W. Kuhn

Interleukin-8 synthesis and the onset of labor

Objective To examine the role of cytokines in cervical dilation. Methods In 55 patients undergoing cesarean delivery, we took samples from the lower uterine segment, the decidua, and the membranes. We determined the concentrations of interleukin (IL)-2, IL-8, tumor necrosis factor-α, matrix metalloproteinase (MMP)-8, and MMP-9 in the different tissues. Results Depending on the state of labor, we observed a significant increase (P < .001) in IL-8 concentrations in the lower uterine segment. The leukocyte enzymes MMP-8 and MMP-9 were highly significantly correlated with the IL-8 concentrations. Conclusion Interleukin-8 is critically involved in the process of parturition in humans. Interleukin-8 concentrations in the myometrium, decidua, and membranes correlated strongly with the observed MMP-8 and MMP-9 concentrations.

ORIGIN OF CERVICAL COLLAGENASE DURING PARTURITION

Cervical biopsy specimens were obtained under standard conditions from the posterior lip of the uterine cervix in 105 patients. A significant increase of collagenase activity was observed during parturition as determined with an assay with iodine 125-labeled native triple-helical collagen type I as the substrate. The collagenase was not likely to originate from cervical fibroblasts because in situ hybridization failed to detect synthesis of the specific procollagenase messenger ribonucleic acid. However, migration of polymorphonuclear leukocytes into the cervical stroma occurred on onset of labor, and an antibody specific for human leukocyte collagenase that did not cross react with fibroblast collagenase revealed the presence of the enzyme in the granules of polymorphonuclear leukocytes and subsequently in the extracellular matrix of the cervix. Therefore it is likely that the cells critically involved in collagen degradation during cervical dilatation are not resident fibroblasts but rather polymorphonuclear leukocytes emigrating from blood vessels.

Circulating endothelial cell adhesion molecules as diagnostic markers for the early identification of pregnant women at risk for development of preeclampsia

OBJECTIVE The aim of the current study was to determine levels of circulating endothelial cell adhesion molecules during preeclampsia and to assess their predictive value as diagnostic markers for the early identification of pregnant women at risk of developing preeclampsia. STUDY DESIGN Plasma samples were obtained from women with preeclampsia; the syndrome of hemolysis, elevated liver enzymes, and low platelets; uncomplicated pregnancy-induced hypertension; and women with normal pregnancy. In addition, longitudinal plasma profiles of pregnant women were randomly collected to determine individual profiles of circulating endothelial cell adhesion molecules. A sandwich enzyme-linked immunosorbent assay technique was used to quantitate concentrations of soluble intercellular adhesion molecule-1 (CD54), vascular cell adhesion molecule-1 (CD106), E-selectin (CD62E), platelet endothelial cell adhesion molecule (CD31), and P-selectin (CD62P). RESULTS Plasma levels of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and platelet endothelial cell adhesion molecule-1 were significantly elevated in women with preeclampsia compared with healthy control pregnant women. Longitudinal analysis of soluble plasma intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels during pregnancy revealed that these molecules (1) show little variation in healthy pregnant women, (2) do not vary during normal pregnancy, and (3) are significantly elevated in women with preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelets compared with control pregnant women and those with uncomplicated pregnancy-induced hypertension. Analysis of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels in longitudinal profiles of pregnant women identified significantly elevated levels of these molecules in the plasma of preeclampsia-prone women 3 to 15 weeks before the onset of clinical symptoms. CONCLUSION Elevated soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 measurements during pregnancy can be considered as major risk factors. Elevated levels of these substances in the plasma of pregnant women with preeclampsia support the concept of a primary endothelial cell involvement in the pathogenesis of preeclampsia. Although currently based on a limited database, significantly elevated levels of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the plasma of otherwise healthy pregnant women suggest a very high predictive value of these molecules for the earliest identification of women at risk of developing preeclampsia.

Biochemical changes in human cervical connective tissue after intracervical application of prostaglandin E2.

Cervical biopsies were taken during the first trimester from primigravidae and plurigravidae at different time points after intracervical application of prostaglandin E2-gel. Collagenase activity was determined by a highly specific technique using native, triple helical collagen as substrate. Elastase-alpha 1-proteinase-inhibitor complex (elastase) was measured by a commercially available assay, and glycosaminoglycan (GAG) analyses were performed as described by Greiling et al. (5, 6). The maximum activity of collagenase was found 2 hours after PGE2 application in plurigravidae and 4 hours after application in primigravidae. Elastase activity rose nearly 7-fold to maximum values 4 hours after PGE2 application. The total GAG concentrations and the dermatan sulfate concentrations increased by approximately 10%, while the hyaluronic acid concentrations were found to be elevated significantly by nearly 50% in the PGE2-primed cervices. We conclude that a time-dependent enzymatic collagen degradation by collagenases and other proteinases and an increase in hyaluronic acid concentrations are the significant biochemical events underlying PG-induced cervical ripening.

