6-ketoprostaglandin-f1-alpha and Pre-Eclampsia

The gynecologic and obstetric implications of the smooth muscle-relaxing, antiaggregatory prostacyclin and its endogenous antagonist, thromboxane A2, are reviewed. In addition to the vascular wall and circulating platelets, which are primary sources for prostacyclin and thromboxane A2, respectively, reproductive tissues produce great amounts of these prostanoids, evidently for the regulation of the vascular tone and/or vascular platelet interaction. Several gynecologic and obstetric disorders are characterized by abnormalities in prostacyclin and/or thromboxane A2. In primary menorrhagia the uterine release of prostacyclin is increased, and consequently menstrual blood loss can be reduced with various prostaglandin synthesis inhibitors. Prostacyclin relaxes the nonpregnant myometrium in vitro and may also do so in vivo, although intravenous infusion of prostacyclin has no effect upon the uterine contractility in nonpregnant or pregnant subjects. Patients with pelvic endometriosis may have increased levels of prostacyclin and thromboxane A2 metabolites in the peritoneal fluid. The prostacyclin/thromboxane A2 balance shifts to thromboxane A2 dominance in patients with gynecologic cancer. During pregnancy the production of prostacyclin and thromboxane A2 increases in the mother and fetoplacental tissue. Preeclampsia and other chronic placental insufficiency syndromes are accompanied by prostacyclin deficiency in the mother and in fetomaternal tissues and by an overproduction of thromboxane A2, at least in the placenta. These changes may account for the vasoconstriction and platelet hyperactivity, which are pathognomonic for hypertensive pregnancies. By directing the prostacyclin/thromboxane A2 balance to prostacyclin dominance (by dietary manipulation, administration of prostacyclin and/or its analogues, drugs with prostacyclin-stimulating and/or thromboxane A2-inhibiting action), it may be possible to prevent and/or treat hypertensive pregnancy complications in the future.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Ascitic Fluid; Endometriosis; Epoprostenol; Estrogens; Female; Genital Diseases, Female; Genital Neoplasms, Female; Humans; Hypertension; Menorrhagia; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Complications, Cardiovascular; Progestins; Thromboxane A2; Thromboxane B2; Thromboxanes; Uterine Contraction; Vasoconstriction

Preeclampsia is a unique disease of pregnancy. Delivery via caesarean section is the most important way of terminating the pregnancy and treating preeclampsia. Perioperative fluid therapy is performed to maintain the circulatory volume and reduce tissue edema. This study evaluated the effects of hypertonic sodium chloride hydroxyethyl starch 40 (HSH40) as perioperative fluid therapy for preeclampsia patients.. Forty preeclamptic women were randomly divided into two groups: the Ringer's solution group and the HSH40 group. Their ECG, HR, MAP, and SPO2 were monitored. Their MVP and HR were recorded at five, eight, and ten minutes after anesthesia induction and at the end of the caesarean section. The corresponding volume of infusion, blood loss, and urine output during the operation were also recorded. Venous samples were collected before HSH40 infusion and 30 min after infusion to measure the plasma concentrations of ET, TXB2, 6-keto-PGF1α, and ANP via a radioimmunoassay.. HSH40 infusion significantly decreased the plasma ET levels (p < 0.01), significantly changed the plasma ANP and TXB2 levels (p < 0.05), and significantly increased the plasma 6-keto-PGF1α levels (p < 0.01) in the experimental group compared with those before infusion. The plasma levels of ET, ANP, TXB2, and 6-keto-PGF1α did not significantly change in the control group. Compared with T1, MAP decreased significantly at T2, T3, T4, and T5 within groups (p < 0.05) and between the two groups. MAP significantly changed at T2, T3, T4, and T5 (p < 0.05). HR did not significant change at T1, T2, T3, T4, and T5 within or between groups. Volume of infusion and urine volume significantly differed between groups (p < 0.05).. Low-dose HSH40 lowers the plasma levels of vasoconstrictor substances (ET and TXB2) and increases the levels of vasodilator substances (6-keto-PGF1α and ANP) during preeclampsia. It effectively maintains and stabilizes the circulating blood volume, increasing renal blood flow, which improves renal function and increases urine output.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Atrial Natriuretic Factor; Cesarean Section; Female; Fluid Therapy; Humans; Hydroxyethyl Starch Derivatives; Isotonic Solutions; Perioperative Care; Plasma Substitutes; Pre-Eclampsia; Pregnancy; Ringer's Solution; Saline Solution, Hypertonic; Therapeutics; Thromboxane B2

To examine the fetal effects of a novel controlled-release, low dose aspirin preparation in normal and hypertensive pregnancies.. Random double-blind study. Participants assigned to receive conventional formulation aspirin (75 mg), controlled-release low dose aspirin (75 mg), or a matching placebo.. National Maternity Hospital, Dublin.. Eighteen women with an uncomplicated pregnancy and 18 women with preeclampsia.. Urine was analysed for metabolites of thromboxane and prostacyclin by gas chromatography, mass spectrometry. Serum thromboxane B2 was determined in maternal and cord blood.. Both aspirin preparations reduced maternal serum thromboxane B2 by 95% and induced similar reductions in the urinary 11-dehydro-thromboxane B2, a major metabolite of thromboxane A2 in vivo. In contrast, neither preparation altered urinary 2,3-dinor-6-keto PGF1alpha, the major metabolite of prostacyclin. Despite their similar effects in the mothers, the two aspirin preparations differed in their effects on the fetus. While both suppressed cord fetal thromboxane B2, this was significantly (P < 0.005) less for the controlled-release preparation (210+/-42 ng/ml for placebo vs 109+/-22 ng/ml for controlled-release aspirin and 44+/-9 ng/ml for regular oral aspirin).. At equivalent maternal suppression of serum thromboxane B2, a controlled aspirin release preparation results in lower fetal exposure than regular oral aspirin.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Cyclooxygenase Inhibitors; Delayed-Action Preparations; Double-Blind Method; Eicosanoids; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Thromboxane B2

To study the effects of oral low-dose magnesium gluconate in prevention of pregnancy induced hypertension (PIH) and its mechanism.. A prospective randomized double-blind study was carried out in 51 pregnant women as treatment group (including 22 cases as treatment group 1 and 29 cases as treatment group 2) and 51 pregnant women as controls (including 28 cases as controls group 1 and 23 cases as control group 2). Low-dose magnesium gluconate (3 g/day) or placebo was given from the 28th week of gestation to delivery consecutively.. 4% of the pregnant women developed PIH after magnesium gluconate treatment, which was substantially lower than that in the control group (16%) (P < 0.05). In the treatment group 2, women showed higher concentration of 6-keto-prostaglandin F1 alpha (PGF1a) and 6-keto-/thromboxane B2(TXB2) (P/T) ratio than that of the control group 2. Moreover, TXB2 level was lower than that in the control group 2. In the treatment group 1 women showed higher ratio of P/T than that of the control group 1. There were no significant differences of serum magnesium concentration among all groups.. Low-dose magnesium gluconate may efficiently prevent PIH in high risk women. The mechanism of action of magnesium gluconate probably involves to keep the balance of PGI2 and TXA2, but not associates with serum magnesium level.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Double-Blind Method; Female; Gluconates; Humans; Pre-Eclampsia; Pregnancy; Prospective Studies; Thromboxane B2

The pathogenesis of preeclampsia is proposed to be due to uncharacterized circulating factors that activate endothelial cells. Support for this hypothesis is provided by in vitro activation of endothelial cells by plasma from preeclamptic women, eg, increased nitric oxide and prostacyclin generation. We performed molecular sizing, lipid extraction, and lipoprotein fractionation of plasma from normal pregnant and preeclamptic women and determined the ability of these plasma fractions to increase nitric oxide or prostacyclin generation by endothelial cells. Fractions from plasma of preeclamptic women were consistently more active than fractions from normal pregnant women, although characterization was qualitatively similar. The factors stimulating nitric oxide and prostacyclin were different. The factor (or factors) stimulating nitric oxide generation was extractable by charcoal and present in lipid extracts and lipoprotein isolates with a molecular weight greater that 1.5 million daltons, which is characteristic of a lipoprotein or lipoprotein aggregate. By contrast, activity to stimulate prostacyclin persisted after charcoal stripping or lipoprotein removal, partitioned to the aqueous fraction, and had a molecular weight of approximately 50,000 D. Two distinct factors in the blood of preeclamptic women alter endothelial function in vitro. This information should guide the search for circulating factors contributing to the pathophysiology of preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Cells, Cultured; Endothelium, Vascular; Epoprostenol; Female; Humans; Lipoproteins; Molecular Weight; Nitric Oxide; Pre-Eclampsia; Pregnancy

Pre-eclampsia is suggested to be characterized by a functional imbalance between vascular prostacyclin and thromboxane A2 production. On the basis of this hypothesis it is attempted to correct this pathologic conditions by pharmacological manipulation with Trapidil, a triazolo pyrimidin derivative, because of its effects on the prostanoid metabolism. A prospective, randomized, double blind, placebo-controlled study was carried out to investigate Trapidil in the prevention of pregnancy-induced hypertension or pre-eclampsia. A total of 160 pregnant women with the risk to develop pre-eclampsia received Trapidil or placebo between week 24 and 38 of gestation. The number of patients in whom pregnancy-induced hypertension or pre-eclampsia developed was significantly lower in the Trapidil-treated (5.5%) compared with the placebo-treated group (14.1%). Additionally, a reduced risk of preterm deliveries and severe fetal growth retardation could be observed. In 7 patients with manifest pre-eclampsia or pregnancy-induced hypertension the circulating eicosanoid concentrations were determined before and during Trapidil medication. Trapidil was associated with an about twofold increase of 6-keto PGF1 alpha concentration in the peripheral venous blood, while the concentration of thromboxane A2 revealed no changes.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Double-Blind Method; Female; Fetal Growth Retardation; Humans; Hypertension; Infant, Newborn; Obstetric Labor, Premature; Pre-Eclampsia; Pregnancy; Risk Factors; Trapidil

A prospective randomized double-blind study was carried out in pregnant women with risk of pregnancy induced hypertension (PIH). Low dose Aspirin (50 mg/day) or placebo was given consecutively from the 28th weeks of gestation. The results have shown that 8% of the pregnant women in the aspirin treatment group had developed PIH, which was substantially lower than that in the control group (24%) (P less than 0.05). The ratio of TXB2/6-keto-PGF1 alpha increased significantly in the control group while it remained unchanged in treatment group. Increasing plasma fibronectin (Fn) and decreasing AT-III level were seen in the control group but no changes of these parameters in the treatment group. It was presumed that low dose aspirin may have prophylactic effect on PIH. The mechanism of aspirin may be the inhibition of TXA2 and Fn synthesis and decreased consumption of AT-III.

Topics: 6-Ketoprostaglandin F1 alpha; Aspirin; Double-Blind Method; Female; Fibronectins; Humans; Pre-Eclampsia; Pregnancy; Prospective Studies; Thromboxane B2

Our aim was to determine the biological investigation of prostacyclin in preeclamptic women seen reduced endothelial vasodilatation by non-invasive technique in vivo.. Using a high resolution ultrasound transducer, diameters of brachial arteries were determined after reactive hyperemia in 15 non-pregnant, 20 normotensive pregnant and 20 preeclamptic women. The concentrations of 6-keto-prostaglandin F 1alpha (6keto-PGF 1alpha) in plasma and the concentrations of adenosine-3', 5'-cyclic monophosphate (cyclic AMP) in platelets and serum were measured among the groups.. Flow-mediated vasodilatation at 1 min after reactive hyperemia was higher in normotensive pregnant than in the non-pregnant or preeclamptic women. The plasma concentration of 6 keto-PGF 1alpha as well as the serum concentration of cyclic AMP were lower in preeclamptic than those in normotensive pregnant women. The increase in cyclic AMP in the presence of a prostacyclin analogue in platelets was seen at similar levels in all three groups.. From these results, the concentrations of prostacyclin in plasma and cyclic AMP in serum might be low possibly due to reduced production of prostacyclin in preeclamptic women seen reduced endothelial function.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Analysis of Variance; Blood Platelets; Brachial Artery; Cyclic AMP; Endothelium, Vascular; Female; Humans; Pre-Eclampsia; Pregnancy; Ultrasonography; Vasodilation

To investigate apical and basal releases of thromboxane (TX) and prostacyclin (PGI2) by trophoblasts (TCs) from normal and preeclamptic (PE) placentas.. TCs isolated from normal and PE placentas were incubated in cell culture inserts for 48h. Medium from the upper (apical) and the lower (basal) chambers were then collected separately and measured for TX and PGI2 by their stable metabolites of TXB2 and 6-keto PGF1alpha by ELISA. Apical and basal releases of TX and PGI were also examined with apical exposure of TCs to arachidonic acid (AA)+/-aspirin at different concentrations. Villous tissue expressions for PGI synthase, TX synthase and TX (TP) receptor were examined by immunohistochemistry.. (1) TXB2, but not 6-keto PGF1alpha, concentrations were significantly higher in the lower than in the upper chambers with both normal and PE TCs (p<0.01); (2) apical exposure of TCs to AA resulted in a significant increase in TX release towards both the upper and the lower chambers in normal TCs (p<0.01), but only a significant increase in the upper chamber in PE TCs (p<0.01); (3) aspirin could attenuate AA-induced TX release both in the upper and the lower chambers in normal, but not in PE, TCs (p<0.01), respectively; (4) there were no differences in 6-keto PGF1alpha productions both in normal and PE TCs treated with AA+/-aspirin; (5) intense staining of TX synthase and TP receptor was seen in syncytiotrophoblast layer, villous core vessels and stromal cells in preeclamptic placental tissue sections.. Predominant basal release of TX together with intense staining of TX synthase and TP receptor in trophoblasts, stromal cells and villous core vessels are found in placentas from PE. We speculate if predominant basal release of TX by TCs occurs in vivo as we found in our in vitro culture condition, basal released TX may play a significant role in increased placental vasoconstriction such as in PE.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Aspirin; Epoprostenol; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Receptors, Thromboxane; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Trophoblasts; Vasoconstriction

