Social inequalities in preterm birth in Scotland 1980-2003: findings from an area-based measure of deprivation.

OBJECTIVE: The preterm birth rate in Scotland has been increasing in recent years. Although preterm birth rates show a social gradient, it is unclear how this gradient has been affected by the overall increase. We examined time trends in singleton live preterm birth rates in relation to area-based socio-economic indicators. DESIGN: Population-based retrospective cohort study. SETTING: Scotland. PARTICIPANTS: All singleton live births delivered in Scottish hospitals between 1980 and 2003 (n= 1 423 993). MAIN OUTCOME MEASURES: Singleton live preterm birth rates in each deprivation quintile were derived. Subgroup analyses of those born moderately preterm (32-36 weeks), very preterm (28-31 weeks) and extremely preterm (24-27 weeks) were performed. RESULTS: The rate of singleton live preterm births increased from 49.7 per 1000 live births in the 5-year period 1980-84 to 56.1 per 1000 in the 4-year period 2000-03, a relative increase of 12.9%. A marked social gradient was apparent at all time periods: relative indices of inequality were 1.63 (95% CI 1.38-1.92) in 1980-84 and 1.55 (1.44-1.66) in 2000-03. Similar social gradients existed for all gestational age subgroups. Smoking status at first antenatal contact and increased obstetric intervention, possibly reflecting improvements in fetal monitoring and neonatal care, appeared to explain some but not all the social gradient. CONCLUSIONS: Social inequalities in preterm birth were apparent in Scotland between 1980 and 2003. In addition to helping pregnant women to stop smoking, other means to reduce social inequalities are required.

The effect of graduated compression stockings on blood velocity in the deep venous system of the lower limb in the postnatal period.

Venous thromboembolism (VTE) is the leading cause of maternal mortality in the UK and is also a major cause of long-term morbidity. Recent UK national guidelines recommend thromboprophylaxis, which includes the use of graduated compression stockings (GCS), for high-risk women to reduce the risk of VTE in both the antenatal and postpartum period. This study of 17 women examined the effects of GCS on the deep venous system in the immediate postpartum period and found a statistically significant reduction in the diameter of the common femoral vein (CFV) (pre- versus post stocking diameter: mean 10.39 mm [SD 2.09] versus mean 9.69 mm [SD 1.99]) and an increase in the rate of blood velocity in the CFV (pre- versus post stocking velocity: mean 10.0 cm/s [SD 2.7] versus 13.9 cm/s [SD 4.2]) 30 minutes after application of thigh length GCS in women 1 or 2 days following a singleton vaginal delivery at term. This confirms reduction in venous stasis in the deep venous system in the immediate postpartum woman by the use of GCS, supporting their use in improving venous function in this context.

Sensitivity of mottled sculpins (Cottus bairdi) and rainbow trout (Onchorhynchus mykiss) to acute and chronic toxicity of cadmium, copper, and zinc.

Studies of fish communities of streams draining mining areas suggest that sculpins (Cottus spp.) may be more sensitive than salmonids to adverse effects of metals. We compared the toxicity of zinc, copper, and cadmium to mottled sculpin (C. bairdi) and rainbow trout (Onchorhynchus mykiss) in laboratory toxicity tests. Acute (96-h) and early life-stage chronic (21- or 28-d) toxicity tests were conducted with rainbow trout and with mottled sculpins from populations in Minnesota and Missouri, USA, in diluted well water (hardness = 100 mg/L as CaCO3). Acute and chronic toxicity of metals to newly hatched and swim-up stages of mottled sculpins differed between the two source populations. Differences between populations were greatest for copper, with chronic toxicity values (ChV = geometric mean of lowest-observed-effect concentration and no-observed-effect concentration) of 4.4 microg/L for Missouri sculpins and 37 microg/L for Minnesota sculpins. Cadmium toxicity followed a similar trend, but differences between sculpin populations were less marked, with ChVs of 1.1 microg/L (Missouri) and 1.9 microg/L (Minnesota). Conversely, zinc was more toxic to Minnesota sculpins (ChV = 75 microg/L) than Missouri sculpins (chronic ChV = 219 microg/L). Species-average acute and chronic toxicity values for mottled sculpins were similar to or lower than those for rainbow trout and indicated that mottled sculpins were among the most sensitive aquatic species to toxicity of all three metals. Our results indicate that current acute and chronic water quality criteria for cadmium, copper, and zinc adequately protect rainbow trout but may not adequately protect some populations of mottled sculpins. Proposed water quality criteria for copper based on the biotic ligand model would be protective of both sculpin populations tested.

