- Email: [email protected]
dehydroepi- androsterone sulfate ratio (fetal stress index)
SMFM Abstracts
www.AJOG.org 199
EARLY ONSET NEONATAL SEPSIS (EONS): ACCOMPANIED BY AN INCREASED INTERLEUKIN-6 (IL-6) CYTOKINE INDEX, LINKED TO HISTOLOGICAL CHORIOAMNIONITIS CATALIN S. BUHIMSCHI1, STEPHEN F. THUNG1, MERT O. BAHTIYAR1, VICTOR A. ROSENBERG1, ANTONETTE T. DULAY1, SONYA S. ABDEL-RAZEQ1, CHRISTIAN M. PETTKER1, GUOYANG LUO1, GUOMAO ZHAO1, ANNA SFAKIANAKI1, HEATHER S. LIPKIND1, EDMUND F. FUNAI1, VINEET BHANDARI2, IRINA A. BUHIMSCHI1, 1Yale University, Ob./Gyn.&Reprod.Sci, New Haven, Connecticut, 2Yale University, Pediatrics, New Haven, Connecticut OBJECTIVE: In an era of widespread intrapartum chemoprophylaxis, neonatal sepsis is rarely confirmed by culture. To prevent neonatal death and poor neurodevelopmental outcome which accompanies EONS, we propose that attention should be drawn to the assessment of the inflammatory condition prior to and at birth. This study was conducted to determine the inflammatory status associated with EONS in pregnancies complicated by preterm birth. STUDY DESIGN: The relationship between amniotic fluid (AF), umbilical cord IL-6, histological chorioamnionitis (HCA) and EONS was studied prospectively in 117 consecutive preterm singleton neonates born to mothers (GA: 28.5⫾3.5 wks) who had an amniocentesis to rule out infection. Cord blood was obtained at delivery. Intra-amniotic inflammation (IAI) was diagnosed by mass spectrometry SELDI. The cord blood/AF IL-6 ratio defined the IL-6 cytokine index. Severity of HCA and EONS was based on established histological and hematological criteria. IL-6 levels were measured by sensitive immunoassays. RESULTS: 1) Women with IAI delivered at an earlier GA (p⬍0.001) and had higher AF IL-6 levels (p⬍0.001); 2) Neonates of women with IAI had higher cord blood IL-6 levels (p⬍0.001) and a higher frequency of EONS (p⫽0.001); 3) EONS was characterized by a higher IL-6 cytokine index (p⬍0.001) (Fig. A); 4) The severity of HCA (neutrophilic infiltrate in the chorionic plate) was an independent predictor of the cytokine index (Fig. B) and EONS (p⬍0.001). Relationships were maintained following correction for GA, race, PPROM, amniocentesis to delivery interval, antibiotics and steroid exposure. CONCLUSION: We provide evidence that the intra-amniotic process responsible for HCA impacts the inflammatory status of neonates with EONS.
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.212
200
INTRA-AMNIOTIC INFLAMMATION (IAI) IS ASSOCIATED WITH A LOW FETAL PLASMA CORTISOL / DEHYDROEPI- ANDROSTERONE SULFATE RATIO (FETAL STRESS INDEX) CATALIN S. BUHIMSCHI1, OZHAN M. TURAN2, EDMUND F. FUNAI1, HUMBERTO AZPURUA1, MERT O. BAHTIYAR1, SIFA TURAN2, GUOMAO ZHAO1, ANTONETTE T. DULAY1, JOSHUA A. COPEL1, IRINA A. BUHIMSCHI1, 1Yale University, Ob./Gyn.&Reprod.Sci, New Haven, Connecticut, 2University of Maryland at Baltimore, Ob./ Gyn.&Reprod.Sci, Baltimore, Maryland OBJECTIVE: The fetal adaptive response to stress is regulated in part by the adrenocortical system. Dehydroepinadrosterone sulfate (DHEAS) and cortisol have opposing effects: cortisol suppresses while DHEAS enhances the innate immune system. We sought to determine the impact of IAI on the fetal molar ratio of cortisol/DHEAS in inflammation-associated preterm birth. STUDY DESIGN: The relationship between IAI, fetal adrenal gland volume (AGV), umbilical cord interleukin-6 (IL-6), cortisol and DHEAS was analyzed