Rigmor Austgulen

Interleukin-6, turnour necrosis factor and soluble turnour necrosis factor receptors in women with pre-eclampsia

Objectives Generalised maternal endothelial cell dysfunction appears to be an underlying problem in pre‐eclampsia presumed to be caused, directly or indirectly, by one or more circulating factors derived from the placenta. Recently it has been suggested that tumour necrosis factor (TNF) may play an important role in pre‐eclampsia and contribute to endothelial activation. This study was designed to investigate this proposal.

Tumor necrosis factor, interleukin-1, and interleukin-6 in normal human pregnancy

OBJECTIVE Our purpose was to investigate the cytokines, tumor necrosis factor, interleukin-1, and interleukin-6 in normal human pregnancy and labor. STUDY DESIGN Bioassays were used to measure these factors in extraembryonic coelomic fluid, amniotic fluid, placenta, and maternal and cord serum. RESULTS Little or no tumor necrosis factor, interleukin-1, or interleukin-6 was found in coelomic fluid or amniotic fluid in the first trimester. Interleukin-6 appeared in second-trimester amniotic fluid. At term tumor necrosis factor was present (median 17 pg/ml) and increased with the onset of labor (median 58 pg/ml), as did interleukin-1 (median 188 to 680 pg/ml) and interleukin-6 (median 399 to 4800 pg/ml). Maternal serum interleukin-6 increased during pregnancy with a further increment with the onset of labor. Cord interleukin-6 also increased with labor but at a lower level. CONCLUSION The cytokines tumor necrosis factor, interleukin-1, and interleukin-6 may play a role in the onset of normal labor.

Risk factors and clinical manifestations of pre‐eclampsia

Objective To study associations between established risk factors for pre‐eclampsia and different clinical manifestations of the disease.

TNF, IL-1, IL-6, IL-8 and soluble TNF receptors in relation to chorioamnionitis and premature labor

Inflammatory cytokines seem to play a key role in mechanisms initiating labor. Since cytokine levels are higher in preterm than in term labor, it has been hypothesized that labor-inducing effects of cytokines are inhibited by an upregulated production of cytokine antagonists, such as soluble cytokine receptors, at early stages of gestation. In this study, TNF, IL-1, IL-6, IL-8 and soluble TNF receptors (sTNFRs) were measured in amniotic fluid samples from a) 39 women in premature labor, b) 25 women who where not in labor but delivered prematurely, and c) 33 women in term labor. Fifty-four of the placentas from premature deliveries were evaluated for presence of histological chorioamnionitis. Chorioamnionitis was associated with increased levels of TNF, IL-1 and IL-6, whereas elevated IL-1, IL-6 and IL-8 concentrations were found in premature parturition with no signs of infection. Concentrations of sTNFR were lower in preterm than in term deliveries. The present study confirms the participation of inflammatory cytokines in parturition. Multivariate analysis suggests a dominant, role of IL-1 in the presence of chorioamnionitis, whereas IL-6 seems to be more important during idiopathic premature labor. TNFR data do not support the hypothesis that production of cytokine antagonists is upregulated prematurely to prevent partirution.

Early diagnostic markers for neonatal sepsis: Comparing C-reactive protein, interleukin-6, soluble tumour necrosis factor receptors and soluble adhesion molecules

We compared six inflammatory mediators (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumour necrosis factor receptors (p55 and p75) and soluble adhesion molecules (ICAM-1, E-selectin)) as early diagnostic tests for neonatal sepsis, and studied the possible benefit of combining parameters. Blood samples were obtained from 166 consecutively admitted neonates, who were suspected to suffer from infection within the first week of life. Neonates were retrospectively classified as infected (sepsis, clinical sepsis or pneumonia), possibly infected, or non-infected. Twenty-four infected neonates had higher serum levels of all six mediators (all P < 0.05), and 18 possibly infected neonates had higher levels of CRP, IL-6, ICAM-1 and E-selectin (all P < 0.05), than neonates without infection (n = 124). Receiver operator characteristic plots showed that CRP was the single best diagnostic test. Multiple logistic regression modelling, including various combinations of two to six mediators, consistently showed that IL-6, in addition to CRP, predicted sepsis. With infected and possibly infected neonates as the reference standard, a combined test of CRP > or = 10 mg/l and/or IL-6 > or = 20 pg/ml had a sensitivity of 85%, specificity of 62%, and negative likelihood ratio of 0.24. Using infected neonates as reference standard alone, and including possibly infected as controls, sensitivity increased to 96%, whereas specificity decreased to 58%; a negative test result (CRP < 10 mg/l and IL-6 < 20 pg/ml) ruled out sepsis with high certainty (likelihood ratio = 0.07). CRP performed best as a diagnostic test for neonatal sepsis. Diagnostic accuracy was further improved by combining CRP and IL-6, whereas the other parameters (p55, p75, ICAM-1 and E-selectin) added no further diagnostic information.

