title: Postpartum Circulating Markers of Inflammation and the Systemic Acute-Phase Response After Early-Onset Preeclampsia.
abstract: Preeclampsia is an inflammatory-mediated hypertensive disorder of pregnancy and seems to be an early indicator of increased cardiovascular risk, but mechanisms underlying this association are unclear. In this study, we identified levels of circulating inflammatory markers and dynamic changes in the systemic acute-phase response in 44 women with a history of severe early-onset preeclampsia, compared with 29 controls with only uneventful pregnancies at 1.5 to 3.5 years postpartum. Models used were in vivo seasonal influenza vaccination and in vitro whole-blood culture with T-cell stimulants and the toll-like receptor-4 ligand lipopolysaccharide. Outcome measures were C-reactive protein, interleukin-6 (IL-6), IL-18, fibrinogen, myeloperoxidase, and a panel of 13 cytokines representative of the innate and adaptive inflammatory response, in addition to established cardiovascular markers. The in vivo acute-phase response was higher for women with previous preeclampsia than that for controls without such a history, although only significant for C-reactive protein (P=0.04). Preeclampsia was associated with higher IL-1β (P<0.05) and IL-8 (P<0.01) responses to T-cell activation. Hierarchical clustering revealed 2 distinct inflammatory clusters associated with previous preeclampsia: an adaptive response cluster associated with increased C-reactive protein and IL-6 before and after vaccination, increased weight, and low high-density lipoprotein cholesterol; and a toll-like receptor-4 mediated the cluster associated with increased IL-18 before and after vaccination but not associated with other cardiovascular markers. Furthermore, we found interactions between previous preeclampsia, common TLR4 gene variants, and the IL-18 response to vaccination. In conclusion, preeclampsia is associated with alterations in the inflammatory response postpartum mostly independent of other established cardiovascular risk markers.
authors.affiliation: From the Division of Woman and Baby (B.B.v.R., H.W.B., J.H.V., E.D.P.U., S.V.K., A.F.) and Laboratory for Clinical Chemistry and Hematology, University Medical Center Utrecht (M.R.), Utrecht, The Netherlands; Centre for Trophoblast Disease, University of Cambridge, Cambridge, United Kingdom (J.H.V.); Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands (J.G.v.d.B.); Department of Medical Microbiology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands (G.T.R.); Department of Science, University College Roosevelt, Middelburg, The Netherlands (G.T.R.); and Academic Unit of Human Development and Health, University of Southampton, Southampton, United Kingdom (B.B.v.R.). B.Van-Rijn@soton.ac.uk.
authors.forename: Bas B
authors.initials: BB
authors.lastname: van Rijn
authors.affiliation: From the Division of Woman and Baby (B.B.v.R., H.W.B., J.H.V., E.D.P.U., S.V.K., A.F.) and Laboratory for Clinical Chemistry and Hematology, University Medical Center Utrecht (M.R.), Utrecht, The Netherlands; Centre for Trophoblast Disease, University of Cambridge, Cambridge, United Kingdom (J.H.V.); Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands (J.G.v.d.B.); Department of Medical Microbiology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands (G.T.R.); Department of Science, University College Roosevelt, Middelburg, The Netherlands (G.T.R.); and Academic Unit of Human Development and Health, University of Southampton, Southampton, United Kingdom (B.B.v.R.).
authors.forename: Hein W
authors.initials: HW
authors.lastname: Bruinse
authors.affiliation: From the Division of Woman and Baby (B.B.v.R., H.W.B., J.H.V., E.D.P.U., S.V.K., A.F.) and Laboratory for Clinical Chemistry and Hematology, University Medical Center Utrecht (M.R.), Utrecht, The Netherlands; Centre for Trophoblast Disease, University of Cambridge, Cambridge, United Kingdom (J.H.V.); Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands (J.G.v.d.B.); Department of Medical Microbiology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands (G.T.R.); Department of Science, University College Roosevelt, Middelburg, The Netherlands (G.T.R.); and Academic Unit of Human Development and Health, University of Southampton, Southampton, United Kingdom (B.B.v.R.).
