Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening?
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Coronary Disease↗
Biomedical subjects
Ian A Greer
Publications and source records attributed to Ian A Greer.
Cost-effectiveness of screening for the factor V Leiden mutation in pregnant women.
The factor V Leiden (FVL) mutation is associated with vascular complications in pregnancy, and routine screening of all pregnant women has been suggested. We did a prospective, unselected study in 967 pregnant women to evaluate the cost-effectiveness of screening all women, or only those with a personal or family history of venous thrombosis (n=113). When anticoagulant prophylaxis was assumed to effect a 50% reduction in vascular complications, we recorded an additional management cost of 3768 pounds sterling with selective screening and 39,841 pounds sterling with universal screening. This additional cost would result in prevention of less than one and three vascular events,respectively. Our findings, therefore, suggest that screening of pregnant women for the FVL mutation is not cost-effective.
Cost-Benefit Analysis↗
Statins as novel therapies for osteoporosis?
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Cardiovascular Diseases↗
Exploring the role of low-molecular-weight heparins in pregnancy.
Thromboembolic complications are leading causes of both maternal and fetal morbidity and mortality. To reduce the incidence of venous thromboembolism (VTE) in pregnancy and improve outcomes, a wider understanding of the risk factors involved and better identification of women at risk of thrombosis are required. Optimal management of thromboembolic disease, both to prevent VTE and to avoid recurrence of pregnancy complications such as miscarriage, centers on the use of low-molecular-weight heparin (LMWH). LMWHs, such as enoxaparin and dalteparin, have clinical and practical advantages compared with unfractionated heparin in terms of improved safety (significantly lower incidence of osteoporosis, thrombocytopenia, and possibly allergic skin reactions) and the potential for outpatient treatment of acute VTE. However, many unanswered questions remain, including who to treat, how to treat them, and when to treat in the case of patients with thrombophilia and a history of previous pregnancy complications.
Abnormalities, Drug-Induced↗
Supraphysiological concentrations of estradiol in menopausal women given repeated implant therapy do not adversely affect lipid profiles.
BACKGROUND: The effects of oral estrogen therapy (ERT) on lipids and metabolic parameters are well known, in contrast to the effects of subcutaneously administered estrogen, particularly high concentrations of estrogen. We examined metabolic parameters in cohorts of women with and without subcutaneous estrogen therapy with concomitant supra-normal concentrations of estradiol (SE). METHODS: Lipids and lipoprotein concentrations, low density lipid (LDL) subfractions, and activity of hepatic lipase (HL) were assessed in 30 menopausal women with SE and 19 control subjects not using ERT, matched for body mass index and age. RESULTS: Waist-hip ratio (WHR) and fasting insulin (FI) concentrations were lower in the SE group compared with the women not on ERT (P < 0.05). The concentrations of triglyceride and high density lipid (HDL) cholesterol were similar (P > 0.1), whereas total cholesterol (P < 0.05), LDL cholesterol (P < 0.05), and HL activity (P < 0.01) were lower in the SE group. Concentrations of the large, buoyant LDL I subfraction were significantly lower in the SE group (P < 0.05), but there was no difference in LDL III concentrations. CONCLUSIONS: Women with SE have similar triglyceride and HDL cholesterol levels but lower LDL cholesterol concentrations compared with post-menopausal women not taking ERT. The observations that the SE group showed reduced fasting insulin and WHR suggest that supra-normal circulating concentrations of estradiol, delivered subcutaneously, may beneficially influence insulin metabolism.
Body Constitution↗
Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term.
Each of the proinflammatory cytokines interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor (TNF) alpha has been identified in reproductive tissues during labor. The cellular origin of these cytokines is unclear. The aim of this study was to localize these proinflammatory cytokines in myometrium (upper and lower segment), cervix, and fetal membranes at term. Biopsies were taken from women undergoing cesarean section either before or after the onset of labor. Immunohistochemistry was used to localize each of the cytokines IL-1beta, IL-6, IL-8, and TNFalpha. Leukocytes were localized using an antibody to CD45. In myometrium and cervix, immunostaining for IL-1beta was predominantly in leukocytes. In fetal membranes, IL-1beta localized to leukocytes and to the stromal cells of the decidua. In myometrium, IL-6, IL-8, and TNFalpha were restricted to leukocytes, which were present in greater numbers in tissue obtained during labor. In cervix, IL-6, IL-8, and TNFalpha localized to leukocytes and glandular and surface epithelium. IL-8 also localized to cervical stromal cells. In fetal membranes, IL-6 and TNFalpha were expressed by decidual stromal cells, infiltrating leukocytes, and extravillous trophoblasts. In membranes, IL-8 localized to leukocytes in the chorion but was not detected in the amnion. In fetal membranes collected at labor, IL-8 was expressed in decidual stromal cells. Infiltrating leukocytes are a major source of cytokines in uterine tissues during labor.