in 51 consecutive singleton fetuses of mothers who had an indicated amniocentesis to rule out infection. Proteomic profiling of the amniotic fluid [Mass restricted (MR) score] identified presence or absence of IAI. The MR score ranged from 0 (biomarkers absent) to 4 (all biomarkers present). An MR 3 or 4 confirmed severe IAI. Fetal AGV was assessed by ultrasonographic multiplanar technique (VOCAL). IL-6, cortisol and DHEAS were measured by sensitive immunoassays. Parametric and nonparametric analysis was employed. RESULTS: 1) Women with IAI (n⫽16) delivered at earlier GA (27⫾0.8 wks) compared to those without IAI (32⫾0.5 wks, p⫽⬍0.001, n⫽35); 2) Fetuses exposed to IAI had higher AGVs (p⫽0.02) and cord blood IL-6 (p⫽0.008) compared to those of women with normal MR scores (p⫽0.007); 3) There was a direct relationship between cord blood IL-6 and AGVs (r⫽0.37, p⫽0.025 Fig A), fetal cortisol (r⫽0.37, p⫽0.026) and DHEAS (r⫽0.50, p⫽0.002); 4) Fetuses exposed to IAI had lower cortisol/DHEAS ratios (p⫽0.034 Fig B). These results were maintained after adjusting for GA, contractions, and steroid exposure. CONCLUSION: This study provides evidence for the involvement of stress hormones in the fetal adaptive response to inflammation in utero.
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.213
201
EVIDENCE FOR A ROLE OF INFLAMMATION IN CONTROL OF ANGIOPOIETIN-1, ANGIOPOIETIN-2 AND OF THEIR NOVEL ANTAGONIST SOLUBLE TIE-2 IN PREGNANCIES COMPLICATED BY INTRA-AMNIOTIC INFLAMMATION CATALIN S. BUHIMSCHI1, VINEET BHANDARI2, GUOMAO ZHAO1, VICTOR A. ROSENBERG1, EDUARDO ZAMBRANO3, MICHAEL CACKOVIC1, EDMUND FUNAI1, IRINA A. BUHIMSCHI1, 1Yale University, Ob./Gyn.&Reprod.Sci, New Haven, Connecticut, 2Yale University, Pediatrics, New Haven, Connecticut, 3Yale University, Pathology, New Haven, Connecticut OBJECTIVE: Angiopoietins (Ang-1, Ang-2) are a novel class of angiogenic growth factors that act selectively on endothelial cells and are ligand proteins for the Tie2 receptor. A soluble Tie2 (sTie2) extracellular domain protein blocks activation of the Tie2 receptor and hence the activity of both Ang-1 and Ang-2. We sought to investigate the relationships among Ang-1, Ang-2 and sTie2 proteins in amniotic fluid (AF) and fetal tissues to understand the endothelial signaling pathways and cellular responses to inflammation. STUDY DESIGN: AF was retrieved by amniocentesis in 176 women stratified as follows: 1) 2nd trim control (for karyotype), GA:19⫾1 wk n⫽40; 2) (⫹)IAI: GA⫽27⫾1 wk, n⫽50; 3) (⫺)IAI: GA⫽27⫾1 wks, n⫽49; 4) 3rd trim control (for L/S ratio), GA⫽36⫾1 wk, n⫽37. Proteomic profiling of AF (SELDI) established presence or absence of IAI. Levels of Ang-1, Ang-2 and sTie2 were measured by ELISA. mRNA expression of Ang-1, Ang-2 and sTie2 in amniochorion and placental villous tissue was investigated using quantitative real-time PCR. Fetal tissues (membranes, placenta) were stained for Ang-1 and Ang-2 proteins. RESULTS: 1) There was a significant GA-dependent increase in Ang-1 accompanied by a decrease in sTie2 AF levels while Ang-2 was not GA-regulated; 2) IAI was associated with elevation of Ang2 and sTie2 (p⬍0.001) but not of Ang-1 (Figure); 3) Ang-2 mRNA (p⫽0.03) expression was increased in amniochorion of women with IAI. CONCLUSION: This is the first demonstration of the existence of a soluble Tie2 receptor in human AF that is GA and IAI regulated. The probable source of the increased Ang-2 in IAI is the amniochorion.