Activated protein C resistance and Factor V Leiden in patients with hemolysis, elevated liver enzymes, low platelets syndrome ☆

Objective Hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome is characterized by a distinct activation of the coagulation system. A mutation of the gene coding for coagulation Factor V (Factor V Leiden) has been identified as the most frequent risk factor for thrombosis. To identify risk factors for HELLP syndrome, we determined coagulation parameters and the Factor V Leiden mutation in women who previously had developed HELLP syndrome. Methods Coagulation parameters (activated protein C resistance, antithrombin, protein C, protein S) were determined in 21 women 6 months to 9 years after they had developed HELLP syndrome in the third trimester. In addition, these women were analyzed for the presence of the Factor V Leiden mutation. Results Of these analyzed women, 33% (seven of 21) had an activated protein C resistance (activated protein C ratio less than 2.0). Another 38% of the women had subnormal activated protein C ratios (2.0-2.3). Only 57% of the women with an activated protein C resistance were identified as heterozygous carriers of the Factor V Leiden mutation (four of seven). Conclusion Women with HELLP syndrome have a higher incidence of Factor V Leiden mutations. This increased incidence does not, however, account fully for the increased frequency of activated protein C resistance in these patients.

Expression of the p53 tumour suppressor gene as a prognostic marker in platinum-treated patients with ovarian cancer.

Drug resistance is one of the most important clinical problems in the treatment of ovarian cancer. This study was designed to determine whether expression of p53 could be used as a marker for predicting the response to chemotherapy of ovarian cancer. Tissue blocks were obtained from 187 patients with diagnosed untreated ovarian cancer. Paraffin sections from the primaries were immunohistochemically analysed for p53 expression. All patients underwent platinum-based chemotherapy after surgery. We analysed whether the number of chemotherapy cycles was related to survival in women with p53 positive and p53 negative ovarian cancer. 27/187 cases were p53 positive. Expression of p53 was associated with other factors of unfavourable prognosis. Patients with p53 positive tumours had a significantly worse prognosis compared with patients with p53 negative tumours (P = 0.037). There was a statistically significant dose-response effect of platinum-based chemotherapy in patients with p53 negative tumours, which could not be seen in patients with p53 positive tumours (P = 0.01 versus P = 0.553). This could also be observed in patients with residual tumour after surgery (P = 0.0001 versus P = 0.8866). Expression of p53 may be an additional useful marker in predicting response to chemotherapy. Thus, it is possible to identify a subgroup of patients who may benefit from alternative therapy regimens.

The Renin‐Angiotensin‐Aldosterone System, Antidiuretic Hormone Levels and Water Balance Under Tocolytic Therapy with Fenoterol and Verapamil

The effects of long‐term infusion of fenoterol (a β2‐sympathomimetic drug) in combination with the calcium antagonist verapamil on water balance, the renin‐angiotensin‐aldosterone system and antidiuretic hormone during pregnancy were studied. Within two hours of the start of infusion, plasma renin and antidiuretic hormone levels were significantly increased, but plasma aldosterone was strongly decreased. There was a concomitant marked reduction of urinary, sodium, and potassium excretion and a decreased creatinine clearance. The long‐lasting reduction of urinary excretion which resulted in an elevated water retention is apparently due to other unknown factors. Results are discussed with special regard to the relationship between water balance disturbances and pulmonary edema.

Haptoglobin as a sensitive marker of hemolysis in HELLP-syndrome.

In a prospective study we measured laboratory variables of hemolysis in 25 patients with HELLP‐syndrome. Reduced haptoglobin levels were observed in all 25 patients at diagnosis. Elevated bilirubin and plasma hemoglobin levels were observed in 5/25 patients while an abnormal peripheral blood smear was found in 11/25 patients. Our results suggest that haptoglobin is a sensitive parameter for early detection of moderate hemolysis in HELLP‐syndrome and should be included in laboratory screening to aid diagnosis.

Histological and electron-microscopic examinations of collagenous connective tissue of the non-pregnant cervix, the pregnant cervix, and the pregnant prostaglandin-treated cervix

SummaryThe histological appearance of the prostaglandin-pretreated cervix of early pregnancy (8–13 weeks) showed the changes found in the pregnant cervix at term. Electron microscopy showed collagen fibrils of normal periodicity (640 Å) and also collagen degradation products. Evidence of splitting of collagen fibrils could only be seen with light microscopy.

The importance of early laboratory screening methods for maternal and fetal outcome in cases of HELLP syndrome

Over a period of 5 years and 3 months 50 patients with HELLP syndrome were treated at our hospitals. All of these patients fulfilled the criteria of this syndrome described by Weinstein. Pre-eclampsia with HELLP syndrome was either diagnosed correctly by the referring doctor or on admission by the obstetrician on the basis of the laboratory findings. The median time interval between admission and delivery was 3 hours (range: 0.5-40 hours). In 49 patients, Caesarean section was performed, one patient developed a HELLP syndrome 18 hours after vaginal delivery. The median gestational age at delivery was 35 weeks (range: 26-40). Only three of 51 infants died before delivery, and there was one neonatal death, resulting in a perinatal mortality of 7.8%. Apgar scores below 7 occurred in 15 of the newborns after 1 min and in only 2 after 5 min. In 47 cases, Caesarean section and hospital course were free of complications; in three patients postoperative hemorrhages required relaparotomy, in two of these patients puerperal hysterectomy had to be performed. In our experience, the relevant laboratory parameters should be determined in any pregnant women with right upper quadrant pain independent of the severity of pre-eclampsia in order to diagnose HELLP syndrome as soon as possible. Both early control and follow-up of the laboratory parameters and immediate delivery--by Caesarean section, if necessary--may lead to a reduction of maternal mortality and morbidity and to an improvement of perinatal results.