Cytomegalovirus antibody status at 17-18 weeks of gestation and pre-eclampsia: a case-control study of pregnant women in Norway.

OBJECTIVE: To assess the association between maternal cytomegalovirus (CMV) antibodies in mid-pregnancy and pre-eclampsia. DESIGN: Nested case-control study. SETTING: Pregnancies registered in the Norwegian Mother and Child Cohort Study (MoBa): a large population-based pregnancy cohort (1999-2006). SAMPLE: A cohort of 1500 women with pre-eclampsia and 1000 healthy pregnant women. METHODS: Plasma samples and pregnancy-related information were provided by the MoBa. Antibody status (CMV IgG and CMV IgM) and levels (CMV IgG) at 17-18 weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). MAIN OUTCOME MEASURE: A diagnosis of pre-eclampsia, as defined in the Medical Birth Registry of Norway. RESULTS: There was no evidence of an effect of CMV IgG seropositivity on the likelihood of developing pre-eclampsia, and CMV IgG antibody levels among women who were seropositive did not differ between groups. Adjusted for maternal age, parity and smoking, the odds ratio for pre-eclampsia in women seropositive for CMV IgG was 0.89 (95% CI 0.74-1.05; P = 0.17). The proportions of women who were seropositive for IgM did not differ between women with pre-eclampsia and women who were healthy (P = 0.98). Among nulliparous women, the proportion of women who were seropositive for CMV IgG was slightly lower among women with pre-eclampsia (53.5%) than among healthy women (59.8%) (P = 0.03). Subgroup analyses were performed for women with early or late onset pre-eclampsia, with preterm delivery and/or with neonates that were small for gestational age, but antibody status did not differ between pre-eclampsia subtypes and controls. CONCLUSIONS: The presence of maternal antibodies to CMV was not associated with pre-eclampsia in our study. The results suggest that CMV infection is unlikely to be a major cause of pre-eclampsia.

A low COMT activity haplotype is associated with recurrent preeclampsia in a Norwegian population cohort (HUNT2).

The etiology of preeclampsia is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. Although many candidate genes for preeclampsia have been suggested and studied, the specific causative genes still remain to be identified. Catechol-O-methyltransferase (COMT) is an enzyme involved in catecholamine and estrogen degradation and has recently been ascribed a role in development of preeclampsia. In the present study, we have examined the COMT gene by genotyping the functional Val108/158Met polymorphism (rs4680) and an additional single-nucleotide polymorphism, rs6269, predicting COMT activity haplotypes in a large Norwegian case/control cohort (n(cases)= 1135, n(controls)= 2262). A low COMT activity haplotype is associated with recurrent preeclampsia in our cohort. This may support the role of redox-regulated signaling and oxidative stress in preeclampsia pathogenesis as suggested by recent studies in a genetic mouse model. The COMT gene might be a genetic risk factor shared between preeclampsia and cardiovascular diseases.

STOX2 but not STOX1 is differentially expressed in decidua from pre-eclamptic women: data from the Second Nord-Trondelag Health Study.

Variation in the Storkhead box-1 (STOX1) gene has previously been associated with pre-eclampsia. In this study, we assess candidate single nucleotide polymorphisms (SNPs) in STOX1 in an independent population cohort of pre-eclamptic (n = 1.139) and non-pre-eclamptic (n = 2.269) women (the HUNT2 study). We also compare gene expression levels of STOX1 and its paralogue, Storkhead box-2 (STOX2) in decidual tissue from pregnancies complicated by pre-eclampsia and/or fetal growth restriction (FGR) (n = 40) to expression levels in decidual tissue from uncomplicated pregnancies (n = 59). We cannot confirm association of the candidate SNPs to pre-eclampsia (P > 0.05). For STOX1, no differential gene expression was observed in any of the case groups, whereas STOX2 showed significantly lower expression in deciduas from pregnancies complicated by both pre-eclampsia and FGR as compared with controls (P = 0.01). We further report a strong correlation between transcriptional alterations reported previously in choriocarcinoma cells over expressing STOX1A and alterations observed in decidual tissue of pre-eclamptic women with FGR.