Chronic toxicity of copper and ammonia to juvenile freshwater mussels (Unionidae).

The objectives of the present study were to develop methods for conducting chronic toxicity tests with juvenile mussels under flow-through conditions and to determine the chronic toxicity of copper and ammonia to juvenile mussels using these methods. In two feeding tests, two-month-old fatmucket (Lampsilis siliquoidea) and rainbow mussel (Villosa iris) were fed various live algae or nonviable algal mixture for 28 d. The algal mixture was the best food resulting in high survival (>or=90%) and growth. Multiple copper and ammonia toxicity tests were conducted for 28 d starting with two-month-old mussels. Six toxicity tests using the algal mixture were successfully completed with a control survival of 88 to 100%. Among copper tests with rainbow mussel, fatmucket, and oyster mussel (Epioblasma capsaeformis), chronic value ([ChV], geometric mean of the no-observed-effect concentration and the lowest-observed-effect concentration) ranged from 8.5 to 9.8 microg Cu/L for survival and from 4.6 to 8.5 microg Cu/L for growth. Among ammonia tests with rainbow mussel, fatmucket, and wavy-rayed lampmussel (L. fasciola), the ChV ranged from 0.37 to 1.2 mg total ammonia N/L for survival and from 0.37 to 0.67 mg N/L for growth. These ChVs were below the U.S. Environmental Protection Agency 1996 chronic water quality criterion (WQC) for copper (15 microg/L; hardness 170 mg/L) and 1999 WQC for total ammonia (1.26 mg N/L; pH 8.2 and 20 degrees C). Results indicate that toxicity tests with two-month-old mussels can be conducted for 28 d with >80% control survival; growth was frequently a more sensitive endpoint compared to survival; and the 1996 chronic WQC for copper and the 1999 chronic WQC for total ammonia might not be adequately protective of the mussel species tested. However, a recently revised 2007 chronic WQC for copper based on the biotic ligand model may be more protective in the water tested.

Intra- and interlaboratory variability in acute toxicity tests with glochidia and juveniles of freshwater mussels (Unionidae).

The present study evaluated the performance and variability in acute toxicity tests with glochidia and newly transformed juvenile mussels using the standard methods outlined in American Society for Testing and Materials (ASTM). Multiple 48-h toxicity tests with glochidia and 96-h tests with juvenile mussels were conducted within a single laboratory and among five laboratories. All tests met the test acceptability requirements (e.g., >or=90% control survival). Intralaboratory tests were conducted over two consecutive mussel-spawning seasons with mucket (Actinonaias ligamentina) or fatmucket (Lampsilis siliquoidea) using copper, ammonia, or chlorine as a toxicant. For the glochidia of both species, the variability of intralaboratory median effective concentrations (EC50s) for the three toxicants, expressed as the coefficient of variation (CV), ranged from 14 to 27% in 24-h exposures and from 13 to 36% in 48-h exposures. The intralaboratory CV of copper EC50s for juvenile fatmucket was 24% in 48-h exposures and 13% in 96-h exposures. Interlaboratory tests were conducted with fatmucket glochidia and juveniles by five laboratories using copper as a toxicant. The interlaboratory CV of copper EC50s for glochidia was 13% in 24-h exposures and 24% in 48-h exposures, and the interlaboratory CV for juveniles was 22% in 48-h exposures and 42% in 96-h exposures. The high completion success and the overall low variability in test results indicate that the test methods have acceptable precision and can be performed routinely.

Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

OBJECTIVES: To assess the risk of clinical complications associated with thrombophilia in three high-risk patient groups: women using oral oestrogen preparations, women during pregnancy and patients undergoing major orthopaedic surgery. To assess the effectiveness of prophylactic treatments in preventing venous thromboembolism (VTE) and adverse pregnancy outcomes in women with thrombophilia during pregnancy and VTE in patients with thrombophilia, undergoing major orthopaedic surgery. To evaluate the relative cost-effectiveness of universal and selective VTE history-based screening for thrombophilia compared with no screening in the three high-risk patient groups. DATA SOURCES: Electronic databases including MEDLINE, EMBASE, and four other major databases were searched up to June 2003. REVIEW METHODS: In order to assess the risk of clinical complications associated with thrombophilia, a systematic review of the literature on VTE and thrombophilia in women using oral oestrogen preparations and patients undergoing major orthopaedic surgery; and studies of VTE and adverse obstetric complications in women with thrombophilia during pregnancy was carried out. Meta-analysis was used to calculate pooled odds ratios (ORs) associated with individual clinical outcomes, stratified by thrombophilia type and were calculated for each patient group. To assess the effectiveness of prophylaxis, a systematic review was carried out on the use of prophylaxis in the prevention of VTE and pregnancy loss in pregnant women with thrombophilic defects and the use of thromboprophylaxis in the prevention of VTE in patients with thrombophilia undergoing major elective orthopaedic surgery. Relevant data were summarised according to the patient groups and stratified according to the types of prophylaxis. A narrative summary was provided; where appropriate, meta-analysis was conducted. An incremental cost-effectiveness analysis was then carried out, from the perspective of the NHS in the UK. A decision analytical model was developed to simulate the clinical consequences of four thrombophilia screening scenarios. Results from the meta-analyses, information from the literature and results of two Delphi studies of clinical management of VTE and adverse pregnancy complications were incorporated into the model. Only direct health service costs were measured and unit costs for all healthcare resources used were obtained from routinely collected data and the literature. Cost-effectiveness was expressed as incremental cost-effectiveness ratios (ICERs); an estimate of the cost per adverse clinical complication prevented, comparing screening with no screening, were calculated for each patient group. RESULTS: In the review of risk of clinical complications, 81 studies were included, nine for oral oestrogen preparations, 72 for pregnancy and eight for orthopaedic surgery. For oral contraceptive use, significant associations of the risk of VTE were found in women with factor V Leiden (FVL); deficiencies of antithrombin, protein C, or protein S, elevated levels of factor VIIIc; and FVL and prothrombin G20210A. For hormone replacement therapy (HRT), a significant association was found in women with FVL. The highest risk in pregnancy was found for FVL and VTE, in particular, homozygous carriers of this mutation are 34 times more likely to develop VTE in pregnancy than non-carriers. Significant risks for individual thrombophilic defects were also established for early, recurrent and late pregnancy loss; preeclampsia; placental abruption; and intrauterine growth restriction. Significant associations were found between FVL and high factor VIIIc and postoperative VTE following elective hip or knee replacement surgery. Prothrombin G20210A was significantly associated with postoperative pulmonary embolism. However, antithrombin deficiency, MTHFR and hyperhomocysteinaemia were not associated with increased risk of postoperative VTE. In the review of the effectiveness of prophylaxis, based on available data from eight studies, low-dose aspirin and heparin was found to be the most effective in preventing pregnancy loss in thrombophilic women during pregnancy, while aspirin alone was the most effective in preventing minor bleeding. All the studies on thrombophilia and major elective orthopaedic surgery included in the review of risk complications were also used in the review of the effectiveness of thromboprophylaxis. However, there were insufficient data to determine the relative effectiveness of different thromboprophylaxis in preventing VTE in this patient group. For the cost-effectiveness analysis, of all the patient groups evaluated, universal screening of women prior to prescribing HRT was the most cost-effective (ICER pound6824). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy (ICER pound202,402). Selective thrombophilia screening based on previous personal and/or family history of VTE was more cost-effective than universal screening in all the patient groups evaluated. CONCLUSIONS: Thrombophilia is associated with increased risks of VTE in women taking oral oestrogen preparations and patients undergoing major elective orthopaedic surgery, and of VTE and adverse pregnancy outcomes in women with thrombophilia during pregnancy. There is considerable difference in the magnitude of the risks among different patient groups with different thrombophilic defects. In women who are on combined oral contraceptives, the OR of VTE among those who are carriers of the FVL mutation was 15.62 (95% confidence interval 8.66 to 28.15). However, in view of the prevalence of thrombophilia and the low prevalence of VTE in non-users of combined oral contraceptives, the absolute risk remains low. Significant risks for VTE and adverse pregnancy outcomes have been established with individual thrombophilic defects. Thrombophilic defects including FVL, high plasma factor VIIIc levels and prothrombin G20210A are associated with the occurrence of postoperative VTE in elective hip or knee replacement therapy. These associations are observed in patients who were given preoperative thromboprophylaxis and are, therefore, of clinical significance. Universal thrombophilia screening in women prior to prescribing oral oestrogen preparations, in women during pregnancy and in patients undergoing major orthopaedic surgery is not supported by current evidence. The findings from this study show that selective screening based on prior VTE history is more cost-effective than universal screening. Large prospective studies should be undertaken to refine the risks and establish the associations of thrombophilias with VTE among hormone users and in patients undergoing orthopaedic surgery. The relative value of a thrombophilia screening programme to other healthcare programmes needs to be established.

