Signs of platelet activation, but not lipid peroxidation, in fetal blood associated with functional and structural umbilicoplacental lesions in pregnancies complicated by impaired glucose metabolism.

OBJECTIVES: To study the influence of platelet activation and lipid peroxidation in fetal blood on umbilical vascular prostanoid synthesis and placental morphology in diabetic pregnancy. METHODS: The concentrations of thromboxane A2 (TxA2) and malondialdehyde (MDA) were determined in umbilical cord plasma in 21 women with diabetes mellitus/impaired glucose tolerance (DM/IGT) and ten healthy women. Segments from the umbilical artery and vein were incubated and prostacyclin (PGI2) and TxA2 metabolites were determined. Prostanoid synthesis was stimulated with calcium ionophore at a second incubation. Histological examination was carried out in samples from the umbilical cord, membranes and placental parenchyma. Non-parametric statistical analysis was used, with a two-tailed p < 0.05 considered statistically significant. RESULTS: Cord plasma TxA2, but not MDA, was higher among DM/IGT women (p = 0.07). There were indications that cord plasma TxA2, but not MDA, was positively correlated with vascular prostanoid synthesis and synthesis capacity. In the umbilical vein, both the basal and stimulated PGI2 production and the stimulated TxA2 production were lower in the DM/IGT group. Ischemic placental lesions were associated with a high TxA, and a low MDA concentration in cord plasma. CONCLUSIONS: Even in less severe forms of impaired glucose metabolism, disturbances in platelet activation significantly affect both biochemical and morphological vessel wall and tissue functions in the umbilicoplacental unit. This could indicate an abnormal programming of fetal cell functions and designate cases at increased risk of developing cellular and organ damage.

Prostanoid production in the umbilicoplacental arterial tree relative to impaired glucose tolerance.

The purpose of this study was to investigate prostanoid synthesis in different segments of the umbilicoplacental vascular tree and its relationship to impaired maternal glucose tolerance. Segments from the umbilical artery and vein, allantochorionic artery branches, and the cotyledon artery from 21 women with diabetes or impaired glucose tolerance and 10 healthy women were studied. Production of prostacyclin (PGI2) and thromboxane (TxA2) metabolites was determined. The Mann-Whitney U test, Wilcoxon signed-ranks matched-pairs test, Kruskal-Wallis test, analysis of variance, and simple linear regression analysis were used. A two-tailed P value of < 0.05 was considered statistically significant. From the umbilical artery distal to the cotyledon artery, the PGI2 synthesis decreased and the TxA2 synthesis increased gradually towards the periphery in normal pregnancy. The PGI2/TxA2 ratio was more than 200 times higher in the umbilical artery than in the cotyledon artery. The TxA2 production tended in general to be higher in the diabetic group than in the control group, resulting in significantly lower PGI2/TxA2 ratios in some vessels. The prostanoid production was not significantly correlated to maternal HbA1c or cord C-peptide concentrations. The balance between vascular prostacyclin and thromboxane synthesis in the umbilicoplacental arterial tree changed gradually towards the periphery: the more peripheral, the lower the prostacyclin and the higher the thromboxane production. The physiological role of this phenomenon is unknown, but may be of importance for the equilibration of vascular tone between arteries of different calibers. The altered prostanoid balance found in diabetic pregnancy was not directly attributable to the degree of maternal glycemic control, but may reflect increased free radical activity and peroxide production in diabetes.

Association between a low umbilical artery pulsatility index and fetal distress in labor in very prolonged pregnancies.

OBJECTIVE: To investigate the association between fetal, umbilical and uterine circulatory changes and adverse perinatal findings in very prolonged pregnancies. STUDY DESIGN: 44 women proceeding to 43 completed weeks of gestation with the intention of a trial of vaginal delivery were studied prospectively with ultrasound Doppler velocimetry. An intensified fetal surveillance was routinely commenced at 42 weeks and only uncomplicated pregnancies were allowed to proceed. The endpoint perinatal measures were oligohydramnios, fetal meconium release, fetal distress in labor and birth asphyxia. Flow variables in different groups were compared with the Mann-Whitney U test, Student's unpaired t-test, Wilcoxon signed-rank matched-pairs test, Fisher's exact test and contingency table analysis, and a two-tailed P value <0.05 was considered statistically significant. RESULTS: The umbilical artery pulsatility index was significantly lower in cases of fetal meconium release (n=12) and fetal distress (n=7). The umbilical venous flow velocity was significantly lower in cases of meconium, and the fetal aortic volume flow significantly higher in cases of fetal distress. No significant flow changes were found in connection with oligohydramnios (n=5) and birth asphyxia (n=2). Uterine flow was not significantly affected in any group. CONCLUSIONS: In very prolonged pregnancies, fetal distress in labor was not associated with an increased placental vascular resistance. In contrast to previous reports, the umbilical artery pulsatility index was low in cases of fetal distress and meconium release. The etiology is unknown, but a subclinical fetal hypoxia might have triggered a vasodilation of placental vessels. Vasodilation at an unchanged volume flow could also explain the decrease of umbilical venous flow velocity. The increased aortic volume flow indicates an increase of cardiac output in fetuses later developing distress in labor.