In this study we determined whether hypoxia could promote vasoactivator thromboxane (TX) and prostacyclin (PGI2) as well as phospholipase A2 (PLA2) production by placental trophoblast cells (TCs) from normal and preeclamptic (PE) pregnancies. Placentas were obtained immediately after delivery from normal (n=9) and preeclamptic (n=9) pregnancies. TCs were isolated by dispase digestion of villous tissue and purified by Percoll gradient centrifugation. TCs (5x10(6) cells/well) were cultured with Dulbecco's Modified Eagles Medium (DMEM) under hypoxia condition (2% O2/5% CO2/93% N2) for 48 h. TCs cultured under normoxia condition (5% CO2/air) were used as control. Culture medium was collected at the end of incubation. Productions for TX, PGI2 and PLA2 were measured by ACE competitive enzyme immunoassay (EIA). Comparisons were made using the Mann-Whitney U test or paired t-test and the data are expressed as mean+/-SE (pg/microg cellular protein). Significance was set at a p-value of <0.05. We found: (1) PE-TCs produced more TXB2 and PLA2 than normal-TCs under normoxia conditions, TXB2: 4.33+/-1.03 vs. 1.84+/-0.29 pg/microg protein, p<0.05; PLA2: 0.38+/-0.08 vs. 0.21+/-0.03 pg/microg protein, p<0.05, respectively. (2) Hypoxia promoted both PE- and normal-TCs to generate more TXB2 and PLA2, TXB2: 6.36+/-1.72 vs. 3.05+/-0.45 pg/microg; PLA2: 0.52+/-0.10 vs. 0.30+/-0.04 pg/microg, respectively. (3) No change in 6-keto PGF1alpha production was observed for normal-TCs or PE-TCs when compared under normoxia vs. hypoxia condition, normal-TCs: 0.20+/-0.05 vs. 0.21+/-0.05 pg/microg; PE-TCs: 0.38+/-0.05 vs. 0.36+/-0.04 pg/microg, respectively. We concluded that hypoxia promotes both PLA2 and TX, but not PGI2, production by placental trophoblast cells cultured under hypoxia condition. These results suggest that increased PLA2 release may alter the arachidonic acid cascade and promote TX synthesis. Relative hypoxia could contribute to the increase in TX production and result in vasoconstriction in placental vasculature in preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cell Hypoxia; Cells, Cultured; Epoprostenol; Female; Humans; Kinetics; Phospholipases A; Phospholipases A2; Pre-Eclampsia; Pregnancy; Thromboxane B2; Thromboxanes; Trophoblasts

The purpose of this study was to examine 6-keto-prostaglandin F(1)(alpha) and thromboxane B(2) plasma levels throughout normotensive and preeclamptic pregnancies and to analyze the predictive values of these quantifications for the detection of preeclampsia during the second trimester of pregnancy.. Blood samples were collected from 30 healthy, nonpregnant women and at 4-week intervals from a cohort of nulliparous women who were recruited before 16 weeks of gestation. Preeclampsia developed in 26 patients; 52 normotensive control subjects were matched from the same cohort. The 6-keto-prostaglandin F(1)(alpha) and thromboxane B(2) were assayed by radioimmunoassay. Trends were compared between pregnancy groups and with the nonpregnant women. Predictive values were determined with the second-trimester assessments.. The 6-keto-prostaglandin F(1)(alpha)/thromboxane B(2) ratio decreased throughout pregnancy in women with preeclampsia; there were no significant changes in normotensive women. We found higher thromboxane B(2) levels within the group with preeclampsia during the first gestational trimester (preeclampsia, 188 +/- 17 pg/mL; control, 119 +/- 4.8 pg/mL [mean +/- SEM]; P =.001). During the third trimester, patients with preeclampsia had lower 6-keto-prostaglandin F(1)(alpha) levels than did control subjects (preeclampsia, 191 +/- 9.8 pg/mL; control, 288 +/- 10 pg/mL; P =.001). The 6-keto-prostaglandin F(1)(alpha)/thromboxane B(2) ratio was suitable to calculate predictive values; the best cutoff point and time interval were 3.0 and 22 to 26 weeks of gestation, respectively. Sensitivity, specificity, and positive and negative predictive values were 88%, 97%, 69%, and 99%, respectively; the odds ratio was 14.6 (95% CI, 6.9-30.4).. The prostacyclin/thromboxane ratio favored vasoconstriction early in gestation in women in whom preeclampsia developed. A 6-keto-prostaglandin F(1)(alpha)/thromboxane B(2) ratio of

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Biomarkers; Case-Control Studies; Cohort Studies; Female; Humans; Longitudinal Studies; Odds Ratio; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Reference Values; Sensitivity and Specificity; Thromboxane B2

The objective of this study is to compare the serum levels of fibronectin, nitric oxide (NO), cyclic guanosine-monophosphate, endothelin-1, and 6-keto-prostaglandin-F 1alpha in women with and without preeclampsia before and after delivery.. We studied 20 singleton pregnancies complicated by preeclampsia, and 20 women undergoing elective cesarean delivery were selected as controls. The normalization of circulating concentrations of maternal plasma NO, cyclic guanosine-monophosphate, fibronectin, endothelin-1, thromboxane-B 2 and renin, and urinary 6-keto-prostaglandin-F 1alpha after delivery was evaluated.. Mean systolic and diastolic blood pressure (BP) in the puerperium of preeclamptic women remained high after discharge from hospital, and only circulating fibronectin levels were found to be elevated in affected women at the end of hospital stay 5 days after delivery. Normalization of the imbalance in vasoactive substances and renal impairment in preeclampsia occur more rapidly than the patient's clinical recovery, within 2-3 days postpartum.. Slow normalization of circulating fibronectin concentrations reflects slow recovery of endothelial damage in preeclampsia, which may play a major role in maintaining high BP in the puerperium. Plasma levels of endothelin-1 declined to normal levels by the third postpartum day and the finding is consistent with the hypothesis that endothelin-1 is not the major vasoconstrictor in the pathophysiology of preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Biomarkers; Cesarean Section; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Female; Fibronectins; Humans; Longitudinal Studies; Nitric Oxide; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Time Factors; Vasoconstrictor Agents; Vasodilator Agents

Preeclampsia and fetal growth restriction are associated with poor placental perfusion, which may be accompanied by a compensatory release of vasoactive substances in the fetoplacental circuit. This study examines the effects of preeclampsia and fetal growth restriction on nitric oxide and prostacyclin signaling pathways in fetal endothelial cells.. Human umbilical vein endothelial cells from 30 control pregnancies, 18 pregnancies with preeclampsia, and 9 pregnancies with intrauterine growth restriction were cultured. Intracellular cyclic guanosine monophosphate accumulation and 6-keto-prostaglandin F1alpha production were determined.. Intracellular accumulation of cyclic guanosine monophosphate was significantly higher in the preeclampsia group and lower in the growth restriction group than in the control group (9.8, 1.8, and 3.9 pmol/microg protein for 5 minutes, respectively), whereas 6-keto-prostaglandin F1alpha production was not significantly different in the 3 groups.. The data suggest that the fetoplacental vascular response to preeclampsia is to increase production of cyclic guanosine monophosphate, perhaps to maintain vessel dilatation and maximum flow through placental villi. In fetal growth restriction the umbilical vein endothelial cells do not or cannot respond to chronic hypoxia by increasing cyclic guanosine monophosphate, which may lead to fetoplacental vasoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Arginine; Case-Control Studies; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Female; Fetal Growth Retardation; Humans; Kinetics; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pre-Eclampsia; Pregnancy; Scintillation Counting; Statistics, Nonparametric; Tritium; Umbilical Veins

To determine the in vitro effect of serum from preeclamptic patients on the proliferation, viability and secretion of vasoactive substances by human umbilical vein endothelial cells (HUVEC).. HUVEC were incubated for 24h with sera from 16 preeclamptic, 19 healthy pregnant and 8 healthy nonpregnant women. Proliferation rates were determined by cell counting and vitality by trypan blue staining. The vasoactive substances, 6-keto-prostaglandin F(1alpha), nitrite and nitrate, and endothelin-1 (ET-1) were measured in endothelial cell supernatants.. The preeclamptic serum had no effect on cell proliferation or vitality compared with control sera. It induced more HUVEC production of ET-1, but not of prostacyclin (PGI2) or nitric oxide compared with control serum.. Preeclamptic serum appears to contain a factor(s) that specifically stimulates ET-1 secretion from HUVEC without altering cell growth or vitality.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood; Cell Division; Cells, Cultured; Culture Media; Endothelin-1; Endothelium, Vascular; Female; Humans; Nitrates; Nitric Oxide; Nitrites; Pre-Eclampsia; Pregnancy; Umbilical Veins

Low endothelial generation of prostacyclin (PGI(2)) is a typical feature of pregnancy-induced hypertensive disorders. The aim of the current study was to establish whether changes in PGI(2) are accompanied by alterations in fetoplacental blood flow and to test the hypothesis that PGI(2) deficiency contributes to reduced fetoplacental perfusion in pregnancy-induced hypertension (PIH) and preeclampsia.. The study included 11 women with normal pregnancies, 12 with PIH/preeclampsia, and 7 with otherwise complicated pregnancies. Fetoplacental blood flow was assessed both by umbilical artery Doppler sonography measuring the resistance index (RI) and by means of neonatal birth weight. PGI(2) formation was measured in umbilical arteries prepared immediately after birth. PGI(2), RI and birth weight were correlated with and without correction for gestational age. Furthermore, data from patients with PIH/preeclampsia were compared with normal pregnancies as controls.. A significant inverse correlation was found between umbilical PGI(2) formation and umbilical RI and between birth weight and RI, whereas PGI(2) and birth weight were directly related. Patients with PIH/preeclampsia showed reduced PGI(2) formation, markedly increased gestational age-corrected RI and significantly reduced percentile birth weight.. These results provide evidence showing that PGI(2) is a relevant mediator of fetoplacental blood flow and suggest an important role of PGI(2) deficiency in PIH/preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Birth Weight; Epoprostenol; Female; Fetus; Gestational Age; Humans; Hypertension; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Ultrasonography; Umbilical Arteries; Vascular Resistance

To analyse whether pregnancies resulting in a small for gestational age neonate are preceded by a prostacyclin deficiency or an imbalance between thromboxane and prostacyclin.. At five fixed time points during pregnancy, 24-h urine samples were collected for the measurement of thromboxane and prostacyclin metabolites thromboxane-B(2) (TXB(2)) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)). In order to study trend differences between pregnancies with appropriate (AGA; n=26) and small for gestational age neonates (SGA; n=17), trend analysis with simple contrasts were accomplished for TXB(2), 6-keto-PGF(1alpha) and the TXB(2)/6-keto-PGF(1alpha) ratio.. Trend analysis showed higher TXB(2) levels and higher TXB(2)/6-keto-PGF(1alpha) ratios in patients with SGA versus AGA newborns. No statistically significant difference in 6-keto-PGF(1alpha) excretion between patients with SGA and AGA newborns was detected.. The birth of an SGA neonate is not preceded by prostacyclin deficiency. With ongoing pregnancy an imbalance between thromboxane and prostacyclin becomes more obvious in pregnancies with SGA newborns.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Birth Weight; Female; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Pre-Eclampsia; Pregnancy; Thromboxane B2

To study the effect of plasma from women with preeclampsia on endothelial cell activators in vitro and determine whether factor(s) in the plasma of women with preeclampsia induces activation of vascular endothelial cells.. Twenty women with preeclampsia and 15 normal ones at late trimester of pregnancy were studied, from whom maternal venous blood samples were collected. Plasma 6-keto-PGF1 alpha, the end products of prostacyclin (PGI2) and TXB2, the end products of thromboxane A2(TXA2), were measured by radioimmunoassay. Plasma from women with preeclampsia or from normal women at late trimester was added to the bovine pulmonary microvessel endothelial cells in vitro. Twenty-four hours later, levels of 6-keto-PGF1 alpha produced by cultured endothelial cells were measured.. The mean values of 6-keto-PGF1 alpha in matrnal venous plasma were (94.49 +/- 25.23) ng/L in preeclamptic group and (248.81 +/- 51.99) ng/L in normal pregnant group. Plasma TXB2 values were (104.61 +/- 13.12) ng/L in preeclamptic group and (66.26 +/- 38.80) ng/L in normal pregnant group. TXB2/6-keto-PGF1 alpha ratios were (1.11 +/- 0.03) in preeclamptic group and (0.28 +/- 0.02) in normal pregnant group. Maternal plasma values of 6-keto-PGF1 alpha were lower in peeclamptic group than those of normal pregnant group (P < 0.01). On the other hand, plasma TXB2 values were higher in preeclamptic group than in normal pregnant group (P < 0.01). TXB2/6-keto-PGF1 alpha ratios, however, were significantly different between the two groups (P < 0.01). The values of 6-keto-PGF1 alpha produced by cultured endothelial cells exposed to 2% plasma were (1,363.00 +/- 99.16) ng/L in preeclamptic group and (819.49 +/- 96.62) ng/L in normal pregnant group (P < 0.01).. PGI2 and TXA2 may play an important role in preeclampsia. Plasma from women with preeclampsia could stimulate the production of prostacyclin in cultured endothelial cells in vitro.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Endothelium, Vascular; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2; Thromboxane B2

An imbalance in vasodilating (prostacyclin [PGI2]) and vasoconstricting (thromboxane A2 [TxA2]) eicosanoids may be important in preeclampsia, but prospective data from large studies needed to resolve this issue are lacking. Because most trials using aspirin to reduce TxA2 production have failed to prevent preeclampsia, it is critical to determine whether eicosanoid changes occur before the onset of clinical disease or are secondary to clinical manifestations of preeclampsia.. To determine whether PGI2 or TxA2 changes occur before onset of clinical signs of preeclampsia.. Multicenter prospective study from 1992 to 1995 of subjects from the placebo arm of the Calcium for Preeclampsia Prevention Trial. Women who developed preeclampsia (n = 134) were compared with matched normotensive control women (n = 139).. Excretion of urinary metabolites of PGI2 (PGI-M) and TxA2 (Tx-M) as measured from timed urine collections obtained prospectively before 22 weeks', between 26 and 29 weeks', and at 36 weeks' gestation.. Women who developed preeclampsia had significantly lower PGI-M levels throughout pregnancy, even at 13 to 16 weeks' gestation (long before the onset of clinical disease); their gestational age-adjusted levels were 17% lower than those of controls (95% confidence interval [CI], 6%-27%; P=.005). The Tx-M levels of preeclamptic women were not significantly higher overall (9% higher than those of controls; 95% CI, -3% to 23%; P=.14). The ratio of Tx-M to PGI-M, used to express relative vasoconstricting vs vasodilating effects, was 24% higher (95% CI, 6%-45%) in preeclamptic women throughout pregnancy (P=.007).. Our results show that reduced PGI2 production, but not increased TxA2 production, occurs many months before clinical onset of preeclampsia. Aspirin trials may have failed because an increase in thromboxane production is not the initial anomaly. Future interventions should make correcting prostacyclin deficiency a major part of the strategy to balance the abnormal vasoconstrictor-vasodilator ratio present in preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Biomarkers; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Prospective Studies; Randomized Controlled Trials as Topic; Thromboxane A2; Thromboxane B2

