Cardiotocography only versus cardiotocography plus ST analysis of fetal electrocardiogram for intrapartum fetal monitoring: a Swedish randomised controlled trial.

BACKGROUND: Previous studies indicate that analysis of the ST waveform of the fetal electrocardiogram provides information on the fetal response to hypoxia. We did a multicentre randomised controlled trial to test the hypothesis that intrapartum monitoring with cardiotocography combined with automatic ST-waveform analysis results in an improved perinatal outcome compared with cardiotocography alone. METHODS: At three Swedish labour wards, 4966 women with term fetuses in the cephalic presentation entered the trial during labour after a clinical decision had been made to apply a fetal scalp electrode for internal cardiotocography. They were randomly assigned monitoring with cardiotocography plus ST analysis (CTG+ST group) or cardiotocography only (CTG group). The main outcome measure was rate of umbilical-artery metabolic acidosis (pH <7.05 and base deficit >12 mmol/L). Secondary outcomes included operative delivery for fetal distress. Results were first analysed according to intention to treat, and secondly after exclusion of cases with severe malformations or with inadequate monitoring. FINDINGS: The CTG+ST group showed significantly lower rates of umbilical-artery metabolic acidosis than the cardiotocography group (15 of 2159 [0.7%] vs 31 of 2079 [2%], relative risk 0.47 [95% CI 0.25-0.86], p=0.02) and of operative delivery for fetal distress (193 of 2519 [8%] vs 227 of 2447 [9%], 0.83 [0.69-0.99], p=0.047) when all cases were included according to intention to treat. The differences were more pronounced after exclusion of 291 in the CTG+ST group and 283 in the CTG group with malformations or inadequate recording. INTERPRETATION: Intrapartum monitoring with cardiotocography combined with automatic ST-waveform analysis increases the ability of obstetricians to identify fetal hypoxia and to intervene more appropriately, resulting in an improved perinatal outcome.

Brain-specific NSE and S-100 proteins in umbilical blood after normal delivery.

BACKGROUND: To determine normal blood levels of brain-specific proteins S-100 and neuron specific enolase (NSE) in healthy newborns and their mothers following uncomplicated birth. METHODS: Umbilical artery and vein blood and maternal venous blood was collected at 112 consecutive uncomplicated deliveries. Venous blood samples were taken from 18 of the neonates 3 days after birth. S-100 and NSE were analyzed quantitatively by double antibody immunoluminometric assay (Sangtec Medical AB, Sweden). RESULTS: Compared with adults, healthy neonates had higher levels of both S-100 and NSE. For S-100, median levels (range) were 1.10 microg/l (0.38-5.50 microg/l and 0.98 microg/l (0.43-2.70 microg/l) in umbilical artery and vein, respectively. For NSE, median levels (range) in umbilical artery blood and vein were 27 microg/l (10-140 microg/l) and 10.75 microg/l (8.80->/=200 microg/l) respectively. The maternal venous blood levels of both S-100 and NSE were significantly lower than in their infants. At 3 days of life, neonatal venous levels of the proteins were still high: S-100, 0.48-9.70 microg/l; NSE, 17->/=200 microg/l. In contrast to adults, haemolysis affected the S-100 levels in umbilical blood significantly. CONCLUSION: Concentrations of both S-100 and NSE in blood are greater in newborns after normal birth than in healthy adults. The higher levels in umbilical artery blood than in umbilical vein blood are consistent with a fetal origin of these proteins. High levels in venous blood at 3 days of life suggest that the high levels at birth are not related to the birth process but reflect a high activity of these proteins during fetal development.

Increased expression of interleukin 6 in term compared to the first trimester human placental villi.