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.214
Supplement to DECEMBER 2007 American Journal of Obstetrics & Gynecology
S67
www.AJOG.org 199
EARLY ONSET NEONATAL SEPSIS (EONS): ACCOMPANIED BY AN INCREASED INTERLEUKIN-6 (IL-6) CYTOKINE INDEX, LINKED TO HISTOLOGICAL CHORIOAMNIONITIS CATALIN S. BUHIMSCHI1, STEPHEN F. THUNG1, MERT O. BAHTIYAR1, VICTOR A. ROSENBERG1, ANTONETTE T. DULAY1, SONYA S. ABDEL-RAZEQ1, CHRISTIAN M. PETTKER1, GUOYANG LUO1, GUOMAO ZHAO1, ANNA SFAKIANAKI1, HEATHER S. LIPKIND1, EDMUND F. FUNAI1, VINEET BHANDARI2, IRINA A. BUHIMSCHI1, 1Yale University, Ob./Gyn.&Reprod.Sci, New Haven, Connecticut, 2Yale University, Pediatrics, New Haven, Connecticut OBJECTIVE: In an era of widespread intrapartum chemoprophylaxis, neonatal sepsis is rarely confirmed by culture. To prevent neonatal death and poor neurodevelopmental outcome which accompanies EONS, we propose that attention should be drawn to the assessment of the inflammatory condition prior to and at birth. This study was conducted to determine the inflammatory status associated with EONS in pregnancies complicated by preterm birth. STUDY DESIGN: The relationship between amniotic fluid (AF), umbilical cord IL-6, histological chorioamnionitis (HCA) and EONS was studied prospectively in 117 consecutive preterm singleton neonates born to mothers (GA: 28.5⫾3.5 wks) who had an amniocentesis to rule out infection. Cord blood was obtained at delivery. Intra-amniotic inflammation (IAI) was diagnosed by mass spectrometry SELDI. The cord blood/AF IL-6 ratio defined the IL-6 cytokine index. Severity of HCA and EONS was based on established histological and hematological criteria. IL-6 levels were measured by sensitive immunoassays. RESULTS: 1) Women with IAI delivered at an earlier GA (p⬍0.001) and had higher AF IL-6 levels (p⬍0.001); 2) Neonates of women with IAI had higher cord blood IL-6 levels (p⬍0.001) and a higher frequency of EONS (p⫽0.001); 3) EONS was characterized by a higher IL-6 cytokine index (p⬍0.001) (Fig. A); 4) The severity of HCA (neutrophilic infiltrate in the chorionic plate) was an independent predictor of the cytokine index (Fig. B) and EONS (p⬍0.001). Relationships were maintained following correction for GA, race, PPROM, amniocentesis to delivery interval, antibiotics and steroid exposure. CONCLUSION: We provide evidence that the intra-amniotic process responsible for HCA impacts the inflammatory status of neonates with EONS.
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.212
200
INTRA-AMNIOTIC INFLAMMATION (IAI) IS ASSOCIATED WITH A LOW FETAL PLASMA CORTISOL / DEHYDROEPI- ANDROSTERONE SULFATE RATIO (FETAL STRESS INDEX) CATALIN S. BUHIMSCHI1, OZHAN M. TURAN2, EDMUND F. FUNAI1, HUMBERTO AZPURUA1, MERT O. BAHTIYAR1, SIFA TURAN2, GUOMAO ZHAO1, ANTONETTE T. DULAY1, JOSHUA A. COPEL1, IRINA A. BUHIMSCHI1, 1Yale University, Ob./Gyn.&Reprod.Sci, New Haven, Connecticut, 2University of Maryland at Baltimore, Ob./ Gyn.&Reprod.Sci, Baltimore, Maryland OBJECTIVE: The fetal adaptive response to stress is regulated in part by the adrenocortical system. Dehydroepinadrosterone sulfate (DHEAS) and cortisol have opposing effects: cortisol suppresses while DHEAS enhances the innate immune system. We sought to determine the impact of IAI on the fetal molar ratio of cortisol/DHEAS in inflammation-associated preterm birth. STUDY DESIGN: The relationship between IAI, fetal adrenal gland volume (AGV), umbilical cord interleukin-6 (IL-6), cortisol and DHEAS was analyzed in 51 consecutive singleton fetuses of mothers