Insulin-like growth factors and foetal programming--a workshop report.
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Animals↗
Biomedical subjects
R Austgulen
Publications and source records attributed to R Austgulen.
Alpha-foetoprotein in umbilical cord in relation to severe pre-eclampsia, birth weight and future breast cancer risk.
Women born after pre-eclamptic pregnancies have been reported to be at reduced risk of breast cancer as adults, because of reduced intrauterine oestrogen influence on breast tissue; high levels of alpha-foetoprotein (a glycoprotein with anti-oestrogenic properties), however, could also be important. In severe pre-eclampsia, placental function and foetal growth are reduced, and umbilical cord plasma levels of alpha-foetoprotein could reflect the underlying processes. Umbilical cord blood was collected in 12804 consecutive deliveries. Among 307 pregnancies with clinical pre-eclampsia, 66 singleton pregnancies were identified as clinically severe, and 610 singleton pregnancies were selected as controls. Oestradiol and alpha-foetoprotein were measured from umbilical plasma, and birth weight was standardized as the ratio between the observed and expected birth weight, adjusted for differences in gestation length and offspring sex. Cord plasma levels of alpha-foetoprotein were significantly higher in severe pre-eclampsia than controls (P<0.01) after adjustment for gestational age and birth weight. For oestradiol, there was no difference in cord plasma levels between the severe pre-eclampsia group and controls, after adjustment for length of gestation and birth weight. These results suggest that an anti-oestrogenic effect associated with pre-eclampsia may be mediated through high levels of alpha-foetoprotein rather than low levels of oestradiol.
Adult↗
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.
Adult↗
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.
Biomarkers↗
Inflammatory mediators in umbilical plasma from neonates who develop early-onset sepsis.
OBJECTIVES: To study whether early-onset neonatal sepsis is associated with a prenatal immune response with elevated umbilical plasma levels of inflammatory mediators, and to study whether mediator levels may be helpful in identifying infected neonates. SETTING: Nested case-control study. METHODS: Cord blood was sampled from 7,073 consecutively delivered neonates. After review of the medical records, neonates suspected to suffer from infection were classified as infected (n = 52) or noninfected but sick controls (n = 33). We also included a group of healthy controls (n = 99). Umbilical plasma levels of tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, IL-6, IL-8, soluble TNF receptors (p55 and p75), IL-1 receptor antagonist (IL-1RA) and C-reactive protein were measured by immunoassays. RESULTS: Infected neonates had higher levels of TNFalpha, IL-1beta, IL-6, IL-8, p55, p75 and IL-1RA than healthy controls (all p < 0.01). Among preterm infants (GA <37 weeks), those with infection (n = 11) had higher levels of IL-1beta, IL-6, IL-8, p55 and p75 than noninfected sick controls (n = 13) (all p < 0.05), but among term infants, the infected did not differ from the noninfected sick controls. Receiver operator characteristic plots showed that IL-1beta, IL-6 and IL-8 identified preterm infected neonates accurately. CONCLUSIONS: Early-onset neonatal sepsis is associated with a prenatal immune response with increased TNFalpha, IL-1beta, IL-6, IL-8, p55, p75 and IL-1RA levels in umbilical plasma. Among neonates who present symptoms suggestive of infection, cytokine levels may be helpful in identifying preterm, but not term infected individuals.
C-Reactive Protein↗
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. DESIGN: A population-based, nested case-control study. SETTING: Information from 12,804 consecutive deliveries that took place over three years at a birth clinic, which alone serves a population of nearly 240,000 in Rogaland county, Norway. SUBJECTS: Cases of pre-eclampsia (n = 323) and healthy controls (n = 650) were selected. Pre-eclampsia was defined as increase in diastolic blood pressure (> or = 25 mmHg to > or = 90 mmHg) and proteinuria (> or = 1+ by dipstick testing) after 20 weeks of pregnancy. MAIN STUDY MEASURES: Parity, previous pre-eclampsia, blood pressure, maternal weight, and maternal smoking were included as study variables. Women with pre-eclampsia were grouped according to clinical manifestations of the disease (i.e. severity [mild, moderate or severe]) and time of onset (early or late gestation). Associations with the study factors were estimated as relative risks (odds ratio, OR). RESULTS: Both nulliparity and hypertension increased pre-eclampsia risk, with no clear preference for any clinical subtype. High maternal weight was related to a higher risk of mild and moderate, but not severe, pre-eclampsia. Previous pre-eclampsia strongly increased the risk for pre-eclampsia in the current pregnancy, and the risk of early onset disease was especially high (OR 42.4; 95% CI 11.9-151.6). Overall, smoking was associated with a reduced risk for pre-eclampsia (OR 0.6; 95% CI 0.4-0.9). However, no effect of smoking was observed in the early onset disease group and among women with repeated pre-eclampsia. CONCLUSION: Nulliparity and hypertension increased the risk for each subgroup of pre-eclampsia, but high maternal weight, previous pre-eclampsia and smoking were not consistently associated with each clinical subtype. This observation may suggest that heterogeneous clinical manifestations of pre-eclampsia may be preceded by different pathological mechanisms.
Body Weight↗
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.
