developing a novel risk prediction model for severe malarial anemia","volume":"2","author":"Brickley","year":"2017","journal-title":"Glob Health Epidemiol Genom"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00757-06","article-title":"Schistosoma japonicum reinfection after praziquantel treatment causes anemia associated with inflammation","volume":"74","author":"Leenstra","year":"2006","journal-title":"Infect Immun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(95)70178-8","article-title":"Favism in a female newborn infant whose mother ingested fava beans before delivery","volume":"127","author":"Corchia","year":"1995","journal-title":"J Pediatr"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.1.360","article-title":"Single-tube multiplex-PCR screen for common deletional determinants of alpha-thalassemia","volume":"95","author":"Chong","year":"2000","journal-title":"Blood"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1086\/656723","article-title":"A novel histological grading scheme for placental malaria applied in areas of high and low malaria transmission","volume":"202","author":"Muehlenbachs","year":"2010","journal-title":"J Infect Dis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/27570","article-title":"Maternal antibodies block malaria","volume":"395","author":"Fried","year":"1998","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01238-4","article-title":": Malaria is a cause of iron deficiency in African children","author":"Muriuki","year":"2021","journal-title":"Nat Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1042\/bj3560883","article-title":"Effect of iron deficiency on placental transfer of iron and expression of iron transport proteins in vivo and in vitro","volume":"356","author":"Gambling","year":"2001","journal-title":"Biochem J"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1172\/JCI127341","article-title":"Effects of maternal iron status on placental and fetal iron homeostasis","volume":"130","author":"Sangkhae","year":"2020","journal-title":"J\u00a0Clin Invest"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00964-07","article-title":"Fetal responses during placental malaria modify the risk of low birth weight","volume":"76","author":"Kabyemela","year":"2008","journal-title":"Infect Immun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200420945","article-title":"IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin","volume":"113","author":"Nemeth","year":"2004","journal-title":"J Clin Invest"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3156.1999.00386.x","article-title":"The contribution of alpha+-thalassaemia to anaemia in a Nigerian population exposed to intense malaria transmission","volume":"4","author":"Mockenhaupt","year":"1999","journal-title":"Trop Med Int Health"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3109\/14767058.2010.507294","article-title":"An elevated fetal interleukin-6 concentration can be observed in fetuses with anemia due to Rh alloimmunization: implications for the understanding of the fetal inflammatory response syndrome","volume":"24","author":"Vaisbuch","year":"2011","journal-title":"J Matern Fetal Neonatal Med"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1986.tb04120.x","article-title":"Circulating transferrin receptor in human serum","volume":"64","author":"Kohgo","year":"1986","journal-title":"Br J Haematol"},{"key":"B52","article-title":"Influence of alpha thalassaemia on haematological parameters in Polynesian patients","volume":"98","author":"Mickleson","year":"1985","journal-title":"N Z Med J"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.2.637","article-title":"Transferrin receptors in rat plasma","volume":"85","author":"Beguin","year":"1988","journal-title":"Proc Natl Acad Sci USA"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.1998.00971.x","article-title":"Alpha thalassaemia is associated with increased soluble transferrin receptor levels","volume":"103","author":"Rees","year":"1998","journal-title":"Br J Haematol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1080\/j.1600-0412.2000.079004276.x","article-title":"Fetal erythropoietin and endothelin-1: relation to hypoxia and intrauterine growth retardation","volume":"79","author":"Ostlund","year":"2000","journal-title":"Acta Obstet Gynecol Scand"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1515\/jpme.1995.23.1-2.71","article-title":"Lack of permeability of the human placenta for erythropoietin","volume":"23","author":"Schneider","year":"1995","journal-title":"J Perinat Med"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.10.7.8635693","article-title":"Expression of erythropoietin by the human placenta","volume":"10","author":"Conrad","year":"1996","journal-title":"FASEB J"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V60.4.984.bloodjournal604984","article-title":"Erythropoietin production in response to anemia or hypoxia in the newborn rat","volume":"60","author":"Caro","year":"1982","journal-title":"Blood"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V79.8.1987.bloodjournal7981987","article-title":"Effect of inflammatory cytokines on hypoxia-induced erythropoietin production","volume":"79","author":"Faquin","year":"1992","journal-title":"Blood"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.624136\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T01:34:24Z","timestamp":1698975264000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.624136\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,30]]},"references-count":59,"alternative-id":["10.3389\/fimmu.2021.624136"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.624136","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2021,4,30]]},"article-number":"624136"}}