title: Fetal origins of malarial disease: cord blood cytokines as risk markers for pediatric severe malarial anemia.
abstract: BACKGROUND
  Severe malarial anemia (SMA) remains a major cause of pediatric illness and mortality in Sub-Saharan Africa. Here we test the hypothesis that prenatal exposures, reflected by soluble inflammatory mediators in cord blood, can condition an individual's susceptibility to SMA.
  
  
  METHODS
  In a Tanzanian birth cohort (n = 743), we measured cord blood concentrations of tumor necrosis factor (TNF), TNF receptors I and II (TNF-RI and TNF-RII), interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-10, and interferon gamma (IFN-γ). After adjusting for conventional covariates, we calculated the hazard ratios (HR) for time to first SMA event with log(e) cytokine concentrations dichotomized at the median, by quartile, and per standard deviation (SD) increase.
  
  
  RESULTS
  Low levels of TNF, TNF-RI, IL-1β, and IL-5 and high levels of TNF-RII were associated statistically significantly and respectively with approximately 3-fold, 2-fold, 8-fold, 4-fold, and 3-fold increased risks of SMA (Hb < 50 g/L). TNF, TNF-RI, and IL-1β concentrations were inversely and log-linearly associated with SMA risk; the HR (95% confidence interval [CI]) per 1-SD increase were respectively 0.81 (.65, 1.02), 0.76 (.62, .92), and 0.50 (.40, .62).
  
  
  CONCLUSIONS
  These data suggest that proinflammatory cytokine levels at birth are inversely associated with SMA risk and support the hypothesis that pediatric malarial disease has fetal origins.
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland Department of Public Health and Primary Care, Strangeways Research Laboratories, University of Cambridge, United Kingdom.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Brickley
authors.affiliation: Department of Public Health and Primary Care, Strangeways Research Laboratories, University of Cambridge, United Kingdom.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Wood
authors.affiliation: MOMS Project, Seattle Biomedical Research Institute, Washington Muheza Designated District Hospital, Tanzania.
authors.forename: Edward
authors.initials: E
authors.lastname: Kabyemela
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland MOMS Project, Seattle Biomedical Research Institute, Washington.
authors.forename: Robert
authors.initials: R
authors.lastname: Morrison
authors.affiliation: Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Brown University Medical School, Providence.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Kurtis
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland.
authors.forename: Michal
authors.initials: M
authors.lastname: Fried
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duffy
mesh_terms: D000293:Adolescent; D000328:Adult; D000740:Anemia / Q000097:blood* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood* / Q000378:metabolism; D016207:Cytokines / Q000097:blood* / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D005333:Fetus / Q000098:blood supply* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D007378:Interleukins / Q000097:blood / Q000378:metabolism; D008288:Malaria / Q000097:blood* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011247:Pregnancy; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood / Q000378:metabolism; D012306:Risk; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; D007378:Interleukins; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: anemia; cord blood; cytokines; developmental programming; inflammation; malaria; risk marker