Fetal and uteroplacental circulatory changes in pregnancies proceeding beyond 43 weeks.

BACKGROUND: Practically all reference curves for Doppler blood flow variables in pregnancy end at 40 weeks. OBJECTIVE: To study fetal and uteroplacental circulatory changes in pregnancies proceeding beyond 43 weeks. STUDY DESIGN: Longitudinal comparisons from 42 to 43 weeks and comparisons with controls at term. MATERIAL: Thirty-four women delivered after 43 completed weeks (301 days) and a control group of 32 women delivered at 271 days of gestation. METHODS: From 42 weeks (294 days), serial Doppler blood flow measurements were performed in the fetal descending aorta, umbilical vessels, and maternal uterine artery. STATISTICAL METHODS: Student's unpaired t-test, Mann-Whitney U-test, and Fisher's exact test for comparison of groups; Student's paired t-test and Wilcoxon's signed-rank matched-pairs test for longitudinal data; simple linear regression analysis for comparison of variables. A two-tailed P-value of < 0.05 was considered statistically significant. RESULTS: From 42 to 43 weeks, the mean flow velocity decreased significantly in the fetal aorta and increased significantly in the umbilical vein. Compared to controls, the velocity and volume flow in the aorta and the umbilical artery flow resistance were significantly lower at 43 weeks. No significant change in uterine artery flow resistance was found. CONCLUSIONS: The changes in Doppler blood flow variables were all in accordance with physiological circulatory alterations enhancing continued fetal growth until the late post-term period. There were no signs of any general circulatory deterioration. Doppler velocimetry reference values at term may not be appropriate for evaluation of very advanced gestations.

Prostanoid production in umbilical vessels and its relation to glucose tolerance and umbilical artery flow resistance.

OBJECTIVE: To study prostanoid synthesis in umbilical vessels relative to maternal glucose tolerance and umbilical artery blood flow resistance. STUDY DESIGN: Umbilical artery pulsatility index was determined by Doppler velocimetry in 21 women with diabetes or impaired glucose tolerance and 10 healthy women. Segments from the umbilical artery and vein were incubated and prostacyclin (PGI2) and thromboxane (TxA2) metabolites determined. Statistical analyses with the Mann-Whitney U test, Kruskal-Wallis test, Wilcoxon signed-ranks matched-pairs test, contingency table analysis, Fisher's exact test, and simple linear regression analysis were used and a two-tailed P value of < 0.05 considered statistically significant. RESULTS: No significant difference in PGI2 or TxA2 production was found in umbilical vessels between the women with diabetes/impaired glucose tolerance and controls, but the PGI2/TxA2 ratio in the vein was significantly lower in the diabetes/impaired glucose tolerance group. The umbilical artery pulsatility index was positively correlated to the PGI2/TxA2 ratio in cord vessel segments and to cord plasma TxA2 concentration. The cord plasma TxA2 concentration was significantly higher in cases with a high umbilical artery pulsatility index. The prostanoid production was not correlated to maternal HbA1c or cord plasma C-peptide concentrations. CONCLUSIONS: In association with diabetes, an increased 'peroxide vascular tone' and an enhanced 'endoperoxide shift' between platelets and vascular endothelium may explain the unexpected positive correlation found between the umbilical artery pulsatility index and the vascular PGI2/TxA2 synthesis ratio.

The prospects for vaginal delivery in gestations beyond 43 weeks.

