Plasma prostanoids in pregnancy-induced hypertension

The concentrations of 13,14-dihydro-15-oxo-prostaglandin F2 alpha (PGFM), 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and thromboxane B2 (T X B2) were measured by radioimmunoassay in peripheral plasma from 183 pregnancy women attending routine antenatal clinics. A total of 141 patients (47 nulliparous, 94 parous) remained normotensive and had uncomplicated pregnancies. The results from this group showed that there was no significant difference in the concentration of any metabolite in relation to parity or gestational age. The concentrations (pmol/l; means +/- SD) were PGFM 373 +/- 105, 6-oxo-PGF1 alpha 391 +/- 104 and T X B2 373 +/- 121. Nineteen patients (12 nulliparous, 7 parous) who had pregnancy-induced hypertension (PIH) by the time of sampling (three) or who subsequently developed the symptom (mean time from sampling to diagnosis 11 weeks, range 1-24 weeks) had significantly higher levels of 6-oxo-PGF1 alpha (574 +/- 216; P less than 0.0005, Student's t-test) and T X B2 (603 +/- 268; P less than 0.0005). The concentrations in seven nulliparous patients with PIH and proteinuria were 656 +/- 276 for 6-oxo-PGF1 alpha and 754 +/- 228 pmol/l for T X B2.     

Primary dysmenorrhoea: the importance of both prostaglandins E2 and F2α

Summary. Menstrual fluid was collected in a contraceptive diaphragm from 16 women with primary dysmenorrhoea and 12 matched control subjects without dysmenorrhoea. Prostaglandins F_2α (PGF_2α), E₂ (PGE₂) and 6-oxo-prostaglandin F_1α (6-oxo-PGF_lα) were extracted and measured using gas-chromatography: mass spectrometry (GC:MS). The concentrations of both PGF_2α and PGE₂ were higher on days 1 and 2 in the dysmenorrhoea group than in the control group and the concentration of PGF_2α was higher on day 1 than on day 2 in the dysmenorrhoea group. The concentrations of 6-oxo-PGF_1α (the stable metabolite of PGI₂) were low in both groups. These results confirm suggestions that PGF_2α is important in the aetiology of dysmenorrhoea and also indicate that PGE₂ may be involved.     

Abnormal concentrations of prostaglandins in amniotic fluid during delayed labour in multigravid patients

Summary. Concentrations of prostaglandins E (PGE), F_2α (PGF), 13,14-dihydro-15-keto prostaglandin F_2α (PGFM), 6-keto F_1α and thromboxane B₂ were measured by specific radioimmunoassay in samples of amniotic fluid from 22 multigravid patients during labour. Normal labour in 10 patients was associated with a significant increase of PGE, PGF and PGFM with close correlation to cervical dilatation ( P < 0.05). In the 12 patients with clinically delayed labour, in the absence of cephalopelvic disproportion, there were significantly lower PGF ( P <0.002) and PGFM ( P < 0.05) concentrations obtained while no differences were observed in the other prostanoids measured. Administration of oxytocin to the latter group to enhance labour did not have any effect on the concentrations of prostaglandins obtained in spite of an improvement in intrauterine pressures and accelerated progress of labour.     

Reduced fetal exposure to aspirin using a novel controlled-release preparation in normotensive and hypertensive pregnancies

Objectives To examine the fetal effects of a novel controlled-release, low dose aspirin preparation in normal and hypertensive pregnancies.
Design Random double-blind study. Participants assigned to receive conventional formulation aspirin (75 mg), controlled-release low dose aspirin (75 mg), or matching placebo.
Setting National Maternity Hospital, Dublin.
Participants Eighteen women with an uncomplicated pregnancy and 18 women with preeclampsia.
Main outcome measures Urine was analysed for metabolites of thromboxane and prostacyclin by gas chromatography, mass spectrometry. Serum thromboxane B₂, was determined in maternal and cord blood.
Results 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 PGF_1α, 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).
Conclusions At equivalent maternal suppression of serum thromboxane B₂, a controlled aspirin release preparation results in lower fetal exposure than regular oral aspirin.     