The role of factor V Leiden in maternal health and the outcome of pregnancy.

There is growing evidence that women with thrombophilia are at increased risk of pregnancy related venous thromboembolism and of adverse pregnancy outcome including pregnancy loss, pre-eclampsia, intrauterine growth retardation and placental abruption. The factor V Leiden mutation is a heritable thrombophilia present in 5-8% of Caucasian populations. In its heterozygous form it is associated with a 4-to 8-fold increase in thrombotic risk. Homozygous inheritance, however, confers around an 80-fold increase in relative risk of thrombosis. The relationship between factor V Leiden and adverse pregnancy outcome has been studied in the recent literature, however the size of the estimated risks varies between individual studies due to heterogeneity of study design and small sample size in many cases. The management of women with factor V Leiden in pregnancy with low molecular weight heparin has been shown to be both safe and effective in preventing venous thromboembolism and improving pregnancy loss. Large scale, randomised controlled studies are required to confirm these findings. Selective screening for factor V Leiden based on prior venous thromboembolism has been shown to be marginally more cost-effective than universal screening in pregnancy and a recent consensus statement has recommended screening for thrombophilia based on a strong personal or family history of venous thromboembolism. There is now some evidence that placental problems may be associated with factor V Leiden in the fetus. There has also been an observed association between maternal factor V Leiden and fetal or neonatal stroke. These areas require further study and at present there is no evidence-based approach to investigation, prevention or management.

Anaesthetic considerations in a parturient with critical coronary artery disease and a drug-eluting stent presenting for caesarean section.

A parturient presented with her first symptoms of coronary artery disease at 18 weeks' gestation. Following an angiogram, a drug-eluting stent was inserted, resulting in resolution of her symptoms. The patient was prescribed anti-platelet medication including clopidogrel. She was delivered by elective caesarean section at 35 weeks under general anaesthesia. The anaesthetic management is discussed and a review of the literature presented.

Increased nitrotyrosine in the diabetic placenta: evidence for oxidative stress.

OBJECTIVE: To evaluate the presence of nitrotyrosine (NT) residues in placental villous tissue of diabetic pregnancies as an index of vascular damage linked to oxidative stress. RESEARCH DESIGN AND METHODS: Villous tissue was collected and flash frozen after delivery from 10 class C and D IDDM patients (37.9+/-3.2 weeks) and 10 normotensive pregnant individuals (37.5+/-3.8 weeks). Serial sections of tissue were immunostained with specific antibodies to NT, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and manganese superoxide dismutase (MnSOD). Sections were scored for intensity of immunostaining (0-3) by three observers blinded to the identity of tissue. RESULTS: All tissues demonstrated immunostaining for eNOS in both syncytiotrophoblast and stem villous vascular endothelium with no apparent differences between groups. Immunostaining for iNOS was seen in the villous stroma, but again was not different between the two groups. Significantly more intense NT staining was apparent in vascular endothelium and villous stroma (both P < 0.02) of diabetic placentas. The endothelium of large villous vessels of diabetic tissues also showed more intense immunostaining for MnSOD (P < 0.01). CONCLUSIONS: In these diabetic pregnancies, we were unable to show increased eNOS, unlike previous findings in preeclamptic pregnancies. The presence of NT may indicate vascular damage in the diabetic placenta due to peroxynitrite action formed from increased synthesis/interaction of nitric oxide and superoxide. The apparently paradoxical increase in MnSOD expression may be an adaptive response to increased superoxide generation.

Interaction of the protein C/protein S anticoagulant system, the endothelium and pregnancy.

Normal pregnancy is associated with significant changes in haemostasis, lipid metabolism and endothelial function. This suggests that maternal adaptation in these systems is required for successful pregnancy outcome. A number of acquired and heritable prothrombotic abnormalities are associated with complications in pregnancy. A common feature of these abnormalities is their ability to alter endothelial function or the protein C/protein S system and increase thrombin generation. In this review the normal function of the endothelium and the protein C/protein S system is detailed. The changes which characterize normal and complicated pregnancies are outlined and the evidence for the impact of heritable and acquired disorders of the protein C/protein S system on pre-eclampsia and fetal loss are discussed.

Placental proopiomelanocortin gene expression, adrenocorticotropin tissue concentrations, and immunostaining increase throughout gestation and are unaffected by prostaglandins, antiprogestins, or labor.