Cytokines and their specific receptors expressed at the feto-maternal interface are known to play a critical role in regulating various placental functions. Interleukin 6 (IL-6) has been shown to be produced by both decidua and the trophoblast cells of the placenta. The aim of the present study was to examine the expression profile of placental IL-6 protein and mRNA at early and late stages of gestation. Placental villi were obtained from women undergoing first trimester pregnancy termination or elective Cesarean section at term. Functionally active placental explant culture system was used to study the release of IL-6 by these tissues. IL-6 was detected in placental conditioned media of all the samples from first trimester and term group. The mean levels of IL-6 produced by term villi were found to be 5.5, 7.5 and 5-fold higher at term when compared with the first trimester at 24 h, 48 h and 72 h of culture, respectively. Expression of IL-6 mRNA was demonstrated by RT-PCR performed on total RNA isolated from these tissues. IL-6 mRNA expression was detected in both early and late gestational placental tissues. Moreover, the level of IL-6 mRNA was found to be approximately 4-fold higher at term compared with first trimester. These data are consistent with the hypothesis that levels of IL-6 production by the placenta are developmental stage-specific and suggest that expression of IL-6 in the placenta could be subjected to transcriptional regulation.

Significance of the plasminogen activator inhibitor of placental type (PAI-2) in pregnancy.

Marked changes in the hemostasis system, especially increases in PAI-2, are observed during pregnancy and at delivery. This inhibitor is produced by placental trophoblasts and by macrophages. PAI-2 occurs in two forms, a LMW and a HMW form. LMW PAI-2 is intracellular, HMW PAI-2 is secreted. PAI-2 inhibits both u-PA and two-chain t-PA. PAI-2 seems to be involved in the processes of invasion and remodeling of fetal and uterine tissues. It may protect against premature placental separation and secure hemostasis at parturition. Excess levels of PAI-2 in amniotic fluid may protect membranes from premature rupture. An imbalance between fibrinolytic activators and inhibitors may also be related to intracranial hemorrhage in premature infants. During preeclampsia t-PA and PAI-1 levels are markedly increased in plasma, and in cases of intrauterine growth retardation, u-PA and PAI-2 levels are decreased. While elevated PAI-1 concentrations might be helpful markers of severity of preeclampsia, decreased PAI-2 levels seem to indicate decreased placental function and intrauterine growth retardation.

Preeclampsia is associated with a reduced response to activated protein C.

OBJECTIVE: Resistance to activated protein C is an inherited mutation of the coagulation factor V gene, a major factor predisposing to thromboembolic events. The purpose of this study was to investigate the occurrence of heterozygote and homozygote activated protein C resistance in women with preeclampsia. STUDY DESIGN: Activated protein C resistance and protein C and antithrombin III levels were determined in women (n = 50) with a history of preeclampsia and in controls (50 women with a previous normal pregnancy). The mutation of the factor V gene was analyzed. RESULTS: Activated protein C resistance was found in 22% of women with previous preeclampsia compared with 10% among controls. Two women in the previous preeclampsia group had a homozygote mutation of factor V; the others were heterozygous. There was a significant difference in the activated protein C ratio between women with previous preeclampsia and the control group, 2.6 +/- 0.4 versus 3.1 +/- 0.5 (p = 0.04). None of the women had protein C or antithrombin III deficiency. CONCLUSION: The results indicate that activated protein C resistance may be a contributory factor in the pathogenesis of preeclampsia.

Plasminogen activators and plasminogen activator inhibitors in plasma of premature and term newborns.

OBJECTIVE: To compare the plasminogen activators (tPA, uPA) and their inhibitors (PAI-1, PAI-2) at different gestational ages, related to levels in women at term and non-pregnant women. METHODS: Blood samples were obtained by puncture of the umbilical cord vein, in gestational weeks 39-40 (n = 21), 30-32 (n = 15), and 27-29 (n = 9). Analyses of PA and PAI antigen concentrations and of PAI-1 activity were performed. RESULTS: The mean tPA antigen level in term newborn infants was 14.5 micrograms/l compared to the premature newborns (7.0 micrograms/l), women at term (7.5 micrograms/l) and non-pregnant women (2.3 micrograms/l). PAI-1 activity and PAI-2 antigen concentrations were also higher in term newborn than in premature infants. CONCLUSIONS: The plasma levels of the plasminogen activators and inhibitors are higher in term newborn compared with premature newborn infants, reflecting maturation of protein synthesis.

Tissue plasminogen activator and plasminogen activator inhibitor-1 in stroke patients.