A disturbance of prostacyclin (PGI2) and thromboxane A2 (TXA2) balance has been reported in preeclampsia. However, little is known about the concentrations of these prostanoids in neonates born to preeclamptic pregnant women. The purpose of this study is to determine whether the PGI2 and TXA2 concentrations are altered and whether the prostanoid balance correlates to the cerebral blood flow in neonates born to preeclampsia.. Spontaneously voided urine samples were collected from 20 neonates of normotensive and 16 neonates of preeclamptic women during the first 24 h after birth. We measured by radioimmunoassay the concentrations of urinary 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) and 11-dehydro-thromboxane B2 (11-dehydro-TXB2), respectively. Blood flow velocity in the middle cerebral artery was studied by pulsed Doppler ultrasonography in the neonates between 17 and 38 h after birth.. There was no significant difference between the urinary 6-keto-PGF1alpha in the neonates of mothers with and without preeclampsia (median, 5.3 vs. 3.6 ng/mg of creatinine). In contrast, the urinary 11-dehydro-TXB2 and the ratio of 11-dehydro-TXB2 to 6-keto-PGF1alpha in the neonates of mothers with preeclampsia were significantly lower as compared with the neonates without preeclampsia, respectively (13.7 vs. 20.6 ng/mg of creatinine and 3.0 vs. 5.2, median). The resistance index in the middle cerebral artery was significantly reduced in the neonates with preeclampsia than without preeclampsia (0.67 +/- 0.01 vs. 0.74 +/- 0.02, mean +/- SEM).. There was an association between maternal preeclampsia and the imbalance in the neonatal urinary excretion of PGI2 and TXA2 metabolites. This imbalance may contribute to the regulation of cerebral blood flow.

Topics: 6-Ketoprostaglandin F1 alpha; Cerebrovascular Circulation; Female; Humans; Infant, Newborn; Pre-Eclampsia; Pregnancy; Thromboxane B2

This study aimed to identify those factors in the non-pregnant state that distinguished women who developed pre-eclampsia from those who had normotensive pregnancies.. This was a retrospective analysis of anthropometry, blood pressure, biochemical and haematological variables in 62 women with pre-eclampsia and 84 normotensive pregnant women who took part in studies of the pathophysiology of pre-eclampsia. Pregnant volunteers were seen, after admission to hospital or in the outpatient clinic, and followed-up at 6 weeks and 6 months post-partum in the outpatient clinic or their home. Participants Proteinuric pre-eclampsia was defined as blood pressure > or = 140/90 mmHg with proteinuria of at least 300 mg/24 h after 20 weeks gestation, in women with no history of hypertension and whose blood pressure returned to normal levels by 6 months post-partum. Normotensive pregnancy was defined as blood pressure < 130/90 mmHg without proteinuria.. The primary outcome measures were blood pressure, body mass index (BMI), triglycerides, total cholesterol, low density lipoprotein (LDL) and high density lipoprotein cholesterol and markers of severity of pre-eclampsia.. Regardless of parity, women with pre-eclampsia had elevated BMI before, during and after pregnancy compared with women who had normotensive pregnancies. Triglycerides were significantly elevated in women who had pre-eclampsia both before and after delivery, while total and LDL cholesterol were elevated significantly at both visits after delivery. Systolic and diastolic blood pressure, which by definition were elevated antepartum in women with pre-eclampsia, remained higher at post-partum visits compared with women who had normotensive pregnancies. Women with pre-eclampsia reported a greatly increased frequency of both maternal hypertension and pre-eclampsia. Markers of severity of pre-eclampsia, which normalized by 6 months postpartum, included plasma creatinine, uric acid, albumin, endothelin 1 and urinary protein, 2,3, dinor-6-keto-PGF1alpha, blood platelet and neutrophil counts.. The relative elevation of blood pressure, BMI and lipids in the non-pregnant state are features of the metabolic syndrome and may be important sensitizing factors contributing to the pathogenesis of pre-eclampsia. A familial predisposition to pre-eclampsia may operate partly through these mechanisms.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Body Mass Index; Causality; Creatinine; Endothelin-1; Female; Heart Rate; Humans; Hyperlipidemias; Hypertension; Lipids; Parity; Pre-Eclampsia; Pregnancy; Retrospective Studies; Serum Albumin; Uric Acid

In order to evaluate whether lipid abnormalities may contribute to endothelial dysfunction in pre-eclampsia, the present study examined the in vitro effects of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), isolated from women with pre-eclampsia and matched controls, on the endothelial synthesis of 6-oxo-prostaglandin F(1alpha) (6-oxo-PGF(1alpha); a metabolite of prostacyclin) and endothelin 1, and on the expression of nitric oxide synthase 3 (NOS3) mRNA. VLDL, LDL and HDL cholesterol were isolated from 20 pre-eclamptic and 20 age- and gestation-matched normal pregnant women. The lipoproteins (50 microgram/ml) and lipoprotein-free control plasma were incubated for 1, 3 and 6 h at 37 degrees C with a human umbilical endothelial cell line. The synthesis of 6-oxo-PGF(1alpha) and endothelin 1, and NOS3 mRNA expression, were measured at each time point. VLDL from pre-eclamptic women stimulated endothelial cell 6-oxo-PGF(1alpha) synthesis to a lesser extent than that from normal pregnant women (P<0.05). LDL from women with pre-eclampsia also stimulated 6-oxo-PGF(1alpha) synthesis to a lesser extent than LDL from normal pregnant women, but the effect was less sustained. The effect of HDL from women with pre-eclampsia on 6-oxo-PGF(1alpha) synthesis was similar to that of HDL from normal pregnant women. The pre-incubation levels of lipid peroxides in VLDL and LDL were not different between the normal pregnant and pre-eclamptic women, and cannot account for the decrease in 6-oxo-PGF(1alpha) synthesis. VLDL, LDL and HDL from women with pre-eclampsia did not affect endothelial cell synthesis of endothelin 1 or expression of NOS3 mRNA differently from lipoproteins from normal pregnant women. This study suggests that VLDL, and to a lesser extent LDL, from women with pre-eclampsia could potentially contribute to the reduced systemic 6-oxo-PGF(1alpha) synthesis observed in the pre-eclamptic syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Case-Control Studies; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Female; Gene Expression; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Polymerase Chain Reaction; Pre-Eclampsia; Pregnancy; RNA, Messenger; Statistics, Nonparametric; Time Factors

Our purpose was to determine placental interleukin (IL)-8 production and its correlation with the prostacyclin production in normal and preeclamptic pregnancies and to evaluate the beneficial effect of IL-8 on prostacyclin production.. We determined 1) the in vitro production of IL-8 and prostacyclin by placental villous tissues from normal and preeclamptic pregnancies and 2) the production of prostacyclin by villous tissues from preeclampsia treated with recombinant human IL-8 (rhIL-8). IL-8 levels were measured by enzyme-linked immunosorbent assay and prostacyclin by radioimmunoassay of 6-keto PGF1alpha, the stable metabolite of prostacyclin.. 1) Placental production of IL-8 and 6-keto PGF1alpha were significantly less in preeclampsia than in normal pregnancies, P<0.05. 2) Placental production of 6-keto PGF1alpha and IL-8 was significantly correlated in preeclampsia, P<0.01. 3) Placental tissues treated with IL-8 exhibited a concentration-dependent increase in 6-keto PGF1alpha production.. Placental tissues from preeclampsia produce significantly less IL-8 than tissues from normal pregnancies, which correlates with decreased prostacyclin production. IL-8 improves placental prostacyclin production in preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Interleukin-8; Placenta; Pre-Eclampsia; Pregnancy

To study the role of tumor necrosis factor (TNF-alpha) in the pathogenesis of pregnancy induced hypertension (PIH).. Radioimmunoassay was used to measure the levels of TNF-alpha in 25 severe PIH patients and 25 normal pregnant women. Umbilical vein endothelial cells were cultured with TNF-alpha (500 U/ml) or without TNF-alpha. The concentration of endothelin-1 (ET-1), 6-ket-PGF1 alpha, nitrite (NO2-), expression of fibronectin(FN) and white blood cells adhesion to the surface of endothelial cells test were measured.. The levels of TNF-alpha in serum of severe PIH patients were significantly higher than that of normal pregnant women (P < 0.05). In endothelium culture supernatant with TNF-alpha group, synthesis of ET-1, NO2- and 6-ket-PGF1 alpha increased, expression of FN on the surface of endothelial cells decreased, white blood cells adhesion to endothelial cells increased. There was significant difference between TNF-alpha group and control group.. TNF-alpha may be involved in the pathogenesis of PIH.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Female; Humans; Infant, Newborn; Pre-Eclampsia; Pregnancy; Tumor Necrosis Factor-alpha; Umbilical Veins

To study the effect of the inhibition of nitric oxide(NO) synthesis on plasma endothelin (ET), prostaglandlin I2(PGI2), thromboxane (TXA2) and angiotensin (ANGII) in pregnant rats, and to investigate the role of these factors in the pathogenesis of pregnancy-induced hypertension(PIH).. Pregnant rats were divided into two groups randomly. Saline solution or L-nitro arginine methyl ester (L-NAME) 125 mg/day was given subcutaneously from day 14 of gestation till delivery. Systolic blood pressure, urine protein, platelet count, and weight of pups and placentae were determined. Plasma NO, ET, PGI2, TXA2 and ANGII were measured by RIA.. Pregnant rats which were given L-NAME produced physical signs similar to those of PIH, such as increase in systolic blood pressure (140.6 +/- 3.8) mmHg and urine protein (801.38 +/- 57.12) mg/L, and decrease in platelet count (533 +/- 42) x 10(9)/L and weight of pups and placentae. Compared with controls, plasma NO, PGI2 and ANG II were decreased significantly while plasma ET and TXA2 were increased significantly in rats given L-NAME.. Inhibition of NO synthesis can cause imbalance of several vaso-regulatory factors, which may be responsible for the pathogenesis of PIH.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Endothelin-1; Female; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pre-Eclampsia; Pregnancy; Random Allocation; Rats; Rats, Wistar; Vasodilation

The objectives of this study were to evaluate the possible mechanisms involved in prolongation of bleeding time in pre-eclamptic patients receiving a magnesium sulfate infusion to prevent convulsions. Eighteen pre-eclamptic patients near term or at term (4 cases 33 to 35 weeks; the remainder > 36 weeks) were studied. Fifteen of them received magnesium sulfate infusion; 3 did not and served as controls. Bleeding time (modified Ivy method with Surgicutt), platelet count, platelet aggregation pattern, as well as serum arachidonic acid metabolites [thromboxane B2 (TxB2) and 6-Keto-prostaglandin F1 alpha (6-Keto-PGF1 alpha)] werde done on admission to the labor floor (before magnesium infusion) and repeated at discontinuation of the infusion, 12-24 hours postpartum; the controls received the second test 24 hours postpartum. Thirteen of 15 patients receiving magnesium sulfate had an increase in bleeding time from an average of 6 minutes 31 seconds to 11 minutes 56 seconds, an 82% rise (p < 0.004). In 2 there was a decrease. Among the 3 controls the averages were 6 minutes 38 seconds and 6 minutes 3 seconds. The total magnesium given ranged from 52.5 to 145 grams. Platelet counts averaged 251,000/mm3 (range 145,000-519,000). Platelet aggregation pattern done in 11 patients and was normal and unchanged after magnesium in 10 of the patients with increased bleeding time and one control. TxB2 and 6-Keto-PGF1 alpha levels did not change significantly either after magnesium administration (688 and 135 pgm/ml, to 654 and 117) or in controls (695 and 230 pgm/ml, to 445 and 225). Likewise, the ratio of these 2 substances did not change in either group (6.3 to 6.6, and 4.2 to 2.2). There was no correlation between duration of infusion or total magnesium given and directions of small changes observed. This study confirms a prior preliminary observation that magnesium sulfate infusion, as currently used to prevent eclamptic convulsions, induces a significant prolongation of bleeding time. This effect is mediated neither by changes in platelets count or aggregation pattern, nor by changing the level or ratios of serum arachidonic acid metabolites (TxB2 and 6-Keto-PGF1 alpha). Further studies are needed to clarify the mechanism of this clinically important observation of increased bleeding following magnesium sulfate infusion.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Bleeding Time; Female; Gestational Age; Humans; Magnesium Sulfate; Platelet Aggregation; Platelet Count; Postpartum Hemorrhage; Pre-Eclampsia; Pregnancy; Seizures; Thromboxane B2

The objective of this study was to evaluate the extent to which endothelin and the eicosanoids prostacyclin and thromboxane A2 are involved in the pathophysiology of gestational hypertension and preeclampsia.. In a longitudinal design, venous blood samples and 24-hour urine specimens were collected from 396 women in each trimester of pregnancy. After delivery of all patients, venous plasma endothelin was assessed in 20 subjects with identified preeclampsia, 48 subjects with gestational hypertension, and 59 normotensive subjects. Urinary excretions of the thromboxane A2 and of the prostacyclin metabolites thromboxane B2 and 6-keto-prostaglandin F1 alpha were assessed in 16 subjects with preeclampsia, 35 subjects with gestational hypertension, and 31 normotensive subjects.. Endothelin levels showed a second-trimester drop in all groups. In all 3 gestational trimesters a high correlation was found between the excretion of thromboxane B2 and that of 6-keto-prostaglandin F1 alpha (P <.001). The overall thromboxane B2 and 6-keto-prostaglandin F1 alpha urinary excretions increased throughout pregnancy and the overall thromboxane B2 /6-keto-prostaglandin F1 alpha ratio decreased. No significant differences in endothelin, thromboxane B2, and 6-keto-prostaglandin F1 alpha excretion levels or in thromboxane B2 /6-keto-prostaglandin F1 alpha ratios were found between women with preeclampsia, gestational hypertension, and normotension. Only in a small group of patients with severe preeclampsia (n = 2) and severe gestational hypertension (n = 2) were increased second-trimester endothelin values and increased thromboxane B2 /6-keto-prostaglandin F1 alpha ratios found.. In this longitudinal study we found no evidence for prostacyclin deficiency or increased endothelin levels in preeclampsia. Only women with severe preeclampsia and severe gestational hypertension expressed increased endothelin levels and thromboxane dominance over prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Eicosanoids; Endothelins; Female; Humans; Hypertension; Longitudinal Studies; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values; Thromboxane A2; Thromboxane B2