Increased maternal plasma levels of soluble adhesion molecules (ICAM-1, VCAM-1, E-selectin) in preeclampsia

The physiological significance of soluble adhesion molecules has not been elucidated but it has been reported that a number of cytokines may increase the cleavage of soluble adhesion molecules. The fact that preeclampsia is associated with both increased cytokine concentrations and endothelial cell damage led us to analyse levels of soluble adhesion molecules in preeclamptic women and to compare these levels to the disease state. Since the cytokine network is altered by reproduction, the present study also raised the question as to whether levels of soluble adhesion molecules differ between pregnant and non-pregnant women, and whether variations occur with relation to gestational age or delivery. Levels of soluble adhesion molecules (intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin) in 25 preeclamptic women were compared to those in healthy pregnant women matched for age, parity and gestation, and the levels of soluble adhesion molecules of 40 healthy pregnant women at different gestational ages were determined and compared to those of 15 non-pregnant women. Concentrations were measured by ELISAs. Levels of ICAM-1, VCAM-1 and E-selectin concentrations were elevated in preeclamptic pregnancies, whereas serum levels in normal pregnancy did not differ from those of non-pregnant women. No changes were observed in relation to gestational age or delivery.

Interleukin-6 concentrations in neonates evaluated for sepsis

OBJECTIVES This study was performed to determine serum concentrations of interleukin-6 (IL-6) during bacterial infections in the first week of life and to evaluate the usefulness of IL-6 as a diagnostic test for perinatal bacterial infections, alone and in combination with C-reactive protein (CRP). STUDY DESIGN Blood was obtained from 241 newborn children on admission to the neonatal intensive care unit and at 3 to 4 days after admission. Both samples were analyzed for IL-6, CRP, and white blood cell count with differential. RESULTS Twenty-four newborns were classified as having an infection. Increased serum IL-6 levels were detected in infected compared with noninfected newborns on admission (p < 0.0001). Detection of IL-6 (> or = 20 pg/ml) alone yielded a sensitivity of 78%, a specificity of 71%, a positive predictive value of 40%, and a negative predictive value of 93%. A combined parameter of IL-6 (> or = 50 pg/ml) and CRP (> or = 10 mg/L) yielded a sensitivity of 96%, a specificity of 74%, a positive predictive value of 49%, and a negative predictive value of 99%. CONCLUSIONS Used in combination with CRP, IL-6 seems to be a valuable parameter in the early diagnosis of neonatal infections.

Histologic chorioamnionitis and umbilical serum levels of pro-inflammatory cytokines and cytokine inhibitors.

Objective To study 1. whether leucocyte infiltration in placenta tissues is associated with elevated umbilical serum levels of inflammatory mediators, and 2. whether leucocyte infiltration in the presence of neonatal disease is associated with additional increase in mediator levels.

Increased levels of cytokines and cytokine activity modifiers in normal pregnancy

Accumulating evidence suggests that cytokines are major participants in human reproduction. Cytokines may have beneficial or negative influence on pregnancy outcome, depending on the cytokine level present. Thus, successful reproduction appears to depend on a tight regulation of cytokine activities. The present study raised the question whether normal pregnancy is associated with an activation of native cytokine buffer mechanisms. Soluble interleukin 6 receptors (IL-6Rs) and soluble interleukin 1 receptor antagonists (IL-1RAs) may modify the activity of IL-6 and IL-1, respectively. The production of soluble IL-6R and IL-1RA in pregnancy was studied by assessing the IL-6R and IL-1RA concentrations in serum samples from healthy pregnant women at different gestational ages. At delivery, both maternal and umbilical blood was obtained. Concentrations of IL-6 and IL-1 in the samples were determined to study the influence of cytokines on the activity level of the corresponding buffer mechanism. Serum levels of both IL-6R and IL-1RA were increased in pregnant women, as were levels of IL-6 and IL-1. Cytokine levels did not demonstrate a significant correlation with the concentration of the corresponding activity modifier. IL-1RA and IL-6 increased with gestational age and with labor activity. A significant correlation was observed between the levels of IL-6 and IL-1RA.

Cytokine levels in amniotic fluid and inflammatory changes in the placenta from normal deliveries at term

Cytokine levels in amniotic fluid have been shown to increase towards term in normal pregnancies, and may play a regulatory role in parturition by stimulating the local production of prostaglandins. The work reported in the present paper was conducted in order to test the hypothesis that the increased cytokine levels may be induced by a subclinical inflammatory reaction in intrauterine tissues. The concentrations of tumor necrosis factor (TNF), interleukin 1 (IL-1), interleukin 2 (IL-2) and interleukin 6 (IL-6) were determined in samples of amniotic fluid from 38 women in delivery at term, after a clinically normal pregnancy. In 33 of the cases, tissue material was available for histological examination. In these, the extent of inflammatory cell infiltration was assessed in the fetal membranes, placenta and umbilical cord. A close interrelation was observed between the levels of the mediators typically released during inflammatory processes (TNF, IL-1, IL-6). Frank chorioamnionitis was not found in any of the histological specimens, although most placentae showed varying degrees of granulocyte infiltration in the fibrin layer under the chorion, sometimes also in the chorionic membrane. The degree of such leukocytic infiltration correlated positively with the levels of TNF, IL-1 and IL-6. These findings lend support to the hypothesis that a low-level inflammatory process may be a normal occurrence in the term placenta, and that this process may induce the production of cytokines, which, in turn, may play a role in the regulation of parturition. Such inflammation could be due to exposure of the fetal membranes to microbial material from the vagina, as the cervix dilates towards term.