BACKGROUND AND PURPOSE: Abnormal endogenous fibrinolytic activity may be a risk factor for stroke. Since the possible variation of tissue-type plasminogen activator (TPA) antigen and plasminogen activator inhibitor-1 (PAI-1) antigen concentrations over time after stroke has been rarely studied, it was examined in plasma from stroke patients in the acute and convalescent phases of the disease and in a control group. METHODS: Plasma concentrations of TPA and PAI-1 were determined in 135 stroke patients and in 77 control subjects. All but 4 patients were examined within 7 days after stroke onset, and 32 patients and 18 control subjects were reexamined 2 to 4 years later. RESULTS: In the acute phase, stroke patients had significantly higher TPA (median, 10 micrograms/L) and PAI-1 (median, 14 micrograms/L) antigen concentrations, compared with control subjects (median values, 6 micrograms/L [P = .0001] and 8 micrograms/L [P < .01], respectively); TPA levels were higher in both the cerebral infarction (n = 122) and cerebral hemorrhage (n = 12) subgroups, whereas PAI-1 levels were higher in the cerebral infarction subgroup only. Stepwise logistic regression analysis (with correction for age, sex, history of hypertension, diabetes mellitus, and heart disease) showed TPA antigen level to be an independent discriminator between the cerebral infarction subgroup and control subjects (P = .0001), whereas the corresponding difference for PAI-1 antigen levels just failed to reach significance (P = .05). TPA antigen levels were correlated with concentrations of serum cholesterol (Spearman's rho = 0.15; P < .05), serum triglyceride (rho = 0.33; P = .0001), and plasma homocysteine (rho = 0.19; P < .01). PAI-1 antigen levels were correlated with serum triglyceride levels only (rho = 0.41; P = .0001). At reexamination after 2 to 4 years, neither TPA nor PAI-1 levels had changed significantly from the baseline values. CONCLUSIONS: In stroke patients, high TPA antigen concentrations may indicate an activation of the fibrinolytic system or may be due to a delayed clearance of TPA complexed with inhibitors. High PAI-1 antigen concentrations in patients with cerebral infarction represent increased fibrinolytic inhibition. The findings in this longitudinal study suggest that TPA and PAI-1 antigen concentrations both differ little between the acute and convalescent phases after stroke.

Transdermal estrogen replacement therapy: beneficial effects on hemostatic risk factors for cardiovascular disease.

OBJECTIVES: To assess the effect of estrogen replacement therapy on hemostatic risk factors for cardiovascular disease (CVD) in postmenopausal women during 2 years of treatment. METHODS: In an open prospective study, patients (n = 42) were investigated before and during 2 years of treatment, and compared to an untreated postmenopausal control group (n = 18) followed during the same period, healthy premenopausal women (n = 20) being included as a reference group for premenopausal values. The patients underwent treatment with transdermal 17 beta-estradiol (E2) (50 micrograms/24 h), oral medroxyprogesterone acetate (5 mg/day) being added for 12 days every second month. RESULTS: After 2 years of treatment there was a significant increase in t-PA antigen (P = 0.01) and a significant decrease in F VII antigen (P = 0.01). PAI-1 antigen concentrations decreased slightly. Fibrinogen concentrations were already significantly decreased at 3-month follow-up (P = 0.01), and were still low after 2 years. By contrast, at 2-year follow-up the postmenopausal control group manifested significant increases in F VII and PAI-1 antigen and slight increases in fibrinogen, which resulted in significant differences between patients and controls. Regression analysis showed the increase in the serum estradiol concentrations to be inversely correlated to the decreases in the plasma concentrations of F VII antigen (r = -0.34, P = 0.001) and fibrinogen (r = -0.35, P = 0.001). There were no changes in AT III or protein C in any group. CONCLUSIONS: The increase in serum estradiol concentrations due to replacement therapy did not adversely affect the studied components of the fibrinolytic and protein C defense system against thrombosis, and resulted in beneficial decreases in F VII antigen and fibrinogen. These findings may help to explain the beneficial effects of estrogen replacement therapy in terms of protection from cardiovascular disease.