In order to investigate the pathophysiological significance of anti-endothelial cell antibody (AECA) in pre-eclampsia, the effects of AECA on endothelin-1 (ET-1) and prostaglandin I2 (PGI2) release from cultured human umbilical vein endothelial cells (HUVEC) was evaluated. Serum samples were taken from 85 pre-eclamptic and 20 normal pregnant women. Anti-endothelial cell antibody was measured by ELISA using HUVEC. The release of ET-1 and 6-keto PGF1-alpha, a stable metabolite of PGI2, from HUVEC were evaluated after incubation with IgG-AECA-positive sera and IgG isolated from AECA-positive sera. The incidence of IgG- and IgM-AECA was 24.7 and 8.2%, respectively. The release of ET-1, in the medium containing IgG-AECA-positive sera was significantly greater than in the medium containing IgG-AECA-negative sera. There was significant correlation between the levels of IgG-AECA and the release of ET-1 from endothelial cells. The ET-1 release by IgG isolated from AECA-positive sera was greater than that from AECA-negative sera. However, the release of 6-keto PGF1-alpha by AECA-positive sera was not significantly different from that of AECA-negative sera. It is concluded that IgG-AECA in pre-eclampsia increases ET-1 release from endothelial cells and that AECA may affect local vascular function in this disorder.

Topics: 6-Ketoprostaglandin F1 alpha; Autoantibodies; Cells, Cultured; Dose-Response Relationship, Immunologic; Endothelin-1; Endothelium, Vascular; Female; Humans; Immunoglobulin G; Interleukin-1; Pre-Eclampsia; Pregnancy; Time Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Our purpose was to determine whether serum from women with preeclampsia or gestational hypertension (1) decreased endothelial cell prostacyclin, (2) increased endothelial cell endothelin, and (3) caused endothelial cell damage.. Production of 6-keto-prostaglandin F1 alpha and endothelin by cultured endothelial cells was measured after 48 hours' incubation with sera from 23 nonpregnant women, 23 normal pregnant women, 12 women with preeclampsia, and 11 women with gestational hypertension. Structure damage of endothelial cells was assessed by a chromium release assay.. Serum from normal pregnant women induced more endothelial prostacyclin but less endothelin than did serum form nonpregnant women (p<0.05). No difference was found between normal pregnant and hypertensive pregnant women for prostacyclin production, but serum of preeclamptic women induced less endothelin production than did that of normal pregnant women (p<0.05). Chromium 51 release by endothelial cells was similar between normal pregnant and hypertensive pregnant groups.. Serum from preeclamptic women stimulates less endothelin production than does serum from normal pregnant women but does not alter prostacyclin production and is not cytotoxic to endothelial cells after short-term incubation.

Topics: 6-Ketoprostaglandin F1 alpha; Blood; Cell Membrane; Cells, Cultured; Chromium Radioisotopes; Culture Media; Endothelins; Endothelium, Vascular; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Umbilical Veins

The aim of the study was to investigate whether pre-eclampsia is associated with an altered release of vasoactive substances from trophoblastic cells in vitro. Trophoblastic cells from 15 uncomplicated control pregnancies and 18 pre-eclamptic pregnancies at preterm (weeks 31-36; n = 12) and term (weeks 37-40; n = 21) were cultured for 5 days. The concentrations of angiotensin II (AII), endothelin-1,2 (ET-1,2), thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene B4 (LTB4) were measured daily in culture media for 5 days by radioimmunoassay. In pre-eclampsia, concentrations of ET-1,2 were decreased (P < 0.01) at both preterm and term, TXB2 concentrations were increased (P < 0.05) only at preterm and the TXB2-6-keto-PGF1 alpha ratio was increased at both preterm and term (P < 0.01) as compared with the controls. Concentrations of AII, 6-keto-PGF1 alpha and LTB4 were similar to the controls. The data suggest that pre-eclampsia is associated with a decreased release of ET-1 and an increased release of TXB2 from trophoblastic cells in vitro.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cell Survival; Cells, Cultured; Endothelins; Epoprostenol; Female; Humans; Immunohistochemistry; Leukotriene B4; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Thromboxane A2; Thromboxane B2; Trophoblasts; Vasodilator Agents

Little is known about the pathophysiological processes leading to superimposed preeclampsia. We present an animal model where the uteroplacental blood flow in spontaneously hypertensive rats (SHR) was reduced by a silver clip. Thus, a superimposed preeclampsia-like syndrome could be studied under defined conditions. Urinary excretion of 2,3-dinor-6-keto PGF1 alpha and 11-dehydro-TxB2 were measured by enzyme immunoassays at day 16 and 20 of pregnancy. In gravid, sham-operated animals excretion of 2,3-dinor-6-keto-PGF1 alpha was largely elevated compared to non gravid control animals (day 16: 1259 vs. 258 ng/kg 24h; day 20: 471 vs. 269 ng/kg.24h). However, in the gravid rats with reduced uteroplacental blood flow urinary excretion of 2,3-dinor-6-keto-PGF1 alpha decreased to non gravid levels (day 16: 335 ng/kg.24h; day 20: 238 ng/kg.24h). By antihypertensive therapy with dihydralazin this effect was largely abolished. Only minor alterations were found in the excretion of 11-dehydro-TxB2. Our findings suggest, that a reduction of uteroplacental blood flow in the spontaneously hypertensive rat decreases the systemic prostacyclin synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Dihydralazine; Disease Models, Animal; Female; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Inbred SHR; Thromboxane B2

Villous trophoblasts isolated from term placentae of normal pregnancies, and pregnancies complicated by chronic hypertension or pre-eclampsia, were examined over 7 days in primary culture. Low levels of prostaglandin E2 and prostacyclin (measured as 6-keto prostaglandin Fl alpha) were secreted by trophoblast cells from all three clinical groups. Secretion was maximal at day 1 and decreased exponentially thereafter. Thromboxane secretion also fell sequentially from day 1. Thromboxane secretion by pre-eclamptic trophoblasts was three to four times that of cells from normal or chronically hypertensive subjects. Prostanoid secretion by isolated cultured cytotrophoblasts was not dependent on aggregation or morphological alteration, nor related to changes in progesterone or human chorionic gonadotrophin production. Because the local maternal circulation is exposed to substances secreted by this cell population, thromboxane could be the trigger for vasoconstriction and coagulation found within the maternal uteroplacental circulation in pre-eclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Cells, Cultured; Chorionic Gonadotropin; Dinoprostone; Epoprostenol; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Progesterone; Prostaglandins; Thromboxanes; Trophoblasts

Increasing circumstantial evidence suggests that the maternal endothelial cell is centrally involved in the syndrome of preeclampsia, and a number of reports have described the presence of a factor(s) that alters endothelial cell function in serum from women with preeclampsia. We have previously described differences between endothelial cells from the decidual vascular bed and those from the umbilical vein. The purposes of this study were (1) to examine the effect of serum from normal and preeclamptic women on secretion of vasoactive substances by maternal decidual endothelial cells, (2) to compare these results with those from umbilical vein endothelial cells, widely used as a surrogate for endothelial cells in general, (3) to compare responses to these sera by decidual endothelial cells from normal and preeclamptic pregnancies, and (4) to determine whether these responses are amplified by preincubation in test sera.. Endothelial cells were isolated from umbilical veins and from decidual biopsy specimens collected at caesarean section delivery, from both normal and preeclamptic women. Cells were maintained in culture until passage 2, when secretion by the three endothelial cell populations of the vasodilator prostacyclin (measured as its stable metabolite, 6-keto-prostaglandin F1 alpha) and the vasoconstrictor endothelin-1 was compared in the presence of serum from preeclamptic or gestational age-matched normal pregnant women.. Prostacyclin secretion by all endothelial cell populations was higher in the presence of serum from preeclamptic women than in medium containing serum from gestational age-matched normal pregnant women. Values for endothelin were not significantly different in cells incubated in serum from normal or preeclamptic women. Preincubation of decidual cells from preeclamptic women in test serum, particularly in preeclamptic serum, resulted in more marked stimulation of prostacyclin secretion.. Preeclamptic serum contains a factor(s) that stimulates prostanoid secretion from endothelial cells. This effect was observed in both umbilical vein and decidual cells. Cells from preeclamptic women were more susceptible to perturbation of their secretion by this factor. Serum from preeclamptic women did not specifically affect endothelin-1 secretion.

Topics: 6-Ketoprostaglandin F1 alpha; Blood; Cells, Cultured; Decidua; Endothelins; Endothelium, Vascular; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy

Placentas obtained from women with preeclampsia produce more lipid peroxides and more thromboxane, but less prostacyclin, than normal. The tissue compartments within the placenta that are responsible for this are not known. The placenta is a heterogeneous tissue compartmentalized into trophoblast cells and villous core tissue that is comprised of stromal and vascular tissue. In this study we determined the placental compartments responsible for increased production of lipid peroxides and thromboxane in preeclampsia. Placentas were obtained from six normally pregnant women and seven women with preeclampsia. Trophoblast cells and villous core tissues were isolated and incubated in Dulbecco's Modified Eagle's Medium for 48 h. Samples were collected at 0, 2, 6, 16, 28, and 48 h of incubation and analyzed spectrophotometrically for lipid peroxides by a peroxide equivalent assay and for thromboxane and prostacyclin by RIA of their stable metabolites, thromboxane-B2 and 6-keto-prostaglandin-F1 alpha. Trophoblast cells isolated from preeclamptic placentas produced significantly more lipid peroxides (1972 +/- 502 vs. 1102 +/- 335 pmol/micrograms protein after 48 h of incubation), more thromboxane (328 +/- 57 vs. 153 +/- 53 pg/microgram at 48 h), and more prostacyclin (50 +/- 11 vs. 13 +/- 3 pg/microgram at 48 h, respectively) than trophoblast cells isolated from normal placentas. Villous core tissue isolated from preeclamptic placentas produced significantly more lipid peroxides (455 +/- 107 vs. 241 +/- 34 pmol/microgram) and more thromboxane (148 +/- 51 vs. 76 +/- 14 pg/microgram) than normal villous core tissue, but there was no difference in prostacyclin production (36 +/- 11 vs. 40 +/- 9 pg/microgram). Because of the increase in thromboxane production, the ratio of thromboxane to prostacyclin was higher in preeclamptic than normal villous core tissue (6.29 vs. 2.17). Comparison of production by different compartments within the placenta demonstrated that lipid peroxides and thromboxane were primarily produced by the trophoblast cells and stromal tissue, whereas prostacyclin was primarily produced by the vascular tissue. We conclude that increased placental production of lipid peroxides and thromboxane in preeclampsia originates from both the trophoblast cell and the villous core compartments. As the placenta secretes lipid peroxides, the trophoblast cells could be a source of increased lipid peroxides in the maternal circulation of women with preeclampsia. The

Topics: 6-Ketoprostaglandin F1 alpha; Arteries; Epoprostenol; Female; Humans; Kinetics; Lipid Peroxides; Placenta; Pre-Eclampsia; Pregnancy; Thromboxane B2; Trophoblasts

By combining serial measurements of the circulating concentrations of thromboxane A2 and prostacyclin with measurements of venous distensibility (taken during the pregnancies of both normal women and those with pregnancy induced hypertension or pre-eclampsia), to test the following hypotheses: 1. that changes in the venous plasma ratio of thromboxane (TXB2) and 6-keto-PGF1 alpha would correlate with changes in the blood pressure of women developing and recovering from pregnancy induced hypertension or pre-eclampsia and 2. that changes in venous distensibility would correlate with changes in arterial blood pressure in pregnancy induced hypertension or pre-eclampsia.. Prospective, longitudinal cohort study.. John Hunter Hospital clinic, Newcastle, Australia.. One hundred and sixty primiparous women, recruited when presenting for their first routine antenatal visit, were investigated at, or close to, 19, 28 and 37 weeks of gestation; a subgroup was also studied in the postnatal period. The measurements of the patients who developed pregnancy induced hypertension or pre-eclampsia were compared with those of controls selected from the cohort.. Serial measurements of the circulating concentrations of the stable metabolites of thromboxane A2 and prostacyclin (TXB2 and 6-keto-PGF1 alpha, respectively), venous distensibility and immediate (no rest) and resting (for at least 30 min) blood pressures.. There was no significant difference between the subject and control groups at any time during or after the pregnancy in the concentrations of prostaglandin metabolites, their ratio or venous distensibility. In contrast, there was a significant difference between the groups at 19 weeks for immediate and resting readings of diastolic pressure (6 mmHg (95% CI 1.5 to 10.5) and 4 mmHg (95% CI 0.1 to 7.9), respectively). These differences increased through the pregnancy but mean postnatal readings for the groups were almost identical suggesting that the subjects were not intrinsically hypertensive compared with controls. Blood pressures for the subject group, both immediate and resting, were significantly different from the 19 week readings at 28 weeks (diastolic) and at 37 weeks (systolic and diastolic). The only significant change from first readings among controls was in postnatal systolic pressure which was significantly higher than 19 week values, probably reflecting the vasodilatation, with accompanying hypotension, of early, normal pregnancy. This difference was not observed in those who subsequently developed pregnancy induced hypertension or pre-eclampsia.. Our study was unable to demonstrate differences in circulating metabolites or venous distensibility between normotensive women and those with pregnancy induced hypertension or pre-eclampsia. If pregnancy induced hypertension or pre-eclampsia in humans represents not so much the presence of abnormal constrictor influences as a process initiated by failure of normal vasodilatation in early pregnancy, studies carried out later may detect mainly adaptive and secondary changes.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Cohort Studies; Elasticity; Female; Hand; Humans; Hypertension; Longitudinal Studies; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, First; Pregnancy Trimester, Second; Prospective Studies; Thromboxane A2; Thromboxane B2; Veins