Comparison of recombinant tumor necrosis factor and the monocyte-derived cytotoxic factor involved in monocyte-mediated cytotoxicity.

A direct comparison of recombinant tumor necrosis factor (rTNF) and the monocyte-derived cytotoxic factor (CF) which is involved in monocyte-mediated cytotoxicity revealed immunological, physiochemical, and biological similarities, indicating that TNF is an effector molecule in monocyte-mediated cytotoxicity. Neutralizing antiserum raised against rTNF completely inhibited the ability of CF-containing monocyte supernatants to induce cytolysis and cell death of sensitive target cells and, conversely, antiserum raised against purified CF completely inhibited the cytotoxic activity of rTNF. Both CF and rTNF have an apparent isoelectric point of 5.8-5.9 as determined by chromatofocusing, and a molecular weight of about 40,000 as determined by gel filtration. Moreover, when present in monocyte supernatants with a total protein concentration of about 1 mg/ml and 0.1% sodium dodecyl sulfate, both CF and rTNF migrated with a molecular weight of about 35,000 upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Pure rTNF, however, migrated with a molecular weight of 17,000, suggesting that the relative amount of sodium dodecyl sulfate to protein is critical for dissociating the apparent dimeric structure of TNF. CF and rTNF were also similar with respect to their ability to kill various types of target cells the sensitivity of which to TNF differ, and the dose-response curves of cytotoxicity obtained with CF-containing monocyte supernatants and rTNF were similar. As is the case with anti-CF serum, anti-rTNF serum inhibited drug-dependent cellular cytotoxicity and cytolysis mediated by both freshly isolated monocytes and in vitro cultured unactivated and lymphokine-lipopolysaccharide activated monocytes, indicating that TNF is an effector molecule in both drug-dependent cellular cytotoxicity and "classical" monocyte-mediated cytotoxicity.

Role of monocyte cytotoxic factor in cytolysis of actinomycin D-treated WEHI 164 cells mediated by freshly isolated human adherent mononuclear blood cells.

The role of the monocyte cytotoxic factor (CF) in cytolysis of untreated and actinomycin D (Act D)-treated WEHI 164 cells by freshly isolated human adherent mononuclear cells has been investigated in this study. Murine WEHI 164 cells were used as target cells because of their sensitivity to lysis mediated by monocytes and their resistance to natural killer cells. Monocytes as well as monocyte supernatants mediated cytolysis of WEHI 164 cells. Cytolysis was enhanced by Act D treatment of target cells. The addition of lipopolysaccharide to monocytes accelerated the progression of cytolysis of Act D-treated WEHI 164 cells mediated by monocytes. A polyclonal rabbit antiserum against CF inhibited the cytolytic activity of monocytes and monocyte supernatants against untreated as well as Act D-treated WEHI 164 cells. At low effector:target ratios, the cytolysis was totally abrogated by CF antiserum. Depletion of natural killer cells from adherent cells by the monoclonal antibody Leu 11b and rabbit complement did not reduce cytolysis of Act D-treated WEHI 164 cells. Immunofluorescence microscopy revealed that CF antiserum stained the plasma membrane of freshly isolated monocytes, suggesting that CF is a membrane-associated molecule. Our data indicate that CF is an important effector molecule in cytolysis mediated by freshly isolated monocytes against untreated and Act D-treated WEHI 164 cells.

Human monocyte-released cytotoxic factor: effect on various cellular functions, and dependency of cytolysis on various metabolic processes.