The actions of prostaglandins and their interactions with angiotensin II in the isolated perfused human placental cotyledon

Summary. The prostaglandins PGE₁, PGE ₂, PGD ₂, PGF _2α., U46619 and 6_β-PGI_l were administered as bolus injections both separately and in combination with angiotensin II into the fetal circulation of isolated human placental cotyledons perfused in vitro . PGF_2α, and PGD₂, caused small dosedependent increases in fetal perfusion pressure when compared with U46619 which acted as an extremely potent vasoconstrictor of the fetal-placental vasculature. PGE₁, caused very small dose-dependent decreases in fetal perfusion pressure when injected on its own. In combination with angiotensin 11, PGE₁, PGD₂, and 6_β-PG1₁, caused significant, dose-related attenuations of the angiotensin II vasoconstrictive response whereas PGE₂, PGF_2α, and U46619 potentiated the response. Injections of angiotensin II after the infusion of indomethacin into the fetal circulation resulted in a potentiation of angiotensin II induced vasoconstriction. The results indicate that prostaglandins exert their effects on the fetal-placental circulation by modulating the actions of angiotensin II.     

The actions of prostaglandins and their interactions with angiotensin II in the isolated perfused human placental cotyledon

Summary. The prostaglandins PGE₁, PGE ₂, PGD ₂, PGF _2α., U46619 and 6_β-PGI_l were administered as bolus injections both separately and in combination with angiotensin II into the fetal circulation of isolated human placental cotyledons perfused in vitro . PGF_2α, and PGD₂, caused small dosedependent increases in fetal perfusion pressure when compared with U46619 which acted as an extremely potent vasoconstrictor of the fetal-placental vasculature. PGE₁, caused very small dose-dependent decreases in fetal perfusion pressure when injected on its own. In combination with angiotensin 11, PGE₁, PGD₂, and 6_β-PG1₁, caused significant, dose-related attenuations of the angiotensin II vasoconstrictive response whereas PGE₂, PGF_2α, and U46619 potentiated the response. Injections of angiotensin II after the infusion of indomethacin into the fetal circulation resulted in a potentiation of angiotensin II induced vasoconstriction. The results indicate that prostaglandins exert their effects on the fetal-placental circulation by modulating the actions of angiotensin II.     

The influence of spontaneous and induced labour on the rise in prostaglandins at amniotomy

Summary. Maternal peripheral plasma levels of 13, 14-dihydro-15-keto-prostaglandin F (PGFM) were measured immediately before and 5 min after amniotomy. Three groups of women were studied: women in late pregnancy; women in spontaneous labour; and women who had received intravaginal prostaglandin E₂ (PGE₂) pessary. There was no significant difference in the magnitude of the rise in PGFM after amniotomy in late pregnancy or during spontaneous labour suggesting that labour has no influence on the release of prostaglandin F_2α (PGF_2α) induced by artificial rupture of the fetal membranes. However, local administration of PGE₂ before amniotomy caused a greater rise in PGFM suggesting that PGE₂ can influence the release and/or metabolism of PGF_2α.     

The treatment of premenstrual tension with mefenamic acid: analysis of prostaglandin concentrations

Summary. Eighty patients with premenstrual tension were treated prospectively with mefenamic acid for a mean period of 13 months. Most of them (86%) reported significant relief of premenstrual tension. Symptoms of dysfunctional menorrhagia or primary dysmenorrhoea were also alleviated. In 19 patients, the plasma concentrations of prostaglandin (PG) E₂, PGF_2α and 13,14-dihydro-15-keto-prostaglandin F_2α (PGFM) were measured at intervals throughout three menstrual cycles. During the first cycle the patients received no treatment; in the subsequent two cycles they received either mefenamic acid or placebo in a randomized double-blind crossover manner. Similar measurements were made in 22 matched control subjects. The plasma concentrations of PGE₂, PGF_2α and PGFM were significantly lower in the 19 patients in all three menstrual cycles compared with the values in the control subjects. Excess synthesis of prostaglandins of the 1 series may occur in premenstrual tension and, by precursor depletion, result in decreased synthesis of the 2-series prostaglandins.     