The objective of this study was to demonstrate the ontogeny of POMC gene expression, the distribution of immunoreactive ACTH, and tissue peptide content within the placenta and fetal membranes and to investigate the regulatory effects of PGs and progesterone during the first trimester and of labor at term. Tissues were collected from the following groups: 1) women undergoing first trimester (gestation 5-12 weeks) therapeutic abortion (by suction curettage with and without the synthetic PGE1 analogue, gemeprost administered vaginally 2-4 h before the procedure or with 600 mg mifepristone 48 h before receiving 1 mg gemeprost vaginally); 2) women undergoing second trimester therapeutic abortion (600 mg mifepristone; 1 mg gemeprost); 3) in association with delivery at term by spontaneous labor; 4) induced labor; or 5) elective caesarean section. ACTH was immunolocalized to the placental cytotrophoblasts in the first trimester and to the syncytiotrophoblasts in the second and third trimester. The intensity of the staining increased with advancing gestation. ACTH immunoreactivity also was localized in the epithelial layer of the amnion, the reticular layer of the chorion, and the decidual stroma. ACTH content measured by RIA in placental extracts increased significantly in the third trimester. In situ hybridization demonstrated expression of POMC messenger RNA in syncytiotrophoblasts and cytotrophoblasts from the first trimester and also demonstrated a significant increase in POMC gene expression with advancing gestation. The localization and staining intensity for ACTH and POMC gene expression were not affected by the administration of PGs or mifepristone or by labor at term. These data demonstrate the localization of ACTH immunoreactivity within the placenta throughout pregnancy, supporting the hypothesis that the placenta may activate and maintain the maternal and/or fetal hypothalamo-pituitary-adrenal axis throughout pregnancy.

Lipoprotein subfraction changes in normal pregnancy: threshold effect of plasma triglyceride on appearance of small, dense low density lipoprotein.

A detailed longitudinal examination of plasma lipoprotein subfraction concentrations and compositions in pregnancy was performed with the objective of discovering the pattern of change in lipoprotein subfractions. Plasma triglyceride, cholesterol, very low density lipoprotein (VLDL1), very low density lipoprotein (VLDL2), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and its subfractions (LDL-I, LDL-II, LDL-III), and high density lipoprotein-cholesterol (HDL cholesterol) were quantified in 10 normal pregnant women from 10 weeks of gestation and at 5 weekly intervals thereafter, until 35 weeks of gestation, together with circulating hepatic lipase (at 10 and 35 weeks) and serum estradiol concentration. Median concentrations of VLDL1 (19-109 mg/dL), VLDL2 (17-103 mg/dL) and IDL (26-124 mg/dL) increased in parallel (maximum increase around 5-fold) as plasma triglyceride increased with advancing gestation. This contrasts with observations in the normal non-pregnant female, where higher concentrations of plasma triglyceride are associated with preferentially higher VLDL1 concentrations. The rise in IDL was also remarkable as this does not normally accompany changes in plasma triglyceride. LDL mass increased by 70% (200-353 mg/dL) between 10 and 35 weeks, and in 6 of the 10 women studied, the LDL subfraction pattern was modified towards a smaller denser pattern in a manner suggestive of a "threshold" transition, with the proportion of LDL-III increasing at the expense of LDL-II, whereas in the other 4 women, LDL subfraction profile remained unchanged throughout pregnancy. Interestingly, this "threshold" transition, if it occurred, did so at varying gestational ages and triglyceride concentrations for different women. The likelihood of LDL subfraction change and the final concentration of small, dense. LDL-III were related to the 10-week triglyceride concentration (R2 = 36.7%, P = 0.063) and to the rate of change in triglyceride for a given increment in estrogen (R2 = 48.6%, P = 0.025). In addition, VLDL1 mass exceeded 100 mg/dL during pregnancy only in those individuals in whom LDL profile perturbation was evident (chi 2, P < 0.001). LDL profile change was evident at the lowest triglyceride concentrations in the 2 individuals with the highest increments in triglyceride corrected for estrogen. On the basis of these longitudinal observations, we conclude the following: 1) as plasma triglyceride increases in pregnancy, there are parallel rises in median concentrations of VLDL1, VLDL2 and IDL, around 5-fold; 2) as a result of this progressive increase in plasma triglyceride, in particular in VLDL1, the LDL profile is altered in some individuals towards smaller, dense particles; 3) in general, the higher the initial (booking) fasting plasma triglyceride concentration or the larger the rate of change in triglyceride for a given increment in estradiol, the greater the probability of change in LDL profile towards smaller denser species; 4) significantly, LDL subclass perturbation towards smaller denser species occurs not in a gradual and progressive manner but exhibits "threshold" behavior; and finally, 5) this threshold is achieved at differing gestational ages and triglyceride concentrations for different women.