The ability of the human monocyte-released cytotoxic protein factor(s) (CF) to mediate cytolysis when various metabolic processes in target cells were inhibited, and its effect on various cell functions have been studied. Cytolysis was reduced when target cells were exposed to either chloroquine or colchicine, indicating that lysosome function and the formation of microtubule are of importance with respect to the interaction between CF and target cells, possibly by effecting internalization and processing CF and its receptor. A decrease in the energy charge of the target cells did not affect the ability of CF to mediate cytolysis, since the 60-70% reduction of the cellular ATP content by uncoupling oxidative phosphorylation had little effect on CF-induced lysis. It was unnecessary for target cells to be actively growing and dividing for CF to induce lysis because inhibition of cellular protein, RNA, and DNA synthesis potentiated the cytolytic effect of CF. CF-induced cell lysis of Walter and Eliza Hall Institute (WEHI) 164 target cells was first detected between 3.0 and 4.5 hr after addition of CF. Target cell DNA synthesis nearly terminated within 3-4 hr, about the time of first cell lysis detection. Compared to the effect on DNA synthesis, the CF effect on protein synthesis was negligible and only a slight reduction was detected in the RNA synthesis and in the cellular ATP content. The results indicated that the DNA-synthesizing machinery may either be a primary target site of CF or a rapid influence of CF action on its primary target site; however, neither the protein- or RNA-synthesizing machinery nor the cellular ATP generating systems are likely to be primary target sites.

In vitro cultured human monocytes release fibroblast proliferation factor(s) different from interleukin 1.

Human monocytes cultured in vitro released factors with growth stimulatory effect upon human dermal fibroblasts. Monocytes in RPMI 1640 released a growth enhancing activity in nearly constant amounts during in vitro differentiation to macrophage-like cells. The growth stimulatory effect mediated by supernatants was reduced when lipopolysaccharide (LPS) or opsonized zymosan particles (OpZ) were added to monocytes during the first 5 days of in vitro culture, thereafter reaching similar levels. The release of interleukin 1 (IL-1) from monocytes was restricted to the first 2 days of culture. IL-1 production by unstimulated monocytes was negligible, while LPS induced a high release of IL-1 from monocytes. A rabbit antibody against human IL-1 abolished the IL-1 activity of the monocyte supernatants as assessed in a mouse thymocyte proliferation assay, but caused only a small reduction of the fibroblast proliferation activity. Thus, the fibroblast growth stimulatory activity mediated by monocytes was caused by factor(s) in addition to IL-1.

Toll-like receptor profiling of seven trophoblast cell lines warrants caution for translation to primary trophoblasts.

INTRODUCTION: Excessive placental inflammation is associated with pregnancy complications. Toll-like receptors (TLRs) are sensors for danger signals from infections and damaged tissue and initiate inflammation. Trophoblasts in the placenta broadly express TLRs. Trophoblast cell lines are used as surrogates for primary trophoblasts for in vitro studies, but the inflammatory translatability of trophoblast cell lines warrants examination. We aimed to assess TLR1-10 gene expression and activation in seven trophoblast cell lines and compare this to primary trophoblasts. METHODS: The five choriocarcinoma trophoblast cell lines BeWo, JAR, JEG-3, AC1M-32 and ACH-3P, and the two SV40 transfected trophoblast cell lines HTR-8/SVneo and SGHPL-5 were included and compared to primary first trimester trophoblasts (n = 6). TLR1-10 gene expression was analyzed by RT-qPCR. Cells were stimulated by specific TLR1-9 ligands for 24 h and cytokine release was measured by a 10-plex immunoassay. RESULTS: All choriocarcinoma cell lines demonstrated broad TLR gene expression, but lacked functional cytokine response to TLR ligand activation. In contrast, SV40 transfected cell lines showed restricted TLR gene expression, but SGHPL-5 cells displayed significantly increased levels of interleukin (IL)-6, IL-8, IL-12 and vascular endothelial growth factor A after TLR3 and/or TLR4 activation (P < 0.01), while TLR2 activation increased IL-6 and IL-8 levels (P < 0.05). HTR8/SVneo cells responded to TLR3 activation by increased IL-6 and interferon (IFN)-γ (P < 0.05). The SGHPL-5 TLR profile most closely resembled primary trophoblast. DISCUSSION: The characterized trophoblast cell line TLR profiles serve as a reference and warrant caution when selecting trophoblast cell lines as in vitro models for immune responses in primary trophoblasts.