Amniotic fluid prostaglandins do not reflect human fetal lung maturation

Summary. Experimental data suggest the involvement of classic prostaglandins (PG), prostacyclin (PGI,) and thromboxane A₂ (Tx A₂ ) in fetal pulmonary development. To explore this possibility in man, we assayed serial amniotic fluid samples from 33 women for 13, 14 -dihydro-15-keto-PGF_2α (M-PGF_2α a metabolite of PGF_2α), 6-keto-PGF_1α (a breakdown product of prostacyclin (PGI₂)), and thromboxane B₂ (a metabolite of TxA₂) as well as for the lecithin/sphingomyelin (L/S) ratio and phosphatidylglycerol. No difference in these prostanoids was seen between the samples with the immature (< 2) or mature 2) L/S ratio, or between the samples with undetectable or detectable phosphatidylglycerol. The L/S ratio matured in 16 women and phosphatidylglycerol became detectable in 19 women during serial smpling, but even in these women the changes in the amniotic fluid prostanoids were inconsistent. It is concluded that the amniotic fluid M-PGF_2α, 6-keto-PGF_1α, and TxB₂ do not reflect fetal pulmonary maturity.     

Effect of cervical application of prostaglandin (PG) E2 on plasma 13,14-dihydro-15-keto-PGF2α and oxytocin in pregnant women at term

Summary. The concentrations of 13,14-dihydro-15-keto-prostaglandin F_2α (PGFM) and oxytocin were measured by radioimmunoassay in the peripheral plasma of 21 women with low Bishop scores in whom cervical ripening and labour were induced with a cervical cap containing 1.5 mg of prostaglandin (PG) E₂, left in place for 6 h. Blood samples were taken before and at 3, 6, 9 and 24 h after the cap was applied. Four women (control group) had a cap without PGE₂. Labour began in 13 women receiving PGE₂, 12 of whom were delivered within 24 h. In these women plasma PGFM rose progressively to levels seen during spontaneous labour, paralleling the changes in cervical dilatation. The increase became significant at 6 h, when cervical dilatation was 4.5 cm (SEM 0.5). Plasma oxytocin also increased significantly while the cap was in place and then decreased. Plasma PGFM and oxytocin did not change in the control subjects, and in the eight women needing further induction of labour the initial rises were transient and not statistically significant.     

Maternal plasma prostaglandin E2 metabolite levels during human pregnancy and parturition

Summary. Because of methodological problems associated with the measurement in biological fluids of both prostaglandin E₂ (PGE₂) and its unstable principal circulating metabolite 13,14-dihydro-15-keto-PGE₂ (PGEM), there is little reliable information on these prostaglandins in human pregnancy and parturition. The recent discovery of a stable PGEM degradation product 11-deoxy-13,14-dihydro-15-keto-11β, 16-cyclo-PGE₂ (bicyclo-PGEM) has provided a means of studying endogenous plasma levels of PGEM which circumvents the problems encountered with direct measurements of PGE₂ and PGEM. Using a radioimmunoassay for bicyclo-PGEM we have therefore determined maternal peripheral plasma PGE₂ metabolite levels during human gestation. PGE₂ metabolite levels did not alter significantly during the second or third trimesters nor during labour. This contrasts with maternal peripheral plasma levels of the principal circulating metabolite of PGF_2α 13,14-dihydro-15-keto-PGF_2α (PGFM) which increases several fold during labour. Compared t o PGE₂ therefore. PGF_2α may be quantitatively the more significant prostaglandin associated with human parturition.     

Vaginal and abdominal delivery increases maternal urinary 6-keto-prostaglandin F1α excretion

Summary. To study the role of the antiaggregatory and vasodilatory prostacyclin (PGI₂) during human delivery, serial urine samples collected from 13 women delivered vaginally and from eight delivered abdominally were assayed for 6-keto-prostaglandin F_1α (6-keto-PGF_1α a breakdown product of PGI₂) by high-performance-liquid-chromatography and radioimmunoassay. In women delivered vaginally the mean urinary 6-keto-PGF_1α concentration was 41.9 (SE 8.3) ng/mmol creatinine, before the onset of labour and increased progressively to a maximum of 186.5 (SE 47.6) ng/mmol creatinine 2 h after delivery irrespective of the use of oxytocin and epidural analgesia. In women delivered by caesarean section under epidural anaesthesia, the urinary 6-keto-PGF_1α rose from 33.4 (SE 4.2) ng/mmol creatinine to 2153 (SE 314) ng/mmol creatinine 2 h after section. In both groups the increased levels had fallen by 24 h postpartum to levels below those found before delivery. In neonatal urine 6-keto-PGF_1α concentrations were some 12–30 times higher than those in postpartum urine. Thus, vaginal and abdominal delivery is accompanied by significant increases in maternal PGI₂ release, perhaps in the myometrium and/or intrauterine tissues. This may be of significance in the regulation of fetoplacental blood flow and in the prevention of intra- and postpartum thrombosis.     