Determinations of total calcium, total magnesium, calcium ion, parathyroid hormone and 6-keto-prostaglandin-F1 alpha levels were carried out on 84 blood samples from 4 groups of women categorised as non-pregnant normotensive (NNP), pregnant normotensive (NP), pregnancy-induced hypertension (PIH) and pre-eclampsia (PE). PIH was clinically diagnosed when the diastolic pressure was more than 90 mmHg and was only hypertensive during pregnancy while PE was with additional proteinuria after 20 weeks of gestation. Compared to NNP women, total calcium and parathyroid hormone levels were of lower levels (p < 0.05) in NP women while in PIH women, total calcium and 6-keto-prostaglandin-F1 alpha levels were also lowered (p < 0.05). Compared to NNP women, PE women's levels of total calcium, calcium ion and 6-keto-prostaglandin-F1 alpha decreased (p < 0.05) while parathyroid hormone level increased (p < 0.05). When compared to the NP women, PE women had decreased levels (p < 0.05) of total calcium as well as calcium ion and increased level (p < 0.05) of parathyroid hormone. Calcium ion was found to be negatively correlated (NNP : r = -0.883, p = 0.008/NP : r = -0.931, p = 0.000) while parathyroid hormone was positively correlated (NNP : r = 0.904, p = 0.013/NP : r = 0.913, p = 0.000) with mean arterial pressure.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Calcium; Female; Humans; Hypertension; Infant, Newborn; Iron; Magnesium; Parathyroid Hormone; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values; Trace Elements

The aim of the present study was to assess whether changes in prostacyclin (PGI2) and thromboxane (TXA2) generation precede the manifestation of pregnancy-induced hypertension (PH). The metabolites 6-oxo-PGF1 alpha and TXB2 were measured in the urine of 69 randomly selected pregnant women from 16-20 weeks of gestation (wg) until delivery and more than 6 weeks postpartum. Between 16-20 and 21-24 wg 6-oxo-PGF1 alpha excretion did not change in patients who later developed PIH (n = 6) but increased significantly in the control group (n = 63). In contrast, a marked rise in TXB2 excretion was found in the PIH group but not in controls. Thereafter significant differences between both groups persisted from 25 wg until delivery. The 6-oxo-PGF1 alpha/TXB2 ratio was below the 10th percentile from 21-24 wg until delivery in patients with developing PIH. The excretion of both metabolites was substantially lower in the non-pregnant state without any difference between patient groups. These results show an altered urinary excretion of both 6-oxo-PGF1 alpha and TXB2 preceding the onset of the disease. A pathophysiological role of PGI2 deficiency and increased TXA2 formation in PIH appears substantiated.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Postpartum Period; Pre-Eclampsia; Pregnancy; Prospective Studies; Thromboxane B2

Pregnancy-induced hypertension is no uniform disease with one cause and one pathophysiologic course. On the contrary it seems to be a multifactorial event with a very different symptomatology and a variable damage of various organs. Because of the heterogeneity of the disease and the difficulty of differentiation these various kinds of courses clinical studies, mostly retrospectively done, have to be criticized. The aim of this study is to examine vasoactive regulation systems by means of a standardized animal model, using wistar rats. A systemic hypertension could be achieved only in pregnant animals with aid a infrarenal aortic stenosis. Non pregnant and simulated operated pregnant animals are the control group. In the normotensive pregnant rats there was an elevation of all renal prostanoids: PGI2, TxB2 and PGE2. On the contrary hypertensive pregnant rats showed a decrease of all eicosanoids, prononcigated of PGE2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Disease Models, Animal; Epoprostenol; Female; Gestational Age; Homeostasis; Hypertension; Kidney; Pre-Eclampsia; Pregnancy; Prostaglandins; Rats; Rats, Wistar; Thromboxane B2

1. Pre-eclampsia is characterized by reduced plasma active renin concentration and renal prostacyclin production. The aim of this study was to determine whether the plasma active renin concentration could be stimulated in women with pre-eclampsia by intravenous frusemide, which stimulates renin acutely through a prostacyclin-mediated mechanism. 2. Plasma active renin concentration, plasma aldosterone concentration, haematocrit and urinary sodium, creatinine and 6-keto-prostaglandin F1 alpha were measured before (0) and 15, 30 and 60 min after intravenous frusemide in 10 non-pregnant women, 10 normal pregnant women and nine women with pre-eclampsia. Six normal pregnant and six non-pregnant women underwent the same measurements after injection of 2ml of saline to control for effects of time and posture. 3. Baseline plasma active renin concentration (but not plasma aldosterone concentration) was lower in pre-eclamptic women [4.0 (1.7-6.2) pmol of angiotensin I h-1 ml-1; median (interquartile range)] than in normal pregnant women [6.7 (5.3-12.2) pmol of angiotensin I h-1 ml-1] (P < 0.05). Baseline urinary 6-keto-prostaglandin F1 alpha/creatinine ratio, urinary sodium excretion and fractional sodium excretion did not differ between normal pregnant and pre-eclamptic women. 4. After frusemide, plasma active renin concentration rose significantly in non-pregnant (P = 0.002) and normal pregnant (P = 0.008) women, but not in women with pre-eclampsia. Individual results showed stimulation in all non-pregnant and normal pregnant women but in only six out of nine pre-eclamptic women, significantly fewer than in normal pregnancy (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Aldosterone; Female; Furosemide; Hematocrit; Humans; Pre-Eclampsia; Pregnancy; Renin; Sodium

The aim of the present study was to investigate the occurrence of changes in the plasma levels of vasoactive prostanoids and inhibitors of blood coagulation in normal pregnancy and in cases of pregnancy induced hypertension. Levels of the coagulation inhibitors antithrombin III, protein C, Protein S as well as the prostaglandin metabolites thromboxane B2 and 6-oxo-prostaglandin F1 alpha were measured between 13 and 37 weeks gestation in 36 primigravidae. In 8 of the examined patients persistently raised blood pressure values of 140/90 and above were measured after 20 weeks of gestation. Our results indicated that an imbalance of vasoactive prostanoids may precede the appearance of clinical symptoms of PIH. The determination of coagulation factors before blood pressure is elevated has no predictive value regarding the later development of PIH. The reduced levels of protein C associated with our PIH group are considered to be the result of an activated coagulation followed by consumption of clotting factors. Reduced measured levels of protein S in normotensive as well as hypertensive pregnancies offer an explanation for the increased risk of thromboembolic disease. This increased susceptibility to thromboembolic disorders is further enhanced by the altered balance between the platelet aggregator and vasoconstrictor thromboxane A2 and its antagonist prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Antithrombin III; Antithrombins; Epoprostenol; Female; Humans; Hypertension; Infant, Newborn; Longitudinal Studies; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Prostaglandins; Protein C; Protein S; Thromboxane A2; Thromboxane B2; Vascular Resistance

This study examined plasma and urinary endothelin 1 and urinary metabolites of prostacyclin and thromboxane, in women with pre-eclampsia and age and gestation matched controls. To determine if changes in endothelin 1 and urinary prostanoids in pre-eclampsia were due to hypertension per se, a comparison was made to a group of age and gestation matched pregnant uncomplicated essential hypertensive women. Measurements were taken prior to delivery, and at 6 weeks and 6 months post-partum, and were compared to a group of age matched non-pregnant controls. Plasma endothelin 1 was significantly elevated and the urinary metabolite of prostacyclin (2,3-dinor-6-keto-PGF1 alpha) was significantly suppressed in pre-eclamptic pregnancy, compared to normal pregnancy and essential hypertensive pregnancy. As the level of blood pressure was similar in the pre-eclamptic and essential hypertensive groups, these changes are not due to an increase in blood pressure per se. Urinary endothelin 1 was not different in the 3 pregnant groups prior to delivery but fell significantly after delivery. Urinary endothelin 1 was significantly lower in the essential hypertensive group at 6 weeks post-partum compared to pregnant controls with a similar trend at 6 months. Urinary 11-dehydro-TXB2 was elevated in pregnancy, but no further elevation was seen in women with pre-eclampsia. Platelet counts were lower, and circulating neutrophil counts higher in pre-eclampsia prior to delivery. A combination of increased plasma endothelin 1 and reduced tissue prostacyclin synthesis may contribute to hypertension, placental insufficiency, foetal growth retardation and renal dysfunction in pre-eclampsia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Platelets; Blood Pressure; Endothelins; Epoprostenol; Female; Heart Rate; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values; Thromboxane B2

The etiology of pregnancy induced hypertension (PIH) is still unknown. The pathophysiology must be clarified. In this paper we present an animal model where hypertension in pregnant and non-pregnant rats was induced by an experimental reduction of uteroplacental blood flow. Thus, a preeclampsia-like syndrome could be studied under defined conditions. The eicosanoid system was investigated for pathophysiological alterations of the kidney by measuring urinary excretion of 6-keto-PGF1 alpha, TxB2 and PGE2 with radioimmunoassay at day 18 of pregnancy. First, in gravid control animals concentrations of all three prostaglandins were significantly elevated compared to non-gravid controls. However, in hypertensive gravid rats urinary concentrations of these prostaglandins fell even below the levels of non-gravid controls. The observed decrease was more pronounced for the vasodilatory 6-keto-PGF1 alpha and PGE2 than for the vasoconstrictive TxB2. Our results demonstrate that an experimental reduction of uteroplacental blood flow in the rat culminates in symptoms which clinically (hypertension, proteinuria) and pathophysiologically (eicosanoid system) resemble to preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Disease Models, Animal; Female; Pre-Eclampsia; Pregnancy; Rats; Rats, Wistar; Thromboxane B2

Although the changes in prostacyclin and thromboxane A2 levels in preeclampsia have been well studied, little work has previously been done on mononuclear cells, and the cause of the changes in unclear. We determined the prostacyclin and thromboxane A2 production in mononuclear cells and investigated the effect of preeclamptic serum on this production.. The production of prostacyclin and thromboxane A2 was measured by enzyme immunoassay in 16 normal pregnant women, nine preeclamptic women with proteinuria, and six preeclamptic women without proteinuria. Sera from these three groups of women were investigated to see whether the sera have any effect on prostaglandin production.. The levels of thromboxane A2 in preeclamptic patients were found to be much higher than those of normal pregnancy, whereas the levels of prostacyclin tended to be lower. Such changes lead to a markedly increased ratio of thromboxane A2 to prostacyclin in preeclamptic patients. There was no difference in the levels of prostacyclin and thromboxane A2 between the preeclamptic patients with and without proteinuria. Serum from preeclamptic patients with proteinuria slightly reduced prostacyclin synthesis in normal pregnancy but significantly increased increased thromboxane A2 production, resulting in a ratio of thromboxane A2 to prostacyclin similar to that of preeclampsia. However, serum from preeclamptic patients without proteinuria failed to exert such effects.. The imbalance between prostacyclin and thromboxane A2 occurs in mononuclear cells from preeclamptic women, and there is a factor(s) in proteinuric-preeclamptic serum to contribute, in part, to these changes. Our findings also suggested that the cause of abnormal prostaglandin production in preeclampsia was complicated and multifactorial.

Topics: 6-Ketoprostaglandin F1 alpha; Cells, Cultured; Epoprostenol; Female; Humans; Monocytes; Osmolar Concentration; Pre-Eclampsia; Pregnancy; Proteinuria; Reference Values; Thromboxane A2

In recent years an increasing amount of evidence supports the concept that preeclampsia is an endothelial disease. The purpose of our study was to evaluate the extent to which endothelial cell dysfunction is involved in pathophysiology of preeclampsia.. We studied the urinary excretion of thromboxane B2 and 6-keto-prostaglandin F1 alpha and the venous plasma endothelin levels in 23 preeclamptic patients and in control subjects. In six of these patients and in six controls arterial plasma endothelin levels were also measured. In addition, plasma levels of calcitonin gene-related peptide and plasma fibronectin levels were measured. Results were analyzed by Wilcoxon's rank-sum test or signed-rank test.. In preeclampsia the urinary thromboxane B2/6-keto-prostaglandin F1 alpha ratio (p < 0.001), venous plasma endothelin levels (p < 0.001), and plasma fibronectin levels (p < 0.001) were significantly elevated compared with normotensive pregnancy. Arterial plasma endothelin levels were significantly higher than venous plasma endothelin levels in normotensive and hypertensive patients (p < 0.05). Calcitonin gene-related peptide levels showed a wide range in normotensive pregnancy and in preeclampsia, but the difference was not significant.. These results confirm the extensive involvement of the endothelium in the pathophysiology of preeclampsia. Preeclamptic vasoconstriction seems to be mediated by an increase in the vasoconstrictor autocoids thromboxane A2 and endothelin. Production of prostacyclin by the vessel wall and endovascular trophoblast might be just a pivotal escape mechanism of the uteroplacental circulation. Calcitonin gene-related peptide appears not to be involved in the pathophysiology of preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteries; Calcitonin Gene-Related Peptide; Endothelins; Endothelium, Vascular; Female; Fibronectins; Humans; Pre-Eclampsia; Pregnancy; Thromboxane B2; Veins

The short term effect of anisodamine, an alkaloid isolated from the chinese herb anisodas tonguticus, on blood flow of uterine and umbilical arteries in 16 pregnant women with pregnancy-induced hypertension (PIH) was investigated by means of pulsed doppler ultrasound technique Results have shown that anisodamine could decrease the A/B ratio, resistant index (RI), and pulsative index (PI) of blood velocity in these arteries with statistical significant difference. Its mechanism of action might be the improving of the rheology in PIH and adjusting the imbalance of TXA2/PGI2. It was suggested that the resistance in uteroplacental circulation was decreased and its perfusion improved, so that favors the fetal growth and development.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Viscosity; Female; Humans; Microcirculation; Placenta; Pre-Eclampsia; Pregnancy; Regional Blood Flow; Solanaceous Alkaloids; Thromboxane B2; Umbilical Arteries; Uterus; Vascular Resistance