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.

A physico-chemical comparison of the monocyte-derived fibroblast growth factor and the tumour necrosis factor.

The chromatographic characteristics of the human monocyte-derived growth stimulatory activity towards diploid FS-4 human fibroblasts has been studied. The fibroblast growth stimulatory factor had an apparent isoelectric point of 5.8 as determined by chromatofocusing, and a molecular weight in the range 70,000-30,000 as determined by gel filtration. The growth stimulatory factor eluted together with the tumour necrosis factor (TNF) upon cation exchange chromatography, chromatofocusing and gel filtration. Moreover, the fibroblast growth stimulatory activity in crude monocyte supernatants as well as the activity in the gel filtration column fractions was neutralized by antiserum raised against recombinant TNF (rTNF). The results indicate that the monocyte-derived fibroblast growth stimulatory activity is largely due to TNF.

Soluble TNF receptors in amniotic fluid and in urine from pregnant women.

Secretion of soluble cytokine receptors has been suggested as a mechanism for regulation of cytokine activity in vivo. The present investigation was performed to study whether secretion of soluble TNF (tumor necrosis factor) receptors (TNFRs) might be associated with pregnancy. There are two known molecular species of the TNFR, the 55-kDa TNFR and the 75-kDa TNFR. The 75-kDa, as well as the 55-kDa TNFR, was detected in urine from pregnant women, whereas only the 75-kDa TNFR was detected in urine from the non-pregnant group. The concentration of TNFRs in urine increased towards term and was reduced in association with spontaneous delivery. The soluble forms of both TNFRs were also detected in amniotic fluid. Collectively, the data suggest that secretion of soluble TNFRs during pregnancy might be a defence mechanism for the protection of the fetus against TNF action.

LPS mediated production of IL-1, PGE2 and PGF2alpha from term decidua involves tumour necrosis factor and tumour necrosis factor receptor p55.

Prostaglandins, with cytokines involved as intermediate factors, may have an essential role in premature labour when infection is present. We therefore wanted to study tumour necrosis factor (TNF), in cytokine and prostaglandin production in reproductive tissue. Decidual cell cultures were established and cells were stimulated with lipopolysaccharides (LPS). Media concentrations of TNF, interleukin-1 (IL-1), IL-6 and prostaglandin E2 and F2alpha were analysed, and involvement of LPS receptor CD14, TNF and TNF receptors (p55 and p75) were analysed, by studying effects after administration of specific antibodies. LPS induced an early peak elevation of TNF, with a subsequent release of IL-1, IL-6 and prostaglandins. Antibodies against CD14 inhibited these LPS effects. TNF antibodies reduced production of IL-1 and prostaglandins, whereas no significant influence on IL-6 production was observed. Antibodies against the TNF receptor p55 reduced all observed TNF effects. In contrast, p75 antibodies did not influence cytokine or prostaglandin production in this system. Our results suggest that increased TNF production is a prerequisite for LPS stimulated production of IL-1 and prostaglandins from decidual cells. LPS may directly stimulate IL-6 production. Of the two TNF receptors studied, only p55 seemed to be involved in the TNF signal transduction.

Soluble receptors for tumor necrosis factor: occurrence in association with normal delivery at term.

OBJECTIVE: To compare levels of tumor necrosis factor (TNF) and interleukin 1 (IL-1) and 6 (IL-6) with levels of the soluble receptors for TNF in maternal and neonatal urine and amniotic fluid (AF). METHODS: Levels of soluble TNF receptors (p55, p75) in AF and urine from 21 women and their newborns were measured by immunoassay. The amniotic concentrations of IL-1 and IL-6 were assessed by biologic assays, whereas an immunoassay was used to measure TNF levels. The comparison between receptor concentrations in different compartments was performed by one-way analysis of variance, and Student t test was used to compare pairs of groups. Correlation studies were performed when indicated. RESULTS: A high correlation was observed between the concentrations of p55 and p75 in all compartments. The concentration of p55 in AF was significantly higher than that in both maternal and neonatal urine, but the correlation between TNF receptor concentrations in the AF samples and the concomitant levels of cytokines was not statistically significant. CONCLUSION: The high concentration of receptors in the AF compared to those of other biologic compartments suggests that the pregnancy-associated increased receptor shedding takes place in intrauterine tissues. Physiologic levels of cytokines, such as those accompanying normal delivery at term, did not seem to influence the soluble TNF receptor release.