The effect of type 1 diabetes mellitus on vascular responses to endothelin-1 in pregnant women.

Diabetes is associated with vascular dysfunction, which may be due in part to altered vascular responses to endogenous peptides such as endothelin-1. These altered responses may also contribute to the decreased maternal peripheral resistance in pregnancy. The aim of this study was to examine the effect of diabetes on the vasoconstrictor response to endothelin-1 in pregnant women. Small arteries were isolated from nine healthy pregnant, seven type 1 diabetic pregnant women, and five healthy nonpregnant women. Contraction curves were performed on a wire myograph for noradrenaline (1 nM to 30 microM) and endothelin-1 (1 pM to 0.3 microM). Maximum responses and sensitivity were compared by t test. No differences in maximum response to noradrenaline or potassium were seen among the three groups. The maximum response to endothelin-1 was significantly increased in pregnancy (P < 0.05), whereas endothelin-1 sensitivity was reduced in the diabetic compared with the nondiabetic pregnant women (P < 0.05). Pregnant women have an increased maximum vasoconstriction response to endothelin-1 compared with nonpregnant women, whereas diabetic pregnant women demonstrate reduced sensitivity to endothelin-1. These observations suggest that endothelin-1 may play a role in maintaining peripheral vascular tone in normal pregnancy, and the decreased sensitivity seen in pregnant women with diabetes may reflect abnormal vascular reactivity.

Nitrotyrosine residues in placenta. Evidence of peroxynitrite formation and action.

The interaction of nitric oxide and superoxide produces peroxynitrite anion, a strong, long-lived oxidant with pronounced deleterious effects that may cause vascular damage. The formation and action of peroxynitrite can be detected by immunohistochemical localization of nitrotyrosine residues. We compared the presence and localization of nitrotyrosine and of the endothelial isoform of nitric oxide synthase in placental villous tissue from normotensive pregnancies (n = 5) with pregnancies complicated by preeclampsia (n = 5), intrauterine growth restriction (n = 5), and preeclampsia plus intrauterine growth restriction (n = 4), conditions characterized by increases in fetoplacental vascular resistance, fetal platelet consumption, and fetal morbidity and mortality. In all tissues, absent or faint nitrotyrosine immunostaining but prominent nitric oxide synthase immunostaining were found in syncytiotrophoblast. In tissues from normotensive pregnancies, faint nitrotyrosine immunostaining was found in vascular endothelium, and nitric oxide synthase was present in stem villous endothelium but not in the terminal villous capillary endothelium. In contrast, in preeclampsia and/or intrauterine growth restriction, moderate to intense nitrotyrosine immunostaining was seen in villous vascular endothelium, and immunostaining was also seen in surrounding vascular smooth muscle and villous stroma. The intensity of nitrotyrosine immunostaining in preeclampsia (with or without intrauterine growth restriction) was significantly greater than that of controls. Intense nitric oxide synthase staining was seen in endothelium of stem villous vessels and the small muscular arteries of the terminal villous region in these tissues and may be an adaptive response to the increased resistance. The presence of nitrotyrosine residues, particularly in the endothelium, may indicate the formation and action of peroxynitrite, resulting in vascular damage that contributes to the increased placental vascular resistance.

Lipid and lipoprotein concentrations in pregnancies complicated by intrauterine growth restriction.