Amerlex free triiodothyronine and free thyroxine levels in normal pregnancy

Summary. Free triiodothyronine (FT₃) and free thyroxine (FT₄) were measured in 159 women during normal pregnancy and compared with non-pregnancy reference ranges for these hormones. FT₃ values fell from the reference level of 6·34 (SD 1·06) pmol/l to 3·87 (SD 0·54) pmol/l in the 3rd trimester; corresponding figures for FT₄ were: reference 16·92 (SD 2·97) pmol/l, 3rd trimester 11·29 (SD 2·01) pmol/l. There were no significant changes in the 1st trimester; 4% and 69% of FT₃ results in the 2nd and 3rd trimesters respectively fell below the reference range of mean ±2 SD. The corresponding findings for FT₄ were 4% and 42%. FT₃ correlated reasonably well with total T₃ ( r =0·90) and was acceptably precise (within-batch CV 2·1% at 5·6 pmol/l, between-batch CV between 3·1% and 4·7% at six levels).     

Production of prostacyclin, 6-keto-PGFlα and thromboxane B2 by human umbilical vessels increases from the placenta towards the fetus

Summary. The aim of this study was to investigate the production of prostacyclin (PGI₂) and thromboxane B₂ (TXB₂) by incubated samples of umbilical arteries and veins taken at different distances (2, 10,20,30 cm) from the placenta to provide additional information relevant to the haemodynamics of umbilical blood flow. The production of PGI₂, and 6-keto-PGF_1α (the stable metabolite of PGI₂), was higher in both veins and arteries as the distance from the placenta at which the vessels were sampled was increased. A similar correlation between production by venous rings and distance from the placenta was observed for TXB₂, but there was no apparent gradient of TXB₂ production by the samples of arterial rings. No statistically significant variations were discernible in the ratio of 6-keto-PGF_1α:TXB₂ (∼50 in the veins and ∼20 in the arteries) in relation to the sampling distance. The significance of these high ratios is discussed in relation to umbilical blood flow and fetal well-being and development.     

Labetalol does not alter the placental and fetal blood flow or maternal prostanoids in pre-eclampsia

Summary. The effect of intravenously administered labetalol (1 mg/kg) on placental and fetal blood flow was studied in 13 pre-eclamptic women. Although the maternal blood pressure decreased, no changes occurred in the blood flows in the intervillous space, the umbilical vein or the fetal descending aorta, nor did the indices of peripheral vascular resistance in the fetal aorta change, but the placental vascular resistance did decrease. Labetalol had no effect on prostacyclin or thromboxane A₂ as measured by urinary 6-keto-prostaglandin F_1α and serum thromboxane B₂ respectively. These findings are clinically relevant since they suggest that labetalol reduces maternal blood pressure without interfering with the placental or fetal blood flow.     

A Double Blind Dose Trial of Intravaginal Prostaglandin F2α for Cervical Ripening and the Induction of Labour

Summary: A randomised double-blind trial involving 90 patients was set up to compare the efficacy of 25 mg PG F_2α, 50 mg PG F_2α and a placebo on cervical ripening when given in a vaginal tylose gel on the evening before surgical induction of labour. Preliminary stretching of the cervix and sweeping of the fetal membranes was not undertaken. In the 30 control patients, labour was not initiated and the mean improvement in the cervical score before surgical induction the next morning was 0.86. In the group of 30 patients receiving 25 mg PG F_2α, labour commenced during the night in 9 patients and the mean improvement in the cervical score was 3.76 (P < 0.0005); the corresponding figures for the 30 patients receiving 50 mg of PG F_2α were 10 patients coming into labour and cervical score improvement of 4.63 (P < 0.0005). he difference in the mean improvement of the cervical score between the 2 prostaglandin groups was not significant. Significantly fewer prostaglandin-treated patients needed augmentation during labour with intravenous oxytocin (P < 0.025) and there was a significant increase in the spontaneous delivery rate in the combined prostaglandin-treated group (P < 0.025). There was no statistical difference in the outcome of labour between the 2 prostaglandin groups. It was not possible to predict the patients whose cervices would not respond to PG F_2α pretreatment (15%) or those in whom labour would be initiated (30%). No side effects were experienced.     