Umbilical cord plasma interleukin-6 and fetal growth restriction in preeclampsia: a prospective study in Norway.

OBJECTIVE: To study the association between umbilical plasma levels of interleukin-6 (IL-6) in relation to fetal growth in subgroups of preeclampsia, and in control pregnancies. METHODS: Umbilical cord plasma was collected from 12,804 consecutive births. A total of 271 singleton cases of preeclampsia were identified, and classified as mild or severe, and as disease with early or late onset. As controls, 611 singleton pregnancies without preeclampsia were selected, and the ratio between observed and expected birth weight was used as a measure of fetal growth. In the analysis, we also included maternal smoking during pregnancy. Umbilical cord plasma IL-6 concentration was measured with an IL-6 bioassay. Comparing controls with subgroups of preeclampsia (severe and early onset), this study had a statistical power of 90% to detect a difference in cord IL-6 of 10 pg/mL. RESULTS: In severe preeclampsia, cord plasma IL-6 concentration was lower than among controls (P <.001), and there was a sharp decrease in cord plasma IL-6 with decreasing birth weight ratio (P trend <.001). By further dividing the preeclampsia group into early or late onset, the strong association between low IL-6 levels and low birth weight ratio appeared to be present mainly in early-onset disease. These results were not confounded by maternal smoking. CONCLUSION: Restricted fetal growth related to preeclampsia is associated with reduced umbilical cord plasma IL-6 concentration in cases with early-onset disease. In these cases, fetal growth restriction could be mediated by impaired trophoblast function.

Preeclampsia and fetal growth.

OBJECTIVE: To determine if the influence of preeclampsia on birth size varies with clinical manifestations of the disease, and to evaluate whether maternal factors, such as smoking, modify the effect of preeclampsia on fetal growth. METHODS: Among 12,804 deliveries in a population of approximately 239,000 over a 3-year period, 307 live singleton infants were born after preeclamptic pregnancies. We compared those with a sample of 619 control infants. Preeclampsia was defined as increased diastolic blood pressure (BP) (increase of at least 25 mmHg to at least 90 mmHg) and proteinuria after 20 weeks' gestation. Clinical manifestations were classified according to BP and proteinuria into subgroups of mild, moderate, or severe (including cases with eclampsia and hemolysis, elevated liver enzymes, low platelets [HELLP] syndrome) preeclampsia, and according to gestational age at onset, as early or late preeclampsia. Birth size was expressed as the ratio between observed and expected birth weights, and infants smaller than two standard deviations from expected birth weights were classified as small for gestational age (SGA). RESULTS: Preeclampsia was associated with a 5% (95% confidence interval [CI] 3%, 6%) reduction in birth weight. In severe preeclampsia, the reduction was 12% (9%, 15%), and in early-onset disease, birth weight was 23% (18%, 29%) lower than expected. The risk of SGA was four times higher (relative risk [RR] = 4.2; 95% CI 2.2, 8.0) in infants born after preeclampsia than in control pregnancies. Among nulliparas, preeclampsia was associated with a nearly threefold higher risk of SGA (RR = 2.8; 1.2, 5.9), and among paras, the risk of SGA was particularly high after recurrent preeclampsia (RR = 12.3; 3.9, 39.2). In relation to preeclampsia and maternal smoking, the results indicated that each factor might contribute to reduced growth in an additive manner. CONCLUSION: Severe and early-onset preeclampsia were associated with significant fetal growth restriction. The risk of having an SGA infant was dramatically higher in women with recurrent preeclampsia. Birth weight reduction related to maternal smoking appeared to be added to that caused by preeclampsia, suggesting that there is no synergy between smoking and preeclampsia on growth restriction.