Previous studies have shown that in preeclampsia, plasma lipids climb substantially above levels seen in normal pregnancies. Such lipid changes may play a role in the endothelial damage characteristic of preeclampsia. Pregnancies complicated by intrauterine growth restriction (IUGR), without preeclampsia, have similar placental pathology to preeclampsia despite the absence of the maternal systemic manifestations of hypertension and proteinuria. The aim of this study was to perform a cross-sectional study of lipid and lipoprotein concentrations in the third trimester, from normal pregnancies, and those complicated by IUGR without preeclampsia. Our hypothesis was that, in contrast to the exaggerated lipid changes seen in preeclampsia, lipid and lipoprotein concentrations in IUGR would be similar to those of matched healthy pregnant controls. Fasting blood samples for lipids and lipoprotein fractions were taken in the third trimester, from eight women with IUGR; and eight women with uncomplicated pregnancies, matched as a group for age, booking weight, parity, and gestational age at sampling. There were no significant differences (P > 0.05) in the median concentrations of triglyceride, high-density lipoprotein, and very-low-density lipoprotein 1 (VLDL1), between cases and controls. However, women with IUGR pregnancies had significantly lower cholesterol [4.95 mmol/L (3.35-7.10) vs. 7.47 (5.75-8.45); median (range) for IUGR patients and controls, respectively; P < 0.01], low-density lipoprotein (LDL)-cholesterol [2.45 mmol/L (0.95-3.60) vs. 4.25 (3.35-5.60); P < 0.01], VLDL2 mass [59.0 mg/dL (37-87) vs. 103.0 (64-168); P < 0.01], intermediate-density lipoprotein mass [56.0 mg/dL (31-110) vs. 125.6 (91-157); P < 0.01], and total LDL mass [221.0 mg/dL (104-237) vs. 380.3 (267-534); P < 0.01]. In addition, it was noteworthy that, with respect to LDL-cholesterol and total LDL mass, there was little or no overlap in the ranges of concentrations measured between cases and controls. Because VLDL2 and intermediate-density lipoprotein are the synthetic precursors to LDL in the circulation, their significantly lower median concentrations imply a failure of appropriate LDL synthesis in IUGR pregnancies. Whatever the mechanism, if our results are confirmed in larger studies and longitudinal investigations, then LDL-cholesterol measurements (when LDL-cholesterol fails to rise appropriately or is low in the third trimester) may be of use in identifying mothers with, or at risk of, a pregnancy complicated by IUGR.

Lipoprotein (a) levels in normal pregnancy and in pregnancy complicated with pre-eclampsia.

Lipoprotein (a) (Lp(a)) is recognised as a risk factor for arterial and venous thrombosis, a property which may relate to its structural similarity to plasminogen. Pregnancy is associated with a hypofibrinolytic state. Elevated Lp(a) may influence fibrinolysis and have an unfavourable role in pregnancy outcome. In this study alterations in plasma Lp(a) concentrations during normal pregnancy was examined, in a detailed longitudinal investigation, in ten women together with changes in other lipid parameters. In addition, Lp(a) concentrations were examined in subjects with pre-eclampsia (n=10) relative to matched controls (n=10), since it has recently been reported that a substantial increase in circulating Lp(a) occurs in this disorder. Lp(a) concentration increased steadily in normal pregnancy between 10 and 35 weeks with a doubling of the median value from 14.5 to 27.0 mg/dl (P=0.01). A significant increase in Lp(a) values was observed in all subjects with increasing gestation (median rise 190%, range 117-340%). This increase was intermediate to those seen in plasma triglyceride and cholesterol. No significant difference in Lp(a) values was observed in subjects with pre-eclampsia, compared with matched normal pregnancy controls (median 14 mg/dl [IQR 4.7-69.0] in pre-eclampsia vs 20 mg/dl [9.0-56. 3] in controls; P=0.57), at a median gestation of 32 weeks. In conclusion, there is a 2-fold increase in Lp(a) during normal pregnancy, which may influence fibrinolysis. Circulating Lp(a) is not significantly elevated in women with pre-eclampsia, and thus is unlikely to play a role in the pathophysiology of this disorder.

Fetal cord plasma lipoprotein status in uncomplicated human pregnancies and in pregnancies complicated by pre-eclampsia and intrauterine growth restriction.