1. Pregnancy-induced hypertension (or pre-eclampsia) is characterized by vasoconstriction, platelet aggregation and altered capillary permeability, implying disordered endothelial function and/or structure. Serum from women with pregnancy-induced hypertension has been reported by others to be cytotoxic to endothelial cells in vitro. We hypothesized that such serum contains a factor that limits the ability of endothelial cells to produce and/or release prostacyclin. 2. Prostacyclin production by intact and damaged cultured human umbilical vein endothelial cells was measured after incubating these cells with serum from non-pregnant and normal pregnant women and women with pregnancy-induced hypertension. Confluent human umbilical vein endothelial cell monolayers (intact and damaged) were incubated with sera for 24 h at 37 degrees C followed by 1 h of incubation with added thrombin (stimulated production) or media (basal production). Supernatants were then collected for measurement of 6-keto-prostaglandin F1 alpha by radioimmunoassay. 3. Basal production of 6-keto-prostaglandin F1 alpha was greater in response to serum from non-pregnant women than to that from pregnant women. Within each group, sub-lethally damaged cells had a similar basal production of 6-keto-prostaglandin F1 alpha to that of intact cells. 4. Basal production of 6-keto-prostaglandin F1 alpha by intact or damaged cells incubated with sera from normal pregnant women and from women with pregnancy-induced hypertension was similar. 5. In all groups the addition of thrombin to intact endothelial cells increased 6-keto-prostaglandin F1 alpha production approximately 15-30-fold over basal levels, but only three- to five-fold in damaged endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Cells, Cultured; Endothelium, Vascular; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Thrombin

There is an imbalance of increased thromboxane and decreased prostacyclin in placentas of women with preeclampsia, but this may not be the only imbalance. There is also an abnormal increase in serum lipid peroxides in preeclamptic women. Lipid peroxides are toxic compounds that damage cells and inhibit prostacyclin synthesis. The following study examined lipid peroxides to determine if they were also increased in placentas of preeclamptic women.. Placental tissue for nine normal and eight preeclamptic women were frozen in liquid nitrogen immediately after delivery. Frozen tissue samples (1 gm) were homogenized and analyzed for lipid peroxides by malondialdehyde and hydrogen peroxide equivalents and for thromboxane and prostacyclin by radioimmunoassay of their stable metabolites, thromboxane B2 and 6-keto prostaglandin F1 alpha.. Lipid peroxides were significantly higher in preeclamptic placentas than in normal placentas by both analytic methods (49 +/- 5 vs 31 +/- 1 nmol/gm for malondialdehyde and 5.3 +/- 0.3 vs. 3.2 +/- 0.3 mumol/gm for hydrogen peroxide equivalent; mean +/- SE; p < 0.01, respectively). Thromboxane was significantly higher and prostacyclin significantly lower in preeclamptic placentas than in normal placentas (213 +/- 23 vs 158 +/- 14 ng/gm for thromboxane and 24 +/- 3 vs 53 +/- 7 ng/gm for prostacyclin, p < 0.05). The thromboxane/prostacyclin and lipid peroxides/prostacyclin ratios were threefold higher in preeclamptic placentas than in normal placentas.. Placental levels of both lipid peroxides and thromboxane are increased and prostacyclin decreased in preeclampsia. We speculate that abnormally increased levels of lipid peroxides in preeclamptic placentas may be a cause of decreased prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Female; Humans; Lipid Peroxides; Malondialdehyde; Placenta; Pre-Eclampsia; Pregnancy; Reference Values; Thromboxane B2

Intra-uterine growth retardation, intra-uterine fetal death and pre-eclampsia have common abnormalities: A reduction of uteroplacental perfusion, lack of vasodilation of spiral arteries and subsequent thrombosis. These physiological processes have been explained by an imbalance between prostacyclin and thromboxane A2 production. Many studies have suggested that treatment with low-dose aspirin and steroids is effective in preventing pregnancy loss or pre-eclampsia, but the mechanism has not been established. We evaluated the effectiveness of these therapies in patients at risk for pregnancy loss with the aspect of intracellular ionized calcium mobilization. Low-dose aspirin directs the prostacyclin/thromboxane A2 balance to the dominance of prostacyclin and steroids suppress the activities of lupus anticoagulant or antiphospholipid antibodies. The intracellular ionized calcium concentration in platelets is decreased significantly after these therapies. Concerning the pathological examination of placenta, there were deposits of fibrin in only 2 out of 8 cases and there were no abnormal findings in the other 6 cases. These data show that the aggregation of platelets is suppressed in microvascular circulations. These therapies do not cause any adverse effect on the mother or fetus. It is concluded that low-dose aspirin therapy with steroids is useful for patients with a poor obstetrical history.

Topics: 6-Ketoprostaglandin F1 alpha; Aspirin; Calcium; Female; Fetal Death; Fetal Growth Retardation; Humans; Lupus Coagulation Inhibitor; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Thromboxane B2; Treatment Outcome

In normal pregnancy, increased production of platelet thromboxane A2(TXA2) parallels increased biosynthesis of vascular prostacyclin (PGI2). An imbalance in the formation of these prostaglandins is believed to be associated with the pathogenesis of pregnancy-induced hypertension (PIH). Recent evidence suggested that aspirin in low doses was effective in reducing the incidence of PIH, by selective inhibition of platelet-derived TXA2 biosynthesis. In this communication, we determined the urinary 11-dehydro TXB2 and 6-keto-PGF1 alpha, which are major metabolites of TXA2 and PGI2, respectively, from early to late pregnancy of normal pregnant women and of women complicated with PIH. The ratio of 11-dehydro TXB2 to 6-keto-PGF1 alpha decreased significantly from as early as 10wks of gestation when compared with that in non-pregnant controls (1.43 +/- 0.15 vs 1.99 +/- 0.13: Mean +/- SEM, p less than 0.05), and increased in later pregnancy to the control values at term. No significant difference was found in the excretion of 11-dehydro TXB2 between normal pregnant women and women with PIH. In contrast, urinary excretion of 6-keto-PGF1 alpha decreased in women with PIH. The ratio of 11-dehydro TXB2 to 6-keto-PGF1 alpha increased significantly as compared with that of pregnant controls. These results demonstrated that disturbed production of vascular PGI2 may be the primary cause of PIH, and affect the vascular responsiveness to pressor inducers such as angiotensin II.

Topics: 6-Ketoprostaglandin F1 alpha; Endothelium, Vascular; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2; Thromboxane B2

Eleven preterm patients with severe preeclampsia underwent Doppler velocimetry prior to cesarean section. Maternal venous blood and umbilical arterial and venous samples were collected for prostacyclin and thromboxane determination by radioimmunoassay. Umbilical artery pulsatility index correlated positively with umbilical artery thromboxane B2 levels (r = 0.76; P less than 0.05) and maternal thromboxane levels (r = 0.78; P less than 0.05). We conclude that the vasoactive action of thromboxane A2 may alter placental resistance.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Flow Velocity; Female; Humans; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Thromboxane B2; Umbilical Arteries; Uterus

A relative decrease in endothelial cell prostacyclin production may be pivotal in the genesis of preeclampsia. We determined the effect of sera from preeclamptic women on prostacyclin production by monolayers of normal term human umbilical vein endothelial cells. Endothelial cells were incubated with media containing serum from patients with preeclampsia, non-hypertensive, gestational age-matched pregnant controls, or normal non-pregnant controls (N = 7, all groups). 6-Keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin, was measured directly in the culture medium by radioimmunoassay. Treatment with preeclamptic sera, when associated with a statistically significant increase in prostacyclin metabolite production by endothelial cells. Thus, sera from women with preeclampsia stimulate rather than inhibit prostacyclin production by endothelial cells. We speculate that there is a factor in the sera of women with preeclampsia that functions to activate endothelial cells or which may play a role in the homeostatic mechanisms to balance reduced prostacyclin output in preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Biological Factors; Cells, Cultured; Endothelium, Vascular; Female; Humans; Magnesium Sulfate; Pre-Eclampsia; Pregnancy

To find out whether a serum factor in pre-eclamptic women is the cause of the raised serum endothelin concentrations associated with the disorder, the effect of serum from pre-eclamptic women on endothelin production by endothelial cells was compared with that of serum from pregnant and non-pregnant controls. The finding that pre-eclamptic serum suppresses endothelin production suggests that it contains a factor that might be part of a homoeostatic response to raised serum endothelin concentrations in pre-eclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Endothelins; Endothelium, Vascular; Female; Homeostasis; Humans; Magnesium Sulfate; Pre-Eclampsia; Pregnancy; Thrombin

Preeclampsia is associated with an imbalance between thromboxane and prostacyclin. The cause of the imbalance is unknown. Preeclampsia sera contain cytotoxic factors that can damage endothelial cells. Lipid peroxides can damage cell membranes, so elevated levels in the mother's blood could be related to endothelial cell injury and decreased prostacyclin in preeclampsia. This study determined maternal plasma levels of thromboxane and prostacyclin and serum levels of lipid peroxides and vitamin E in women with normal pregnancy (n = 12), mild preeclampsia (n = 16), and severe preeclampsia (n = 19) between 36 and 40 weeks' gestation. In normal pregnancy the ratio of thromboxane to prostacyclin (0.63) favored prostacyclin, and the ratio of lipid peroxides to vitamin E (0.43) favored vitamin E. Prostacyclin was significantly decreased in both mild and severe preeclampsia. Thromboxane was not increased in mild preeclampsia but was significantly increased in severe preeclampsia. The ratio of thromboxane to prostacyclin was increased in mild preeclampsia (0.77) and greatly increased in severe preeclampsia (1.94). Lipid peroxides were significantly increased in mild preeclampsia and increased further in severe preelcampsia. Vitamin E levels were unaltered in mild preeclampsia but significantly decreased in severe preeclampsia. The ratio of lipid peroxides to vitamin E was increased in mild (0.52) and greatly increased in severe (1.09) preeclampsia. We concluded the following: (1) Maternal plasma prostacyclin is decreased in both mild and severe preeclampsia, but thromboxane is increased only in severe cases. (2) Lipid peroxides are significantly increased in both mild and severe preeclampsia and vitamin E is significantly decreased in severe preeclampsia. We speculate that this imbalance could result in endothelial and platelet cell damage and in decreased prostacyclin and increased thromboxane synthesis. (3) Preeclampsia is associated with an imbalance not only between thromboxane and prostacyclin but also between lipid peroxides and vitamin E in maternal blood. The imbalances progressively favor thromboxane and lipid peroxides with the increasing severity of preeclampsia, which is consistent with the clinical symptoms of this disorder.

Topics: 6-Ketoprostaglandin F1 alpha; Female; Humans; Lipid Peroxides; Pre-Eclampsia; Pregnancy; Thromboxane B2; Vitamin E

To clarify the possible role of elevated atrial natriuretic peptide (ANP) in the pathophysiology of preeclampsia, we measured ANP, renin activity (PRA), angiotensin II (Ang II), TXB2 (a stable metabolite of TXA2) and 6-keto-PGF1 alpha (a stable end product of PGI2) concentrations in the plasma of 19 normal pregnant women and 35 severe preeclamptic patients at term. Plasma ANP levels in the preeclamptic patients (n = 35, 71.5 +/- 3.8 pg/ml, mean +/- S.E.) and also umbilical plasma ANP (n = 35, 83.0 +/- 4.2 pg/ml) were significantly (p less than 0.01) higher than those of normal pregnant women plasma (n = 19, 58.7 +/- 3.7 pg/ml) and umbilical plasma (n = 19, 47.6 +/- 4.7 pg/ml). There was a significant (p less than 0.01) positive correlation between maternal ANP levels and fetal ANP levels (n = 54, r = 0.44). Plasma PRA and 6-keto-PGF1 alpha levels in preeclampsia were significantly (p less than 0.05) lower than those of normal pregnancy. The ratio of 6-keto-PGF1 alpha/TXB2 in preeclampsia was significantly (p less than 0.01) lower than that of normal pregnancy as we reported previously. There was no significant correlation between plasma ANP level and plasma PRA, Ang II, plasma TXB2 and 6-keto-PGF1 alpha concentrations. Moreover there was no significant correlation between plasma ANP level and the severity of preeclampsia. These data suggest the possibility of a transplacental crossing of ANP secreted by feto-placental unit, which might be, at least in part, responsible for the high ANP levels observed in preeclampsia. The ANP in preeclampsia is not related directly to hypertension, but it may play a substantial role in the regulation or normalization of blood volume and vascular reactivity.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Epoprostenol; Female; Fetus; Humans; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Renin; Thromboxane A2

Plasma 6-keto-prostaglandin F 1 alpha and thromboxane B2, the metabolites of prostacyclin and thromboxane A2 respectively, were measured in 12 women with pregnancy-induced hypertension, 12 age-matched normotensive pregnant women and 8 non-pregnant women as controls. Pregnancy was divided into 3 stages, namely: 22-27, 28-32 and 33-39 weeks. The concentrations of thromboxane B2 in the plasma of women with pregnancy-induced hypertension was 1.4-1.7 times greater than normotensive pregnant subjects at the same gestational stage, and 2 times higher than controls. Plasma levels of 6-keto-prostaglandin F 1 alpha in normotensive pregnant women was 1.8 times greater than in those with pregnancy-induced hypertension at 28-32 and 33-39 weeks, and was significantly higher than control. The ratio of thromboxane B2 to 6-keto-prostaglandin F 1 alpha was markedly increased in the group of patients with pregnancy-induced hypertension at 28-32 and 33-39 weeks gestation. The ratio of the two metabolites in normotensive patients at each stage of gestation was similar to the control group. The ratio of circulating aggregated platelets in subjects with pregnancy-induced hypertension was significantly lower than in normotensive pregnant subjects at 33-39 weeks, implying increased turnover of platelets in pregnancy-induced hypertension. There was no significant difference in count of platelets, adenosine diphosphate threshold concentration and variables of platelet aggregation induced by adenosine diphosphate among the 3 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Longitudinal Studies; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Thromboxane B2

The causes of the "endothelial dysfunction" accompanying preeclampsia are unknown. Women with preeclampsia have a marked hyperlipidemia which reflects altered lipid metabolism. We asked if the hyperlipidemic sera of preeclamptic women could cause altered endothelial cell properties. Cultured endothelial cells were incubated with sera from women with preeclampsia (PE) or normal pregnancies as controls. Fifty PE-sera were tested and in 45 cases the endothelial cells acquired a large number of sudanophilic granules which by electron microscopy had lipid appearance. In 31 incubations with 31 individual control sera cellular lipid granules were observed in 4 cases. The cellular triglyceride content was increased to 153 +/- 30 compared to 48 +/- 10 micrograms/mg cell protein in the control cells. Furthermore, the endothelial release of prostacyclin, measured as 6-keto PGF1 alpha, was 8.8 +/- 0.6 ng/mg cell protein in cells incubated with PE-sera as compared to 40.3 +/- 6.4 ng/mg in the control cells.. The hyperlipidemic sera from preeclamptic women induced triglyceride accumulation in cultured endothelial cells. This was accompanied by altered endothelial function as demonstrated by reduced prostacyclin release.