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veerbeek
authors.affiliation: From the Division of Woman and Baby (B.B.v.R., H.W.B., J.H.V., E.D.P.U., S.V.K., A.F.) and Laboratory for Clinical Chemistry and Hematology, University Medical Center Utrecht (M.R.), Utrecht, The Netherlands; Centre for Trophoblast Disease, University of Cambridge, Cambridge, United Kingdom (J.H.V.); Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands (J.G.v.d.B.); Department of Medical Microbiology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands (G.T.R.); Department of Science, University College Roosevelt, Middelburg, The Netherlands (G.T.R.); and Academic Unit of Human Development and Health, University of Southampton, Southampton, United Kingdom (B.B.v.R.).
authors.forename: Emiel D
authors.initials: ED
authors.lastname: Post Uiterweer
authors.affiliation: From the Division of Woman and Baby (B.B.v.R., H.W.B., J.H.V., E.D.P.U., S.V.K., A.F.) and Laboratory for Clinical Chemistry and Hematology, University Medical Center Utrecht (M.R.), Utrecht, The Netherlands; Centre for Trophoblast Disease, University of Cambridge, Cambridge, United Kingdom (J.H.V.); Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands (J.G.v.d.B.); Department of Medical Microbiology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands (G.T.R.); Department of Science, University College Roosevelt, Middelburg, The Netherlands (G.T.R.); and Academic Unit of Human Development and Health, University of Southampton, Southampton, United Kingdom (B.B.v.R.).
authors.forename: Steven V
authors.initials: SV
authors.lastname: Koenen
authors.affiliation: From the Division of Woman and Baby (B.B.v.R., H.W.B., J.H.V., E.D.P.U., S.V.K., A.F.) and Laboratory for Clinical Chemistry and Hematology, University Medical Center Utrecht (M.R.), Utrecht, The Netherlands; Centre for Trophoblast Disease, University of Cambridge, Cambridge, United Kingdom (J.H.V.); Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands (J.G.v.d.B.); Department of Medical Microbiology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands (G.T.R.); Department of Science, University College Roosevelt, Middelburg, The Netherlands (G.T.R.); and Academic Unit of Human Development and Health, University of Southampton, Southampton, United Kingdom (B.B.v.R.).
authors.forename: Johanna G
authors.initials: JG
authors.lastname: van der Bom
authors.affiliation: From the Division of Woman and Baby (B.B.v.R., H.W.B., J.H.V., E.D.P.U., S.V.K., A.F.) and Laboratory for Clinical Chemistry and Hematology, University Medical Center Utrecht (M.R.), Utrecht, The Netherlands; Centre for Trophoblast Disease, University of Cambridge, Cambridge, United Kingdom (J.H.V.); Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands (J.G.v.d.B.); Department of Medical Microbiology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands (G.T.R.); Department of Science, University College Roosevelt, Middelburg, The Netherlands (G.T.R.); and Academic Unit of Human Development and Health, University of Southampton, Southampton, United Kingdom (B.B.v.R.).
authors.forename: Ger T
authors.initials: GT
authors.lastname: Rijkers
authors.affiliation: From the Division of Woman and Baby (B.B.v.R., H.W.B., J.H.V., E.D.P.U., S.V.K., A.F.) and Laboratory for Clinical Chemistry and Hematology, University Medical Center Utrecht (M.R.), Utrecht, The Netherlands; Centre for Trophoblast Disease, University of Cambridge, Cambridge, United Kingdom (J.H.V.); Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands (J.G.v.d.B.); Department of Medical Microbiology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands (G.T.R.); Department of Science, University College Roosevelt, Middelburg, The Netherlands (G.T.R.); and Academic Unit of Human Development and Health, University of Southampton, Southampton, United Kingdom (B.B.v.R.).
authors.forename: Mark
authors.initials: M
authors.lastname: Roest
authors.affiliation: From the Division of Woman and Baby (B.B.v.R., H.W.B., J.H.V., E.D.P.U., S.V.K., A.F.) and Laboratory for Clinical Chemistry and Hematology, University Medical Center Utrecht (M.R.), Utrecht, The Netherlands; Centre for Trophoblast Disease, University of Cambridge, Cambridge, United Kingdom (J.H.V.); Department of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, The Netherlands (J.G.v.d.B.); Department of Medical Microbiology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands (G.T.R.); Department of Science, University College Roosevelt, Middelburg, The Netherlands (G.T.R.); and Academic Unit of Human Development and Health, University of Southampton, Southampton, United Kingdom (B.B.v.R.).
authors.forename: Arie
authors.initials: A
authors.lastname: Franx
mesh_terms: D000210:Acute-Phase Reaction / Q000097:blood* / Q000276:immunology; D000328:Adult; D015415:Biomarkers / Q000097:blood*; D002097:C-Reactive Protein / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000097:blood / Q000276:immunology; D049590:Postpartum Period / Q000097:blood*; D011225:Pre-Eclampsia / Q000097:blood* / Q000276:immunology / Q000503:physiopathology; D011247:Pregnancy; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D016207:Cytokines; D002097:C-Reactive Protein
keywords: acute-phase response; inflammation; preeclampsia; pregnancy; toll-like receptors; vaccination