Maternal lipids have been studied extensively in pre-eclampsia (PE) and intrauterine growth restriction (IUGR) but little is known about fetal lipids. We hypothesised that the maternal lipid perturbations in PE and IUGR pregnancies would result in similar alterations in the fetal lipid profile. We performed a cross-sectional case control study of maternal and fetal (delivery venous cord blood) lipid and lipoprotein concentrations in third trimester uncomplicated pregnancies (n = 81) and in pregnancies complicated by PE (n = 23) or IUGR (n = 17). In uncomplicated pregnancies, fetal log total cholesterol (TC), log triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels were significantly affected by mode of delivery. Fetal log TC (r = 0.37, P = 0.02), log TG (r = 0.34, P = 0.04) and TC/HDL-C ratio (r = 0.31, P = 0.05) were positively correlated with placental weight. Maternal TC (r = 0.35, P = 0.03) and LDL levels (r = 0.36, P = 0.02) were associated with fetal HDL-C levels. Maternal TC was significantly elevated in PE [mean 6.75 (standard deviation 1.14) mmol/L] compared to BMI-matched controls [5.94 (0.89) mmol/L P = 0.04]. In PE, fetal log TC [mean 0.36 (0.23) versus 0.11 (0.15) log mmol/L, P = 0.03], fetal log TG [-0.21 (0.32) versus -0.49 (0.26) log mmol/L, P = 0.02] and fetal TC/HDL-C ratio [3.64 (1.62) versus 1.80 (0.86), P = 0.001] were higher than in controls, after adjustment for mode of delivery. In IUGR, fetal log TG [-0.17 (0.35) versus -0.57 (0.10) log mmol/L, P = 0.01] was higher than controls, after adjustment for mode of delivery. There were no correlations between maternal and fetal lipid levels, or between fetal birth weight and either maternal or fetal lipids in the PE or IUGR groups. We conclude that although fetal lipids do not show a direct correlation with maternal lipids in PE or IUGR, these complications of pregnancy significantly impact upon fetal lipid levels possibly due to increased fetal stress or compromised placental lipid transport. Our findings are potentially pertinent to understanding the future cardiovascular health of the offspring.

Mechanical stretch increases proto-oncogene expression and phosphoinositide turnover in vascular smooth muscle cells.

OBJECTIVE: To determine whether changes in haemodynamic load, simulated in vitro by mechanically stretching cultured vascular smooth muscle cells, could be transduced into biochemical signals similar to those produced by growth factors. DESIGN: A system was developed which was capable of stretching cultured vascular smooth muscle cells from 0 to 20%. The effect of stretching quiescent vascular smooth muscle cells on both c-fos messenger RNA (mRNA) expression and release of total inositol phosphates was determined over a time interval of 0-360 min. METHODS: Rat mesenteric artery vascular smooth muscle cells were grown using standard cell culture methods. Induction of the proto-oncogene, c-fos, was determined by Northern blotting. Phosphoinositide breakdown was assessed by measuring [3H]-inositol phosphates released from prelabelled cells. RESULTS: A 20% fixed stretch resulted in a rapid induction of c-fos mRNA which reached maximal levels by 15 min. The amount of c-fos mRNA detected was dependent on the degree of stretch, with maximum induction obtained for 15 and 20% stretch. The effects of mechanical stretch were also assessed on phosphoinositide turnover by measuring [3H]-inositol phosphates released from prelabelled cells. A 20% fixed stretch of vascular smooth muscle cells for 20 min resulted in a 3.2-fold increase in total [3H]-inositol phosphates released compared with unstretched cells. CONCLUSIONS: Our results show that mechanical stretch increases proto-oncogene expression and phosphoinositide turnover in vascular smooth muscle cells in vitro. These observations suggest that mechanical stretch and growth factors share common signal transduction pathways which may be important in the development of vascular hypertrophy.

Differential localization of superoxide dismutase isoforms in placental villous tissue of normotensive, pre-eclamptic, and intrauterine growth-restricted pregnancies.

Several isoforms of superoxide dismutase (SOD), including copper/zinc (cytosolic) and manganese (mitochondrial), exist. In the human placenta, SOD may prevent excessive superoxide accumulation and any potential deleterious oxidative effects. In pre-eclampsia, increased levels of lipid peroxide and decreased SOD activity have been described in the placenta. Oxidative stress such as occurs in pre-eclampsia can alter expression of SOD isoforms. The objective of this study was to localize the copper/zinc and manganese SOD isoforms in the placenta using immunohistochemistry and to compare localization and intensity of immunostaining in tissues from normotensive pregnancies with those from pregnancies complicated by pre-eclampsia and/or intrauterine growth restriction (IUGR). Western blotting with specific antibodies recognized a 17-kD copper/zinc and a 23-kD manganese SOD subunit in placental homogenates. Intense immunostaining for the manganese SOD isoform was seen in villous vascular endothelium, but only faint staining was found in the syncytiotrophoblast or villous stroma. In serial sections, intense immunostaining for copper/zinc SOD was seen in certain cells of the villous stroma but only faint immunostaining in syncytiotrophoblast and vascular endothelium. No apparent differences in localization or intensity of immunostaining for either isoform were seen between tissues of normotensive or pre-eclamptic pregnancies, with or without IUGR. The different cellular localizations of the SOD isoforms suggest that they fulfill different functional roles within the placenta.