Reduction of menstrual blood loss in women suffering from idiopathic menorrhagia with a novel antifibrinolytic drug (Kabi 2161).

OBJECTIVE: To compare the effect of Kabi 2161 (a prodrug of tranexamic acid) and placebo on the reduction of menstrual blood loss in women suffering from idiopathic menorrhagia and to evaluate tolerance and effectiveness in a two-dose regimen. DESIGN: A randomised, double blind parallel group study using double dummy technique. SETTING: The departments of gynaecology at three medical centres in Sweden. SUBJECTS: Ninety-one outpatients visiting the gynaecological clinics from March 1991 to May 1992 were randomised into the study; 68 women fulfilled the study. INTERVENTIONS: Two run-in cycles, followed by administrations of Kabi 2161 (600 mg) tablets (1 four times daily or 2 twice daily) or placebo for the first five days of three menstrual cycles. MAIN OUTCOME MEASURES: Objective measurement of the change in menstrual blood loss during the treatment periods compared with menstrual blood loss during the run-in periods. RESULTS: A statistically significant reduction of menstrual blood loss was found for each treatment group, compared with the placebo group (P < 0.001). The mean reduction with 95% confidence interval (CI) was 33% (24-40) in the group treated with 1 four times daily and 41% (33-49) in the group treated 2 twice daily. The difference between the treated groups in reduction of menstrual blood loss is not significant. No significant differences were found in the frequencies of reported unwanted events during run-in and during treatment between the different treatment groups. There were also no significant differences between the treatment groups and the placebo group. CONCLUSION: Kabi 2161 in a dosage of 2.4 g per day gave a statistically significant reduction in objectively measured menstrual blood loss in a two (41%) as well as in a four (33%) dosage regimen compared with placebo. Frequency of unwanted events did not differ from those during run-in or from those in the placebo group. The optimal daily dosage needs to be further evaluated in a dose titration study.

Plasminogen activator of urokinase type and its inhibitor of placental type in hypertensive pregnancies and in intrauterine growth retardation: possible markers of placental function.

OBJECTIVE: Our purpose was to study the plasma concentrations of the plasminogen activator of urokinase type and its specific inhibitor of placental type in pregnancies complicated by hypertension or fetal growth retardation. STUDY DESIGN: Consecutive patients with pregnancy-induced hypertension (n = 17), mild preeclampsia (n = 17), severe preeclampsia (n = 19), and intrauterine growth retardation (n = 19) were studied. Blood samples were obtained just before delivery (mean 2 days). Women with normal pregnancies (n = 40), longitudinally followed between the tenth and fortieth gestational weeks, served as a control group. RESULTS: The plasma concentrations of the urokinase type antigen were significantly lower in women with severe preeclampsia or intrauterine growth retardation than those in women with normal pregnancies (p < 0.001). In all four groups with complicated pregnancies the antigen concentrations of the urokinase type and its inhibitor were significantly correlated with both placental weight and birth weight. CONCLUSIONS: The plasma concentration of the urokinase type antigen would appear to reflect placental function, and both the antigen and its inhibitor concentrations are correlated with placental and fetal growth.

Treatment with a GnRH analogue: effects on hemostatic risk factors for thrombo-embolic disease.

OBJECTIVE: Steroid hormones, especially estrogens, are known to affect hemostatic risk factors for thromboembolism, cardiovascular disease, and stroke. We examined these risk factors during depression of the serum estradiol concentration by a GnRH analogue. DESIGN: Patients were treated with a GnRH analogue, goserelin (Zoladex), 3.6 mg/inj monthly, for a period of 6 months. Blood samples were collected during and after treatment and in a control group. In ten patients a blood sample was also drawn before treatment. Measurements were made of serum estradiol, and the plasma concentrations of tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor (PAI-1) antigen, antithrombin III (AT III) and protein C activity, factor VII (FVII) antigen, and fibrinogen. SETTING: Outpatient clinics at the Departments of Obstetrics and Gynecology at two university hospitals in southern Sweden. PARTICIPANTS: Twenty-seven women with endometriosis were consecutively included. A control group comprised 20 women with normal menstrual cycles. MAIN OUTCOME MEASURES: The concentrations of the hemostatic components during depression of the serum estradiol concentrations, as compared to those during normal ovulatory cycles. RESULTS: Serum estradiol concentrations during treatment were comparable to those of postmenopausal women (mean, 23.2 pmol/L), and both AT III and protein C activity were significantly increased (P < .005 and P < .02, respectively). As compared to controls, plasma concentrations of PAI-1 and t-PA of patients were significantly higher both during and after treatment. In the subgroup also studied prior to treatment, there were no differences in hemostatic components, when comparing pretreatment and posttreatment values. CONCLUSIONS: Treatment with this type of GnRH analogue for 6 months is safe with regard to its effect on hemostatic risk factors. The similar responses of t-PA and its inhibitor, PAI-1, to alterations in estrogen levels as well as inflammatory reactivity presumably constitute a balance mechanism preserving fibrinolytic defenses.