Immunohistologic detection of non-pancreatic phospholipase A2 (type II) in human placenta and its possible involvement in normal parturition at term.

Placenta is one of the richest sources of non-pancreatic phospholipase A2 (npPLA2) (type II) in the human body, and the enzyme is the key enzyme releasing unsaturated fatty acids from membrane phospholipids. Prostaglandins (PGs) play a critical role in the initiation and progression of parturition. Cytokines are presumed to play a central role in the initiation of normal labor at term, and cytokines are also found to regulate both synthesis and secretion of npPLA2 enzyme. In an attempt to resolve the physiologic function of the npPLA2 enzyme in placental tissue, immunohistologic localization and enzymatic activity measurements of npPLA2 enzyme were performed. NpPLA2 protein was detected in vascular smooth muscle, endothelial cells and connective tissue cells in placenta and umbilical cord, and the protein was weakly stained in trophoblast cells in placenta. Enzymatic activity was not increased in sera from mother nor child compared to sera from healthy individuals, but the activity in amniotic fluid was considerably higher. Our findings support the candidacy for npPLA2 in enzymatic arachidonic acid release from foetal membranes.

Reduced production of PGE2 and PGF2 alpha from decidual cell cultures supplemented with N-3 polyunsaturated fatty acids.

A diet rich in n-3 polyunsaturated fatty acid (PUFA) may reduce the intrauterine production of prostaglandins and prolong pregnancy. We tested this hypothesis by assessing the influence of various PUFAs on the spontaneous production of PGE2 and PGF2 alpha from decidual cell cultures. In addition, we assessed prostaglandin and cytokine production stimulated by lipopolysaccharides (LPS) in order to mimic parturition where infection is involved. In both settings, we found that after supplementing with n-3 PUFA, PGE2 and PGF2 alpha were significantly reduced. After supplementing with n-6 PUFA, there was a significant increase in both prostaglandins. Both n-3 and n-6 PUFAs reduced the production of interleukin 1 (IL-1), while n-6 PUFAs reduced TNF production. PUFAs did not influence IL-6 production. Our findings support the hypothesis that dietary n-3 PUFA may prolong pregnancy by reducing intrauterine production of prostaglandins.

Increased serum concentrations of soluble tumor necrosis factor receptors p55 and p75 in early onset neonatal sepsis.

Sepsis and pneumonia are major causes of morbidity and mortality in the neonatal period. The symptoms are variable and unspecific. So far, no reliable diagnostic test for neonatal infection has been found. In this study we measured serum levels of soluble tumor necrosis factor receptors (sTNFR) p55 and p75 in non-infected and infected neonates, and evaluated the diagnostic value of these mediators as tests for early detection of neonates with sepsis or pneumonia. Blood was collected on admission and after 3-4 days from 161 neonates consecutively admitted to the Neonatal Intensive Care Unit (NICU) during the first week of life. Twenty two neonates suffered from infection and 127 were classified as non-infected (controls). Samples were analyzed for p55 and p75, C-reactive protein (CRP) and white blood cell count with differential. Both preterm and term infected neonates had initially higher concentrations of p55 (both p <0.01) and p75 (p = 0.01 and p = 0.05, respectively) than controls. In non-infected neonates p55 levels decreased in the perinatal period, whereas p75 levels remained stable. Levels of both p55 and p75 decreased in neonates with infection during the perinatal period. CRP was a more specific parameter than p55 and p75 (CRP: 97%, p55: 65% and p75: 75%) whereas the sensitivity of all three parameters was at similar levels (CRP: 59%, p55: 70% and p75: 67%). We conclude that assessment of sTNFR may not improve accuracy in the diagnosis of early onset neonatal sepsis compared to the use of CRP.

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.

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.