Thromboxane A2 and prostacyclin levels in molar pregnancy

Summary. Plasma levels of thromboxane (TX) A₂ and prostacyclin (PGI₂), as measured by radioimmunoassay of their respective stable metabolites TXB₂ and 6–keto PGF_1α, were studied in six molar pregnancies immediately before, immediately following and 24 h after evacuation of the uterus. The mean (SD) levels for TXB₂ were 150 (41), 137 (32) and 125 (25) pg/ml respectively, and for 6–keto PGF_1α the respective values were 225 (52), 226 (127) and 213 (49) pg/ml. There was no significant difference in the levels of prostanoids between the samples taken at the various time intervals. The concentration of these prostanoids in molar intravesicular fluid was also determined. Their respective mean (SD) pg/ml values were 3682 (760) for TXB₂ and 2969 (744) for 6–keto PGF_1α. In 15 normal pregnancies of equivalent gestation, the mean amniotic fluid levels of TXB₂ and 6–keto PGF_lα were 34 (17) and 146 (86) pg/ml respectively. The ability of molar trophoblast to generate the prostanoids from [¹⁴C]arachidonic acid in vitro was also demonstrated. Mean (SD) values for TXB₂ and 6-keto PGF_1α were 12.2 (2.6) and 13.2 (1.8) pg/mg protein/min, respectively. It is likely that the high concentrations of prostanoids in vesicular fluid reflect the synthesizing ability of the villus vesicles. The mole contributes little to the circulatory prostanoids possibly because its villi are deficient in blood circulation.     

Vitamin D metabolism in normal and hypoparathyroid pregnancy and lactation

Summary. Plasma concentrations of vitamin D metabolites in −17 non-pregnant women, 22 pregnant women at delivery, and in eight lactating women 3 and 16 days after delivery, were compared with those in a postpartum hypoparathyroid patient treated with 1α-hydroxyvitamin D (1α-OHD). The mean concentration of 1,25-dihydroxy vitamin D [1,25–(OH)₂D] was 203 (SD 61) pmol/1 in the pregnant, and 86 (SD 27) pmol/1 in the non-pregnant women ( P <0.0005). The levels 3. and 16 days after delivery were similar [57 (11) compared with 62 (19) pmol/1], and lower than the non-pregnant value ( P <0.01). The 25-hydroxyvitamin D (25-OHD) concentration remained unchanged between the 3rd and 16th days after delivery, whereas the 24,25-dihydroxyvitamin D [24,25-(OH)₂D] level increased from 2.7 (SD 1.8) to 3.7 (SD 2.3)nmol/l ( P <0.025). The patient temporarily required an increased supplement of 1α-OHD during pregnancy, but a dose which was appropriate before pregnancy resulted in marked hypercalcaemia and a rise of 1,25-(OH)₂D concentration within 16 days of delivery despite lactation. The results suggest that the metabolic need for the active vitamin D metabolite 1,25-(OH)₂D is increased during pregnancy and rapidly reduced during early lactation in healthy and hypoparathyroid women.     

Determination of the stage of gestation by the assay of chorionic gonadotrophin and Schwangerschaftsprotein 1

Summary. Serial assays of Schwangerschaftsprotein 1 (SP1), SP1_α, SP1_β and human chorionic gonadotrophin were performed in 12 subjects from ovulation until the pregnancies had reached 16 weeks. From these data formulae were devised for deducing the stage of gestation from the concentration of the placental protein. These formulae were then tested by assays on 34 women not included in the original study. Assays of hCG do not give reliable indications of the stage of gestation when this has progressed beyond 9–10 weeks but SP1 assays give predictions of gestation corresponding closely to that derived from the last menstrual period up to 16 weeks gestation.     

Serum protein pattern in normal pregnancy with special reference to acute-phase reactants

Summary. The concentrations of acute-phase protein reactants, total protein, albumin and globulin fractions were measured throughout normal pregnancy in 27 women. α₁-Antitrypsin and caeruloplasmin concentrations increased gradually to reach their highest levels in the third trimester. Orosomucoid and haptoglobin showed similar patterns: higher levels in the first and third trimester with a decline around 24 weeks gestation. C-Reactive protein showed levels similar to those of non-pregnant healthy individuals (< 5 mg/1) throughout pregnancy. α₁,-, α₂ and β-Globulin concentrations increased from the first trimester towards term. γ-Globulin concentration changed little during gestation. The data obtained provide reference ranges for serum proteins in healthy pregnancy.