Treatment with tranexamic acid during pregnancy, and the risk of thrombo-embolic complications.

Tranexamic acid (AMCA) is an inhibitor of fibrinolysis used to treat fibrinolytic bleeding (e.g., menorrhagia and gastro-intestinal haemorrhage), and to prevent bleeding at surgery, in cases of abruptio placentae and general haemorrhage. As AMCA stabilises preformed clots and prolongs their dissolution, it has been debated whether treatment with AMCA might predispose to thrombosis by depressing the fibrinolytic system. Pregnant women constitute a group with low fibrinolytic capacity and an increased frequency of thrombosis further increased after Caesarean section, and are thus more likely to be susceptible to antifibrinolytic therapy. We therefore carried out a retrospective analysis of the case records of 2,102 patients with various bleeding disorders during pregnancy. Of the 256 patients treated with AMCA (mean duration of treatment, 46 days), 169 were delivered by Caesarean section. Of the remaining 1,846 patients (i.e., controls), 443 were delivered by Caesarean section. The relationship between the use of AMCA and the occurrence of thrombo-embolism was calculated with 95% confidence limits. Of the AMCA treated group (n = 256), two patients--one of whom belonged to the Caesarean section subgroup (n = 168)--had pulmonary embolism. Of the controls (n = 1,846), three patients had deep vein thrombosis and one had pulmonary embolism, all four cases belonging to the Caesarean section subgroup (n = 443). Thus, the findings in this high risk group of women with complicated pregnancies, frequently entailing delivery by Caesarean section, provided no evidence of any thrombogenic effect of AMCA.

Passage of the menopause is followed by haemostatic changes.

The passage of the menopause has been reported to be followed by a steadily increasing risk of cardiovascular disease (CVD). Changes in the concentrations of certain coagulation factors and fibrinolytic components are considered risk factors for CVD. We evaluated the differences in some of these variables between a premenopausal group (A) (n = 28) and two postmenopausal groups, one of women less than 18 months past the menopause (B) (n = 28), the other of women more than 18 months past the menopause (C) (n = 21). The variables measured were serum oestradiol content, plasma antithrombin III (AT III) activity, protein C activity and the plasma concentrations of tissue type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor (PAI-1) antigen, and fibrinogen. As compared with the premenopausal women (group A), group C showed significantly higher values for AT III and protein C activity and for t-PA and PAI-1 antigen; and group B and C both showed significantly higher fibrinogen concentrations. This probably means that haemostatic balance was maintained in the postmenopausal women, although the increased concentrations of fibrinogen and PAI-1 might constitute risk factors for the development of cardiovascular disease.

Diclofenac versus pethidine in the treatment of pain after hysterectomy.

A double-blind study was performed in 63 patients to compare diclofenac (a non-steroidal anti-inflammatory drug), pethidine and placebo with regard to efficacy and tolerability in the treatment of pain after abdominal hysterectomy. The compounds were injected post-operatively and the duration of pain relief was chosen as the parameter of efficacy. Pain intensity was measured on a visual analogue scale by the patient and according to a six-point scale by the investigator. Diclofenac gave significantly longer pain relief than pethidine or placebo. Few side-effects were reported after diclofenac and placebo, and post-operative bowel paralysis tended to be shorter with diclofenac.