OBJECTIVE: To reveal factors influencing the prospect for vaginal delivery in very prolonged pregnancy. MATERIAL AND METHODS: Thirty-six nulliparae and 14 multiparae delivered beyond 43 weeks followed a routine surveillance protocol. Labor was induced on strict indications (n = 11; oligohydramnios, large fetus, hypertension) and on "soft' indications (n = 24; favorable cervix, emotional stress). STATISTICS: Receiver operating characteristic curves were obtained for maternal stature and birthweight with regard to mode of delivery. Student's unpaired t-test, Mann-Whitney U test, and Fisher's exact test were used with a two-tailed p < 0.05 considered statistically significant. RESULTS: Labor started spontaneously within three days in > 50% of cases managed expectantly. All multiparae had nonoperative vaginal deliveries. Of nulliparae, 89% delivered vaginally if spontaneous labor and 56% if induced. Failure to progress was the most common reason for operative delivery. A maternal height of < or = 160 cm, a very unripe cervix, and a birthweight > 4250 g were unfavorable factors in induced nulliparae. No case of perinatal mortality, severe birth asphyxia, meconium aspiration, or shoulder dystocia occurred. Fetal meconium release, fetal distress in labor, and birth asphyxia did not significantly differ with regard to parity or mode of labor. CONCLUSIONS: The prospect for vaginal delivery was strongly associated with parity. All multiparae had nonoperative vaginal deliveries, irrespective of spontaneous or induced labor. In nulliparae, a spontaneous onset was favorable but a maternal height of < or = 160 cm, a very unripe cervix, and a birthweight > 4250 g were unfavorable factors. In uncomplicated pregnancy with favorable factors spontaneous labor can be awaited for a few days.

Lack of association between Doppler velocimetry and synthesis of prostacyclin and thromboxane in umbilical cord vessels from growth retarded fetuses.

BACKGROUND: The aim of this study was to investigate the possible association between Doppler velocimetry and synthesis of prostacyclin (PGI2) and thromboxane A2 (TxA2) in umbilical cord vessels. The hypothesis was that an altered balance between PGI2 and TxA2 production is associated with a change of artery flow resistance. METHODS: 17 cases with a suspicion of intrauterine growth retardation and 21 normal pregnancies were studied. The umbilical artery pulsatility index (PI) and venous mean velocity were recorded in vivo by Doppler velocimetry. Cord vessel prostanoid synthesis was determined in vitro. The Mann-Whitney U test and simple linear regression were used for statistical analyses. RESULTS: The umbilical vessel synthesis of both PGI2 and TxA2 was in general lower in small-for-gestational age (SGA) cases (n = 10) compared to appropriate-for-gestational age (AGA) (n = 28). In the vein, the PGI2/TxA2 ratio was significantly lower in SGA cases. No certain correlations were found between umbilical artery PI and venous velocity, respectively, and PGI2 or TxA2, or their ratio. CONCLUSION: The prostanoid synthesis was in general lower in SGA cases, resulting in a significantly lower PGI2/TxA2 ratio in the umbilical vein. This indicates that fetal growth retardation might be associated with a disturbed endothelial function in this vessel. The synthesis of PGI2 and TxA2 in the juxtaplacental umbilical cord vessels was not correlated to the umbilical artery PI or venous flow velocity. It is possible that an altered release of prostanoids in the placental vasculature and tissue accounts for the rise of umbilical artery flow resistance instead.

Increased production of thromboxane A2 by coronary arteries after thrombolysis.

The coronary artery produces large amounts of prostacyclin (PGI2) and a small amount of thromboxane A2 (TXA2); this high PGI2/TXA2 ratio contributes to the antithrombotic properties of the coronary artery. This study was designed to determine whether this ratio changes after coronary artery thrombosis and thrombolysis and accounts for coronary artery reocclusion. Anesthetized dogs (N = 12) were subjected to electrically induced coronary artery thrombosis and tissue plasminogen activator-induced thrombolysis. Thrombolysis was achieved in 11 dogs, and the coronary artery reoccluded in five of these dogs after the initial reperfusion. Spontaneous and ionophore A23,187-stimulated PGI2 and TXA2 synthesis in normal circumflex and ischemic-reperfused left anterior descending coronary artery segments was measured by radioimmunoassay of thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively. Production of TXA2 was 413% to 656% greater in left anterior descending segments (from the region of thrombosis and sites proximal and distal to the thrombus) compared with normal circumflex segments (p < 0.001). Production of PGI2 was also increased but only by 46% to 80% in the left anterior descending segments compared with normal circumflex segments (p < 0.05). TXA2 production was greater in coronary artery segments that reocculded compared with segments that stayed open (p < 0.02). Scanning electron microscopy revealed platelet deposition in thrombosed left anterior descending segments but not in segments proximal or distal to the thrombus site, indicating that the vascular wall per se may be a source of increased production of TXA2.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of inhibition of thromboxane synthesis in experimental thrombosis and hemostasis.

