title: Repeated measures of inflammation and oxidative stress biomarkers in preeclamptic and normotensive pregnancies.
abstract: Preeclampsia is a prevalent and enigmatic disease, in part characterized by poor remodeling of the spiral arteries. However, preeclampsia does not always clinically present when remodeling has failed to occur. Hypotheses surrounding the "second hit" that is necessary for the clinical presentation of the disease focus on maternal inflammation and oxidative stress. Yet, the studies to date that have investigated these factors have used cross-sectional study designs or small study populations.
  
  
  
  In the present study, we sought to explore longitudinal trajectories, beginning early in gestation, of a panel of inflammation and oxidative stress markers in women who went on to have preeclamptic or normotensive pregnancies.
  
  
  
  We examined 441 subjects from the ongoing LIFECODES prospective birth cohort, which included 50 mothers who experienced preeclampsia and 391 mothers with normotensive pregnancies. Participants provided urine and plasma samples at 4 time points during gestation (median, 10, 18, 26, and 35 weeks) that were analyzed for a panel of oxidative stress and inflammation markers. Oxidative stress biomarkers included 8-isoprostane and 8-hydroxydeoxyguanosine. Inflammation biomarkers included C-reactive protein, the cytokines interleukin-1β, -6, and -10, and tumor necrosis factor-α. We created Cox proportional hazard models to calculate hazard ratios based on time of preeclampsia diagnosis in association with biomarker concentrations at each of the 4 study visits.
  
  
  
  In adjusted models, hazard ratios of preeclampsia were significantly (P<.01) elevated in association with all inflammation biomarkers that were measured at visit 2 (median, 18 weeks; hazard ratios, 1.31-1.83, in association with an interquartile range increase in biomarker). Hazard ratios at this time point were the most elevated for C-reactive protein, for interleukin-1β, -6, and -10, and for the oxidative stress biomarker 8-isoprostane (hazard ratio, 1.68; 95% confidence interval, 1.14-2.48) compared to other time points. Hazard ratios for tumor necrosis factor-α were consistently elevated at all 4 of the study visits (hazard ratios, 1.49-1.63; P<.01). In sensitivity analyses, we observed that these associations were attenuated within groups typically at higher risk of experiencing preeclampsia, which include African American mothers, mothers with higher body mass index at the beginning of gestation, and pregnancies that ended preterm.
  
  
  
  This study provides the most robust data to date on repeated measures of inflammation and oxidative stress in preeclamptic compared with normotensive pregnancies. Within these groups, inflammation and oxidative stress biomarkers show different patterns across gestation, beginning as early as 10 weeks. The start of the second trimester appears to be a particularly important time point for the measurement of these biomarkers. Although biomarkers alone do not appear to be useful in the prediction of preeclampsia, these data are useful in understanding the maternal inflammatory profile in pregnancy before the development of the disease and may be used to further develop an understanding of potentially preventative measures.
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC. Electronic address: kelly.ferguson2@nih.gov.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Ferguson
authors.affiliation: Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI.
authors.forename: John D
authors.initials: JD
authors.lastname: Meeker
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: McElrath
authors.affiliation: Department of Biostatistics, and Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI.
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: David E
authors.initials: DE
authors.lastname: Cantonwine
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002097:C-Reactive Protein / Q000032:analysis; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood / Q000652:urine; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000652:urine*; D018384:Oxidative Stress; D011225:Pre-Eclampsia / Q000097:blood* / Q000652:urine*; D011247:Pregnancy; D016016:Proportional Hazards Models
chemical_list: D015415:Biomarkers; D016207:Cytokines; C075750:8-epi-prostaglandin F2alpha; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002097:C-Reactive Protein; D015237:Dinoprost; D003849:Deoxyguanosine
keywords: biomarker; cytokine; hypertension; inflammation; isoprostane; oxidative stress; preeclampsia