who had an indicated amniocentesis to rule out infection. Proteomic profiling of the amniotic fluid [Mass restricted (MR) score] identified presence or absence of IAI. The MR score ranged from 0 (biomarkers absent) to 4 (all biomarkers present). An MR 3 or 4 confirmed severe IAI. Fetal AGV was assessed by ultrasonographic multiplanar technique (VOCAL). IL-6, cortisol and DHEAS were measured by sensitive immunoassays. Parametric and nonparametric analysis was employed. RESULTS: 1) Women with IAI (n⫽16) delivered at earlier GA (27⫾0.8 wks) compared to those without IAI (32⫾0.5 wks, p⫽⬍0.001, n⫽35); 2) Fetuses exposed to IAI had higher AGVs (p⫽0.02) and cord blood IL-6 (p⫽0.008) compared to those of women with normal MR scores (p⫽0.007); 3) There was a direct relationship between cord blood IL-6 and AGVs (r⫽0.37, p⫽0.025 Fig A), fetal cortisol (r⫽0.37, p⫽0.026) and DHEAS (r⫽0.50, p⫽0.002); 4) Fetuses exposed to IAI had lower cortisol/DHEAS ratios (p⫽0.034 Fig B). These results were maintained after adjusting for GA, contractions, and steroid exposure. CONCLUSION: This study provides evidence for the involvement of stress hormones in the fetal adaptive response to inflammation in utero.
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.213
201
EVIDENCE FOR A ROLE OF INFLAMMATION IN CONTROL OF ANGIOPOIETIN-1, ANGIOPOIETIN-2 AND OF THEIR NOVEL ANTAGONIST SOLUBLE TIE-2 IN PREGNANCIES COMPLICATED BY INTRA-AMNIOTIC INFLAMMATION CATALIN S. BUHIMSCHI1, VINEET BHANDARI2, GUOMAO ZHAO1, VICTOR A. ROSENBERG1, EDUARDO ZAMBRANO3, MICHAEL CACKOVIC1, EDMUND FUNAI1, IRINA A. BUHIMSCHI1, 1Yale University, Ob./Gyn.&Reprod.Sci, New Haven, Connecticut, 2Yale University, Pediatrics, New Haven, Connecticut, 3Yale University, Pathology, New Haven, Connecticut OBJECTIVE: Angiopoietins (Ang-1, Ang-2) are a novel class of angiogenic growth factors that act selectively on endothelial cells and are ligand proteins for the Tie2 receptor. A soluble Tie2 (sTie2) extracellular domain protein blocks activation of the Tie2 receptor and hence the activity of both Ang-1 and Ang-2. We sought to investigate the relationships among Ang-1, Ang-2 and sTie2 proteins in amniotic fluid (AF) and fetal tissues to understand the endothelial signaling pathways and cellular responses to inflammation. STUDY DESIGN: AF was retrieved by amniocentesis in 176 women stratified as follows: 1) 2nd trim control (for karyotype), GA:19⫾1 wk n⫽40; 2) (⫹)IAI: GA⫽27⫾1 wk, n⫽50; 3) (⫺)IAI: GA⫽27⫾1 wks, n⫽49; 4) 3rd trim control (for L/S ratio), GA⫽36⫾1 wk, n⫽37. Proteomic profiling of AF (SELDI) established presence or absence of IAI. Levels of Ang-1, Ang-2 and sTie2 were measured by ELISA. mRNA expression of Ang-1, Ang-2 and sTie2 in amniochorion and placental villous tissue was investigated using quantitative real-time PCR. Fetal tissues (membranes, placenta) were stained for Ang-1 and Ang-2 proteins. RESULTS: 1) There was a significant GA-dependent increase in Ang-1 accompanied by a decrease in sTie2 AF levels while Ang-2 was not GA-regulated; 2) IAI was associated with elevation of Ang2 and sTie2 (p⬍0.001) but not of Ang-1 (Figure); 3) Ang-2 mRNA (p⫽0.03) expression was increased in amniochorion of women with IAI. CONCLUSION: This is the first demonstration of the existence of a soluble Tie2 receptor in human AF that is GA and IAI regulated. The probable source of the increased Ang-2 in IAI is the amniochorion.
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.214
Supplement to DECEMBER 2007 American Journal of Obstetrics & Gynecology
S67