Topics: 6-Ketoprostaglandin F1 alpha; Cells, Cultured; Cytoplasmic Granules; Endothelium, Vascular; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Triglycerides; Umbilical Veins

Decreased fetoplacental prostacyclin (PGI2) production has been shown in preeclampsia, and increased pulmonary PGI2 synthesis has been demonstrated in experimental hypoxia. We measured the urinary excretion of the main metabolites of PGI2, 6-keto-prostaglandin F1 alpha (6-keto) and 2,3-dinor-6-keto-prostaglandin F1 alpha (2,3-dinor), during the first day of life in infants born to mothers with preeclampsia (n = 26), in infants with birth asphyxia (n = 12), and in control infants (n = 14). The mean excretion of 6-keto in control infants increased from 9.3 to 14.3 ng/h/1.73 m2 from 0-12 to 12-24 h of age, and a corresponding change from 3.5 to 7.0 ng/h/1.73 m2 was seen in 2,3-dinor excretion. In infants of preeclamptic mothers the excretion values at 0-12 and 12-24 h and the pattern of change were not significantly different from controls. In asphyxiated infants, the mean excretion values at 0-12 and 12-24 h of 6-keto (11.0 and 11.6 ng/h/1.73 m2) and 2,3-dinor (6.0 and 5.8 ng/h/1.73 m2) were not significantly different from control infants, but no increase was seen. We conclude that PGI2 production in infants of preeclamptic mothers is not impaired, but after perinatal asphyxia there is an altered pattern of PGI2 metabolite excretion, suggesting decreased production capacity.

Topics: 6-Ketoprostaglandin F1 alpha; Asphyxia Neonatorum; Creatinine; Epoprostenol; Female; Humans; Infant, Newborn; Kidney; Male; Pre-Eclampsia; Pregnancy

Prostaglandin E2 (PGE2), Prostaglandin F2 alpha (PGF2 alpha),6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2) were measured with radioimmunoassay in placentae of 18 normotensive and 22 moderate or severe PIH gravidae. The content of PGE2 and PGF2 alpha did not change significantly in placentae of PIH patients suggesting that PGE2 and PGF2 alpha in placenta were not important in causing PIH. The content of placental 6-keto-PGF1 alpha also showed no significant difference, while TXB2 levels were significantly higher in PIH patients. The 6-keto-PGF1 alpha/TXB2 in PIH patients was remarkably lower than in normotensive women. These results indicate that an increase in TXB2 level and thus a decrease in the ratio of 6-keto-PGF1 alpha to TXB2 of placenta may be a pathogenetic factor in PIH.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dinoprost; Dinoprostone; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Angina Pectoris; Animals; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Pre-Eclampsia; Pregnancy; Rabbits; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Female; Humans; Lipid Peroxidation; Pre-Eclampsia; Pregnancy; Thromboxane B2

In order to investigate whether urinary excretion of prostaglandins (PG) is involved in the pathophysiology of pre-eclampsia, urinary immunoreactive 6-keto PGF1 alpha and TXB2 were measured in normal and pre-eclamptic women by radio-immunoassay after extraction with Bond Elut column. Urinary levels of 6-keto PGF1 alpha and TXB2 were expressed as ratio of urinary concentration of prostaglandin vs. creatinine (pg prostaglandin/mg creatinine; pg/mg cre.). Urinary excretion in normal pregnant and postpartum women were 211.2 +/- 33.8 and 160.1 +/- 9.1 pg/mg cre., respectively. In the pre-eclamptic group, urinary excretion of 6-keto PGF1 alpha was 105.3 +/- 28.2 pg/mg cre. in pregnancy and 99.0 +/- 12.5 pg/mg cre. in the postpartum period. Urinary excretion of 6-keto PGF1 alpha in the pre-eclamptic group was significantly lower (P less than 0.05) than in normal controls during pregnancy but not in the postpartum period. Urinary excretion of TXB2 was not significantly different between the two groups. The urinary excretion of 6-keto PGF1 alpha was measured before and after the onset of pre-eclampsia in four cases of edema and weight gain of more than 500 g/week (group e), one case of proteinuria of more than 200 mg/dl with edema (group ep) and three cases of pre-eclampsia (group eph). The urinary excretion of 6-keto PGF1 alpha in these eight patients before onset of pre-eclampsia was slightly lower than of normal controls but not significantly so. In group eph, urinary excretion of PG was decreased after the onset of pre-eclampsia. These results provide further evidence of the involvement of PG in the pathophysiology of pre-eclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Prospective Studies; Prostaglandins

Topics: 6-Ketoprostaglandin F1 alpha; Chorionic Villi; Female; Humans; Microcirculation; Placenta; Pre-Eclampsia; Pregnancy; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane B2

The role of prostaglandin (PG) system in preeclampsia (pre-E) was investigated. Urinary excretion of PGE2,6-keto PGF1 alpha,2,3 dinor 6-keto PGF1 alpha, TxB2 and 2,3-dinor-TxB2 and kallikrein were determined in 10 normotensive pregnant women and 14 with pre-E. 6-keto PGF1 alpha and 2,3-dinor 6-keto PGF1 alpha (the main renal and extrarenal metabolites of vasodilator PGI2) and PGE2 excretion was lower in pre-E. TxB2 metabolites in urine were similar in the two groups of women. Our data are consistent with the hypothesis of an imbalance between vasodilator and vasoconstrictor PGs in pre-E.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dinoprostone; Epoprostenol; Female; Humans; Kidney; Pre-Eclampsia; Pregnancy; Prostaglandins; Prostaglandins E; Thromboxane A2; Thromboxane B2; Vasodilator Agents

In order to characterize the prostacyclin and thromboxane system during gestosis the stable degradation products 6-keto-prostaglandin F1 alpha (6-keto-PG F1 alpha) and thromboxane B2 (TX B2) have been determined by radioimmunoassay in amniotic fluid and maternal venous plasma from 16 normotensive pregnant women and 14 patients with preeclampsia. At preeclampsia as well in amniotic fluid as in plasma a tendency towards lowered levels of 6-keto-PG F1 alpha and at the same time increased levels of TX B2 may be visualized. In the plasma generally significant higher levels of both 6-keto-PG F1 alpha and TX B2 than in amniotic fluid have been established. The imbalance between anti-aggregatory and vasodilatatory prostacyclin and proaggregatory and vasoconstrictory thromboxane in preeclampsia is indicated by an increase of the ratio TX B2/6-keto-PG F1 alpha from 1.38 to 2.44 in amniotic fluid and from 1.88 to 2.81 in plasma.

Topics: 6-Ketoprostaglandin F1 alpha; Amniotic Fluid; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Epoprostenol; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Umbilical Cord

Renal synthesis of the antiaggregatory and vasodilatory prostacyclin and its endogenous antagonist thromboxane A2 may be disturbed in patients with preeclampsia. We tested this hypothesis by measuring 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha; a hydration product of prostacyclin), 2,3-dinor-6-keto-PGF1 alpha (generated from 6-keto-PGF1 alpha through beta-oxidation) and thromboxane B2 (a hydration product of thromboxane A2) in the urine of healthy pregnant and preeclamptic women. Urinary excretion of 6-keto-PGF1 alpha [19.8 +/- 10.5 pmol/mmol creatinine, (mean +/- SD)] and 2,3-dinor-6-keto-PGF1 alpha (19.2 +/- 7.5 pmol/mmol creatinine) increased during normal pregnancy, reaching a maximum (about 5-fold rise) during the last month of pregnancy. No significant changes occurred in the urinary excretion of thromboxane B2. In women with severe preeclampsia (n = 17), the excretion of both 6-keto-PGF1 alpha (37.7 +/- 29.5 pmol/mmol creatinine) and 2,3-dinor-6-keto-PGF1 alpha (54.5 +/- 56.2 pmol/mmol creatinine) was lower (P less than 0.001) than in the normotensive women during the last trimester of pregnancy (80.6 +/- 43.7 and 98.7 +/- 42.9 pmol/mmol creatinine, respectively). The neonates excreted 6-25 times more 6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha and thromboxane B2 than did the nonpregnant women. In contrast to the adults, neonatal 6-keto-PGF1 alpha excretion was 2-3 times greater than that of 2,3-dinor-6-keto-PGF1 alpha suggesting reduced beta-oxidation in the newborns. Infants born to preeclamptic women had reduced output of 6-keto-PGF1 alpha and 2,3-dinor-6-keto-PGF1 alpha on the first day of life. Thus, renal prostacyclin synthesis is diminished in women with severe preeclampsia and their infants.

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Female; Humans; Infant, Newborn; Kidney; Postpartum Period; Pre-Eclampsia; Pregnancy; Thromboxane A2; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Reference Values; Thromboxane A2; Thromboxane B2; Umbilical Arteries

The hemodynamic effects of intravenously infused dihydralazine (incremental doses up to 125 micrograms per minute during 60 minutes) were studied in ten women with acute or superimposed severe preeclampsia. The intervillous and umbilical vein blood flow were measured before and during dihydralazine infusion with 133Xenon method and with a combination of real-time and Doppler ultrasonic equipment, respectively. Maternal blood pressure decreased and pulse rate increased during the infusion. Dihydralazine did not change the intervillous blood flow but it increased the blood flow in umbilical vein. No effect on the 6-ketoprostaglandin F1 alpha in maternal plasma and urine or thromboxane B2 in maternal serum was observed. The results indicate that dihydralazine affects the placental and fetal circulations differently.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Pressure; Dihydralazine; Female; Fetal Heart; Humans; Hydralazine; Hypertension; Infusions, Parenteral; Placenta; Pre-Eclampsia; Pregnancy; Pulse; Regional Blood Flow; Thromboxane A2; Umbilical Veins

Plasma 6-keto prostaglandin F1 alpha, 13,14-dihydro-15-keto prostaglandin F, and thromboxane B2 levels were measured in normotensive and preeclamptic patients during pregnancy and the postpartum period. From 30 to 40 weeks of gestation, 6-keto prostaglandin F1 alpha levels of preeclamptic patients were significantly lower than those of normotensive women; 13,14-dihydro-15-keto prostaglandin F and thromboxane B2 concentrations in preeclamptic patients did not significantly differ from those of the normotensive group. At delivery, 6-keto prostaglandin F1 alpha levels of maternal and umbilical venous plasma of preeclamptic women were also significantly lower than those of normotensive women. In the postpartum period these three prostanoids were not significantly different in normotensive women compared to preeclamptic women, with clinical preeclamptic symptoms soon disappearing in most of our patients. From the results, it seems that prostacyclin plays an important role in preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Dinoprost; Female; Fetal Blood; Humans; Labor, Obstetric; Postpartum Period; Pre-Eclampsia; Pregnancy; Prostaglandins F; Radioimmunoassay; Thromboxane B2; Thromboxanes

Seven patients with acute preeclampsia and six with superimposed preeclampsia were infused intravenously with incremental doses of prostacyclin (up to 8 ng/min/kg during 80 minutes). Prostacyclin infusion was accompanied by significant decreases in maternal blood pressure and consistent rises in maternal plasma or urinary 6-keto-prostaglandin F1 alpha, but it caused no changes in maternal or fetal pulse rate or uterine contractility. Moreover, prostacyclin did not change the placental and umbilical blood flow, which were measured before and at the end of infusion. All women experienced facial flushing and two complained of headache during infusion. There was no difference in prostacyclin effects between women with acute or superimposed preeclampsia. These results may be taken as evidence that intravenous prostacyclin is not a specific therapy to increase placental or umbilical blood flow in preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Blood Pressure; Epoprostenol; Female; Fetus; Heart Rate; Humans; Placenta; Pre-Eclampsia; Pregnancy; Regional Blood Flow; Umbilical Cord

Preeclampsia is characterized by increased vasoconstriction frequently associated with increased platelet aggregation, reduced uteroplacental blood flow, and premature delivery. Because prostacyclin antagonizes the vasoconstrictor, platelet-aggregating, and uterine-activating actions of thromboxane, we considered the hypothesis that placental production of thromboxane was increased coincident with decreased production of prostacyclin in preeclampsia. Fresh human term placentas were obtained immediately after delivery from 11 normal and 10 preeclamptic pregnancies (blood pressure greater than or equal to 140/90 mm Hg, urinary protein greater than 0.3 gm/24 hr). Tissues (350 mg) were incubated sterilely in 6 ml of Dulbecco's Modified Eagle's Medium for 48 hours at 37 degrees C with 95% oxygen and 5% carbon dioxide in a metabolic shaker. Samples were collected at 8, 20, 32, and 48 hours and analyzed for thromboxane by radioimmunoassay of its stable metabolite, thromboxane B2, and for prostacyclin by radioimmunoassay of its stable metabolite, 6-keto prostaglandin F1 alpha. The production of thromboxane was significantly increased in preeclamptic versus normal placental tissue (22.9 +/- 4.7 versus 6.3 +/- 1.5 pg/mg/hr, mean +/- SE, p less than 0.01), whereas the production of prostacyclin was significantly decreased (3.0 +/- 0.3 versus 6.7 +/- 0.5 pg/mg/hr, p less than 0.001). In both normal and preeclamptic placentas, the production rates of thromboxane and prostacyclin were inhibited by indomethacin (5 mumol/L) and not affected (p greater than 0.50) by arachidonic acid (100 mumol/L). Therefore, during normal pregnancy, the placenta produces equivalent amounts of thromboxane and prostacyclin, so that their biologic actions on vascular tone, platelet aggregation, and uterine activity will be balanced. In preeclamptic pregnancy, however, the placenta produces seven times more thromboxane than prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Arachidonic Acids; Culture Media; Epoprostenol; Female; Humans; Indomethacin; Infant, Newborn; Placenta; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Thromboxane B2; Thromboxanes