The effect of a selective inhibitor of thromboxane synthesis (dazoxiben) was evaluated in different acute models for thrombosis and hemostasis. Dazoxiben significantly reduced the thrombogenicity of the modified human umbilical vein (Dardik Biograft) inserted in the carotid artery position in sheep. The effect was evident concerning patency, thrombus weight and platelet accumulation at the distal anastomosis. This paralleled a decreased production of thromboxane in both anastomoses and the midgraft region. Dazoxiben did not reduce either the frequency of jugular vein thrombosis (induced by a combination of endothelial damage and flow restriction) or arteriolar microembolism after laser injury in rabbits. Neither did it influence initial hemostasis as evaluated by measuring the hemostatic plug formation in the rabbit mesenteric microcirculation. It is concluded that thromboxane synthesis inhibition may be of value when attempting to improve the performance of small diameter vascular prostheses, the data obtained indicating a low risk for hemorrhagic complications.

Thromboxane production in umbilical vein grafts.

Umbilical vein grafts were placed in the carotid arteries of sheep and removed after 10 or 90 days for determination of in vitro production of 6-keto-PGF1 alpha and thromboxane B2 (TxB2) in the anastomoses and in the middle of the grafts. At both intervals the grafts produced much more TxB2 than carotid arteries, but no significant difference in production of 6-keto-PGF1 alpha was found between grafts and carotid arteries. The strongly decreased 6-keto-PGF1 alpha/TxB2 ratio indicates a low resistance to platelet adhesion and aggregation, which may be a contributory cause of the thrombogenicity of vascular grafts and may possibly be involved in the pathogenesis of neointimal fibrous hyperplasia.

Prostacyclin (PGI2) and plasminogen activator (PA) activity in umbilical vein grafts. An experimental study.

Glutaraldehyde-tanned human umbilical cord vein grafts (Dardik Biograft, Meadox) (HUV) measuring 6 cm in length and 5-6 mm in diameter were placed in the carotid arteries (CA) or jugular veins (JV) of sheep and the anastomoses were made end-to-end. Sections from the anastomotic sites and mid-graft were submitted to prostacyclin (PGI2) (radioimmunoassay) and plasminogen activator, PA, (histochemical) assays. Anastomotic PGI2 production from 6 grafts placed in the CA and removed 10 days later was similar to that of control arteries. The midgraft PGI2 synthesis tended to be less but the difference was not statistically significant. Anastomotic PGI2 from 11 grafts placed in the CA and removed 90 days later was also similar but the midgraft production was significantly less (p less than 0.025). From the distal anastomoses and mid portion of grafts placed in the jugular veins and removed 10 days later PGI2 synthesis was significantly less than that of control veins (p less than 0.025 and p less than 0.005 respectively) but no difference between the proximal anastomosis and control veins was observed. In none of 11 HUV removed on the 10th postoperative day was there any PA in the neointima; however, in 6 out of the 9 HUV removed on the 90th postoperative day, PA was demonstrated in the neointima. In conclusion, PGI2 synthesis similar to that of control vessels but less from the mid-graft regions. Neointima gained the ability to produce plasminogen activator.

Increased synthesis of thromboxane B2 and 6-keto-PGF1 alpha in hand veins from patients with deep venous thrombosis.

The production of 6-keto-PGF1 alpha and thromboxane B2 (TxB2) was determined in vitro in hand veins from 35 patients with deep venous thrombosis (DVT), 13 patients with stroke and 14 controls. The TxB2 production was significantly increased, approximately doubled, in patients with DVT and unchanged in patients with stroke. The production of 6-keto-PGF1 alpha was significantly increased in both groups. It is suggested that the increased production of TxB2 might be contributory to thrombosis.

6-keto-prostaglandin F1 alpha/thromboxane B2 ratio in vascular and lung tissue.

In vitro production of 6-keto-PGF1 alpha and thromboxane B2 (TxB2) was determined by radioimmunoassay. The 6-keto-PGF1 alpha/TxB2 ratio varied between 5 and 41 in vascular tissue and between 0.5 and 6 in lung tissue from various species. There was a correlation between the production of 6-keto-PGF1 alpha and TxB2; the correlation coefficient being about 0.6. The production of 6-keto-PGF1 alpha and TxB2 was stimulated by arachidonic acid and inhibited by indomethacin. The 6-keto-PGF1 alpha/TxB2 ratio was increased by a thromboxane synthetase inhibitor and various peptides, e.g. DDAVP and bradykinin, and was decreased by arachidonic acid. It is suggested that the balance between 6-keto-PGF1 alpha and TxB2 production in the vessel wall could be of importance in certain pathological conditions, e.g. thrombus formation.