Adult↗
[Two individuals under the same skin--immune mechanisms in pregnancy].
The fetus may be regarded as an allograft in the maternal organism. This paper gives an overview of pregnancy-associated immune mechanisms, based on the literature and studies performed by the authors. During implantation, maternal tissues are invaded by fetal trophoblasts expressing HLA-G, a trophoblast-specific variant of HLA Class I antigens. Recognition of HLA-G stimulates uterine natural killer cells to cytokine production, by which an intrauterine immunosuppression is established. Development, growth and differentiation of placenta is regulated by the cytokines produced. Uterine leukocyte population and expression of cytokine receptors in placental tissues varies throughout gestation, and the complex interplay between trophoblasts and uterine cells, involving a number of cytokines, cytokine receptors, adhesion molecules, enzymes and hormones, changes with gestation. Some cytokines, such as tumour necrosis factor and interleukin-1, may threathen the reproductive process and fetal well-being in high doses. A tight regulation of cytokine activities is probably obtained by the observed upregulation of endogenous cytokine buffer mechanisms in pregnancy. The reproductive success and phenomenons like implantation, placental growth and development, maintenance of pregnancy and delivery, appear to rely on complex, gestational age related interplay between cells of fetal origin and the maternal immune system.
Cytokines↗
[Medical technology--a special course in medical undergraduate education].
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Diagnosis, Computer-Assisted↗
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.
Antigens, CD↗
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.
Biological Assay↗
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.
Cells, Cultured↗
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.
Antigens, CD↗
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.
Amniotic Fluid↗
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.
Adult↗
Infections in neonates delivered at term are associated with increased serum levels of ICAM-1 and E-selectin.
All newborn infants consecutively admitted to the Neonatal Intensive Care Unit (NICU) at the University Hospital of Trondheim during 1993 were eligible to participate in the study. In total, 241 neonates were included, for whom anamnestic, clinical and laboratory characteristics were recorded. Peripheral blood was retrieved at admittance, and serum levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin were determined. Newborn infants were classified as infected or non-infected according to selected criteria, and 24 newborn infants fulfilled the criteria of having an infection, whereas 168 newborn infants were classified as non-infected. ICAM-1, VCAM-1 and E-selectin were detected in all neonatal samples. Serum concentrations of E-selectin varied by gestational age (GA), higher levels were found in non-infected term (GA > or = 37 weeks) neonates (n = 53) than in those (n = 115) delivered prematurely (GA < 37 weeks) without infection (p < 0.0001), whereas ICAM-1 and VCAM-1 concentrations did not differ between groups of non-infected term and preterm newborn infants. Similarly, newborn infants delivered at term (n = 16) demonstrated higher levels of E-selectin than premature infants (n = 8) in association with infection (p < 0.001). Both ICAM-1 and E-selectin were increased in term newborn infants with infection (n = 16) compared to the non-infected term group (n = 53) (both p < 0.01), whereas VCAM-1 concentrations did not differ between the two groups. In the premature groups of infected (n = 8) and non-infected (n = 115) neonates, no differences in ICAM-1, VCAM-1 and E-selectin concentrations were observed. The use of ICAM-1 concentration (cut-off level: 250 micrograms l-1) as a diagnostic test for infection in term neonates yielded a sensitivity of 80% and a specificity of 61%, whereas a sensitivity of 70% and a specificity of 79% were found when E-selectin concentration (cut-off level: 150 micrograms l-1) was used. Conclusively, increased shedding of soluble ICAM-1 and E-selectin is one component of infection-induced neonatal immune response after full-time pregnancies. Our data suggest that the ability of increased shedding of soluble ICAM-1 and E-selectin molecules is developed during the final weeks of pregnancy. Assessment of ICAM-1 and E-selectin concentrations may be used as diagnostic tools with a high sensitivity and a moderate specificity in term neonates suspected of infection.
Age Factors↗
Maternal serum levels of interleukin-6 and clinical characteristics of normal delivery at term.
BACKGROUND: The objective of the present study was to study participation of cytokines and cytokine inhibitors during the process of normal parturition, as assessed by maternal serum levels of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF) and soluble tumor necrosis factor receptors (sTNFRs, p55 and p75). MATERIALS AND METHODS: Twenty-six healthy women in normal term labor were observed during parturition and until 2 h post partum. Serum was sampled every 2 h, and an evaluation of strength and frequency of contractions was performed at the time of sampling. Concentrations of IL-1, IL-6, TNF, p55 and p75 were analyzed, and non-parametric tests were used to study whether any relationship existed between the serum analyzes and the clinical characteristics of parturition. RESULTS: There was a significant association between the strength of contractions and the levels of IL-6 and p55. In addition, IL-6 concentrations and frequency of contractions were correlated. Maternal serum levels of IL-6 and p55 were highest 2 h post partum. TNF activity was detected in samples from nine women, whereas IL-1 was not found in any sample. CONCLUSIONS: The present study suggests a role of IL-6 and p55 in normal labor. However, as women being studied already were in labor, the study does not allow any conclusions whether observed changes in IL-6 and p55 levels have a causal relation to the process of labor or if changes are secondary effects of the process itself.
Adult↗