Much evidence has implied a deficient production of the antiaggregatory and vasodilator agent prostacyclin (PGI2) in preeclampsia and some other chronic fetoplacental insufficiency syndromes. So that we could study whether this might be due to the possible effects of the mode of delivery and maternal epidural or general anesthesia, specimens of the umbilical arteries of infants born after normal (n = 46) or complicated (n = 25) pregnancies were superfused in vitro and their production of PGI2 was determined by measuring 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the hydrolysis product of PGI2) by radioimmunoassay. The amounts of umbilical 6-keto-PGF1 alpha released in normal pregnancies after induced vaginal delivery (20.9 +/- 2.4 ng/gm/min dry weight of tissue, mean +/- SEM) and elective cesarean section (21.8 +/- 2.2 ng/gm/min) were smaller (p less than 0.025) than the amounts released after spontaneous onset of labor (35.0 +/- 6.2 ng/gm/min). Epidural or general anesthesia had no effect on this production. When the types of deliveries were matched, the production of 6-keto-PGF1 alpha was even less (p less than 0.05) in cases of preeclampsia (14.2 +/- 3.7 ng/gm/min; n = 9) than in the control subjects (21.3 +/- 1.6 ng/gm/min) and in cases of essential hypertension (21.6 +/- 5.2 ng/gm/min). Our data suggest that umbilical PGI2 deficiency is a specific feature of preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Anesthesia, Obstetrical; Delivery, Obstetric; Epoprostenol; Female; Fetal Growth Retardation; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Umbilical Arteries

The production of vasodilatory, antiaggregatory prostacyclin (PGI2) and vasoconstrictory, proaggregatory thromboxane A2 (TxA2) by the placenta was studied in the cases of hypertensive pregnancy complications by superfusing pieces from maternal and fetal sides of placentae of 9 pre-eclamptic, 6 hypertensive and 11 healthy women in vitro and measuring the release of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), the breakdown products of PGI2 and TxA2 respectively, from the superfusate. Both sides of the placentae from the controls produced 6-keto-PGF1 alpha (maternal side 0.5 +/- 0.1 ng/g/min dry weight of tissue, mean +/- SEM; fetal side 0.7 +/- 0.2 ng/g/min) and TxB2 (maternal side 2.5 +/- 0.4 ng/g/min; fetal side 2.7 +/- 0.5 ng/g/min) with no correlation between the two. The 6-keto-PGF1 alpha production was normal in hypertensive complications whereas the TxB2 production was increased on the fetal side of the placentae obtained from the pre-eclamptic (3.7 +/- 0.3 ng/g/min: p less than 0.05) and hypertensive women (4.1 +/- 0.4 ng/g/min; p less than 0.025). This may explain the occurrence of microthrombi and infarctions in placentae of hypertensive women.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Humans; Hypertension; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2; Thromboxanes

Production of the antiaggregatory and vasodilatory prostacyclin (prostaglandin I2) and the proaggregatory and vasoconstrictory thromboxane A2 during human labor was studied by measuring serial concentrations of the stable metabolites of these prostanoids, 6-keto-prostaglandin F1 alpha and thromboxane B2, respectively, in the amniotic fluid of 43 parturients whose labor was induced by amniotomy. The concentration of 6-keto-prostaglandin F1 alpha at amniotomy in 28 healthy parturients (92.7 +/- 12.1 pg/ml, mean +/- SE) was higher (p less than 0.02) than that in 15 preeclamptic women (48.6 +/- 5.5 pg/ml). The concentration of thromboxane B2 at amniotomy was 292.4 +/- 56.1 pg/ml, with no difference between the healthy and preeclamptic parturients. Both prostanoid levels rose consistently during labor, reaching peak levels when the cervix was fully dilated, but this rise started only after the established uterine contractility. Epidural anesthesia and paracervical blockade had no effect on 6-keto-prostaglandin F1 alpha and thromboxane B2 in the amniotic fluid, whereas oxytocin infusion was accompanied by reduced levels of thromboxane B2. The rise in amniotic fluid 6-keto-prostaglandin F1 alpha was reduced at every stage of labor in the preeclamptic women (n = 15), and its maximal increase (112.4 +/- 28.3 pg/ml) was smaller (p less than 0.005) than in the healthy women (n = 28, 240.8 +/- 21.4 pg/ml). The ratio of 6-keto-prostaglandin F1 alpha to thromboxane B2 also shifted to thromboxane B2 dominance in the preeclamptic parturients. It is concluded that a relative prostacyclin deficiency deteriorates in preeclamptic women during labor.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Amniotic Fluid; Epoprostenol; Female; Humans; Labor Stage, First; Labor, Obstetric; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Thromboxane A2; Thromboxane B2; Thromboxanes; Uterine Contraction

Topics: 6-Ketoprostaglandin F1 alpha; Adaptation, Physiological; Animals; Blood Coagulation Factors; Epoprostenol; Female; Fetal Death; Hemodynamics; Humans; Hypertension; Imidazoles; Lupus Coagulation Inhibitor; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Thrombosis; Thromboxane-A Synthase; Vitamin E Deficiency

Amniotic fluid from 19 patients with preeclampsia was compared with samples from normotensive control subjects with respect to the levels of prostaglandin 6-keto prostaglandin F1 alpha, thromboxane B2, and the ratio of 6-keto prostaglandin F1 alpha to thromboxane B2. The study found no significant differences in the levels of these prostanoids or the ratio of 6-keto prostaglandin F1 alpha to thromboxane B2 (study patients, 2.7 +/- 2.1; control patients, 2.8 +/- 1.9) between groups.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Amniotic Fluid; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane B2; Thromboxanes

Umbilical blood-flow (UBF) was measured by ultrasonography in 28 pregnant women. A superfusion preparation was used to investigate the production of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), a breakdown product of prostacyclin (PGI2) and thromboxane B2 (TxB2), a breakdown product of TxA2, by specimens from the umbilical arteries of the infants born to these 28 mothers and those born to 36 other women in whom UBF had not been measured. UBF was significantly related to 6-keto-PGF1 alpha production. 6-keto-PGF1 alpha production was lower in infants of the 8 pre-eclamptic mothers (14.5 ng min-1 g-1) than in those of 45 healthy mothers (26.9 ng min-1 g-1). Generation of TxA2 by the umbilical artery was 15-25 times less than that of 6-keto-PGF1 alpha, and TxA2 concentrations were unrelated to UBF or the type of pregnancy. These data provide the first evidence for a direct association between blood-flow and PGI2 generation in human vasculature.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Circulation; Epoprostenol; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2; Thromboxane B2; Thromboxanes; Umbilical Arteries; Umbilicus

This study evaluated the role of platelets in the pathogenesis of toxemia. The findings were: (1) Thrombocytopenia and macrothrombocytosis are characteristic of toxemia. (2) ADP induced platelet aggregation increases during pregnancy, but decreases in severe toxemia significantly. (3) beta-thromboglobulin levels in both plasma and urine rise during pregnancy, and are significantly high in toxemia, especially in a severe type. (4) The plasma TxB2/6-keto-PGF1 alpha ratio markedly increase in severe toxemia due to the increase in the amount of TxB2. And in the IInd trimester, the ratio in the toxemia onset group in which toxemic pregnancy occurred in the IIIrd trimester showed a significantly higher value than the control group. These findings suggest that, in toxemic patients, platelets are in a hyperactive state and there is rapid turnover caused by selective consumption in organs such as the kidneys and placenta, and that platelet aggregation decreases due to the relative increase in the number of exhausted platelets as the toxemic state is impending. Furthermore, the TxA2/PGI2 balance shifts to TxA2 dominant and measurement of the plasma TxB2/6-keto-PGF1 alpha ratio was considered to help prediction of toxemia in the latter term of pregnancy.

Topics: 6-Ketoprostaglandin F1 alpha; beta-Thromboglobulin; Blood Platelets; Female; Humans; Platelet Aggregation; Platelet Count; Pre-Eclampsia; Pregnancy; Thromboxane B2

The implications of the antiaggregatory and vasodilatory prostacyclin (PGI2) and proaggregatory and vasoconstrictory thromboxane A2 (TxA2) during human pregnancy in vivo are briefly reviewed. The level of circulating PGI2 in maternal plasma, as measured by its metabolite (= 6-keto-PGF1a) levels, rises during parturition, but there is no conclusive evidence that the PGI2 production increases already during pregnancy. In pre-eclampsia, PGI2 production can decrease, at least in amniotic fluid, but it is not known whether this PGI2 deficiency is a primary or secondary change in the pre-eclamptic state. TxA2 production in the maternal blood, as measured by the plasma and serum levels of TxB2, is increased during pregnancy, but the effect of pregnancy complication on its production is not known. In amniotic fluid, however, the TxB2 levels did not differ between normal and pre-eclamptic pregnancies. Further in vivo studies are needed to prove or reject the theory that a shift in the PGI2/TxA2 balance to a TxA2 predominance could be of etiological significance in preeclampsia or other pregnancy complications.

Topics: 6-Ketoprostaglandin F1 alpha; Amniotic Fluid; Epoprostenol; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Prostaglandins; Thromboxane A2; Thromboxane B2; Thromboxanes

To determine the significance of EPH-gestosis, the author measured the blood levels of lipid peroxides, vitamin E, thromboxane B2, and 6-Keto-prostaglandin F1 alpha. The basis for this was presence of lipid metabolism abnormalities in this disease. 1. The serum lipid peroxides level. In severe cases of EPH-gestosis, a significant increase was observed compared with normal pregnant women in the 10th month of gestation. 2. The serum V-E level. In severe cases of EPH-gestosis, there was a tendency to decrease compared with the values for the late stage of pregnancy. 3. The serum TXB2 level. In severe cases of EPH-gestosis, a significant increase was observed compared with normal pregnant women in the 10th month of gestation. 4. The serum 6-Keto-PGF1 alpha level. In severe cases of EPH-gestosis, a significant decrease was observed compared with normal pregnant women in the 10th month of gestation. 5. Relationship to the gestosis index (G-I). a. Elevation of the lipid peroxide level was noted in cases with a G.I. of 5 or higher. b. The V-E level tended to drop in cases with a G.I. of 4 or higher. c. There was a significant difference between the TXB2 levels at G.I.-3 and G.I.-4. d. The level of 6-Keto-PGF1 alpha dropped as the G.I. increased in cases with a G.I. of 4 or higher.

Topics: 6-Ketoprostaglandin F1 alpha; Female; Humans; Lipid Peroxides; Pre-Eclampsia; Pregnancy; Thromboxane B2; Thromboxanes; Vitamin E

To study the involvement of the antiaggregatory and vasodilator prostacyclin (PGI2) and proaggregatory and vasoconstrictor thromboxane A2 (TxA2) in complicated pregnancies, we measured by radioimmunoassay the stable metabolites of PGI2 and TxA2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), respectively, in samples of amniotic fluid collected at amniocentesis from 88 women between 30 and 40 weeks' normal or complicated pregnancy. The concentrations (mean +/- SE) of 6-keto-PGF1 alpha were 171.8 +/- 9.0 pg/ml in normal pregnancies (N = 27), 134.4 +/- 9.3 pg/ml in severe preeclampsia (N = 13) (0.001 less than p less than 0.005 in comparison with normal pregnancy), 175.6 +/- 13.9 pg/ml in mild preeclampsia (N = 14) (0.01 less than p less than 0.05 in comparison with severe preeclampsia), 168.5 +/- 16.9 pg/ml in diabetic pregnancies (N = 14), 158.7 +/- 5.9 pg/ml in rhesus-immunized pregnancies (N = 10), and 178.7 +/- 13.7 pg/ml in pregnancies with intrauterine fetal growth retardation (N = 10). The corresponding TxB2 concentrations were, respectively, 35.0 +/- 5.7 pg/ml, 29.1 +/- 4.6 pg/ml, 31.3 +/- 3.1 pg/ml, 35.3 +/- 4.0 pg/ml, 31.4 +/- 5.9 pg/ml, and 39.2 +/- 3.2 pg/ml, and these levels did not differ from each other. The level of 6-keto-PGF1 alpha in amniotic fluid correlated with the pregnancy week in normal and preeclamptic pregnancies, and the levels of TxB2 in amniotic fluid in normal, preeclamptic, and rhesus-immunized pregnancies. Furthermore, these two prostanoids correlated with each other in normal pregnancy and in all complications except rhesus-immunized pregnancies. Thus, it is evident that the release of PGI2 into the amniotic fluid is decreased in severe preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Amniotic Fluid; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Thromboxane B2; Thromboxanes

To study the involvement of antiaggregatory and vasodilatory prostacyclin (PGI2) in various pregnancy complications, we measured the concentrations of 6-ketoprostaglandin F1 alpha, a stable hydration product of PGI2, using a specific radioimmunoassay, in plasma samples from 123 women between 22 and 41 weeks of complicated or normal pregnancy. The levels of 6-keto-PGF1 alpha (mean +/- SE) in pre-eclampsia (267.0 +/- 26.6 pg/ml, n = 22), diabetic pregnancy (266.6 +/- 19.2 pg/ml, n =21), twin pregnancy (310.7 +/- 28.2 pg/ml, n = 10), threatened premature labour (285.9 +/- 23.2 pg/ml, n = 26), placenta praevia or placental abruption (248.9 +/- 24.5 pg/ml, n = 6), hepatosis gravidarum (249.3 +/- 15.0 pg/ml, n = 3) or in pregnancies complicated by intrauterine fetal growth retardation (296.9 +/- 34.2 pg/ml, n = 14) or fetal death (267.5 +/- 20.9 pg/ml, n = 6) did not differ from each other or from the 6-keto-PGF1 alpha levels in normal pregnancy (266.4 +/- 15.0 pg/ml, n = 22). Furthermore, the 6-keto-PGF1 alpha levels bore no relation to the gestational age, maternal drug use (insulin, glucocorticoids, antihypertensive drugs) or to the sex, birth weight or condition of the newborn infant, or to the placenta weight.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Fetal Death; Fetal Growth Retardation; Humans; Obstetric Labor, Premature; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics; Pregnancy, Multiple; Prostaglandins