Adult↗
Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways.
Obesity is increasing in prevalence worldwide and in all age groups. In nonpregnant individuals, obesity is associated with dyslipidemia; hyperinsulinemia; vascular dysfunction; and, more recently, low-grade chronic inflammation. However, whether such effects are sustained during pregnancy has been sparsely investigated but is important to establish, given the association of maternal obesity with numerous adverse metabolic and vascular consequences. We consecutively recruited 47 healthy women in the third trimester of pregnancy and divided the participants into 2 groups, lean [n = 24; median body mass index (BMI), 22.1 kg/m(2)] and obese (n = 23; median BMI, 31.0 kg/m(2)) around the median first trimester BMI. The age, parity, and smoking history were comparable in both groups. A detailed panel of metabolic and inflammatory parameters was measured and an in vivo assessment of endothelial-dependent and -independent microvascular function made using laser doppler imaging. Although low-density lipoprotein cholesterol and glycosylated hemoglobin were similar, fasting triglyceride concentrations were higher [2.70 (interquartile range, 2.3-3.21) vs. 2.20 (IQ range, 2.0-2.6) mmol/liter, P = 0.02] and high-density lipoprotein concentrations were lower [1.55 (IQ range, 1.1-1.7) vs. 1.72 (IQ range, 1.4-2.0) mmol/liter, P = 0.02] in the obese group. Leptin [55.6 (range, 45-64.4) ng/ml vs. 23.8 (range, 13.2-35.2) ng/ml, P < 0.0001] and fasting insulin [14.5 (range, 11.4-27.3) vs. 6.5 (range, 4.6-9.7) mU/liter, P < 0.0001] levels were more than double. Similarly, levels of inflammatory parameters, IL-6 [3.15 (range, 2.4-3.5) vs. 2.1 (range, 1.73-2.85) pg/ml, P = 0.003], and sensitive C-reactive protein [4.45 (range, 2.9-6.6) vs. 2.25 (range, 0.92-3.65) mg/ml, P = 0.0015] were also substantially elevated. Both endothelial-dependent and -independent vasodilatory responses were significantly reduced in the obese group (P = 0.0003 and P = 0.02, respectively, ANOVA) and systolic blood pressure was higher (P = 0.01). Metabolic factors, C-reactive protein (r = 0.289, P = 0.049), and insulin (r = 0.339, P = 0.02) were related inversely to endothelial-dependent function. These comprehensive data demonstrate that, as in nonpregnant obese individuals, obesity in pregnancy is associated not only with marked hyperinsulinemia (without necessarily glucose dysregulation) and dyslipidemia but also impaired endothelial function, higher blood pressure, and inflammatory up-regulation. Such a spectrum of risk factors may contribute to maternal complications in obese women and, as a result, influence fetal programming of adult vascular disease. Clearly, these data provide further rationale to examine the potential benefits of preconceptual weight loss and antenatal exercise.
Adult↗
Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial.
Women with oligomenorrhea and polycystic ovaries show a high incidence of ovulation failure perhaps linked to insulin resistance and related metabolic features. A number of reports show that the biguanide metformin improves ovarian function. However, in these trials the quality of evidence supporting ovulation is suboptimal, and few studies have been placebo-controlled. The aim of our study was to use a double-blind, placebo-controlled approach with detailed assessment of ovarian activity (two blood samples per week) to assess the validity of this therapeutic approach in this group of women. Of the 94 patients randomized, 2 withdrew before treatment commenced, 47 received placebo, and 45 received metformin (850 mg, twice a day). The numbers discontinuing the study prematurely were higher in the treatment group (n = 15) than the placebo group (n = 5; P < 0.05). The ovulation frequency assessed by the ratio of luteal phase weeks to observation weeks was significantly (P < 0.01) higher in the treated group (23%) compared with the placebo (13%), and the time to first ovulation was significantly (P < 0.05) shorter [23.6 d; 95% confidence interval (CI), 17, 30; compared with 41.8 d; 95% CI, 28, 56]. The proportion of patients failing to ovulate during the placebo-treatment period was higher (P < 0.05) in the placebo group, and the majority of ovulations were characterized by normal progesterone concentrations in both groups. The effect of metformin on follicular maturation was rapid, because the E2 circulating concentration increased over the first week of treatment only in the metformin group. Significant (P < 0.01) weight loss (and leptin reduction) was recorded in the metformin group, whereas the placebo group actually increased weight (P < 0.05). A significant increase in circulating high-density lipoprotein was observed only in the metformin-treated group. Metabolic risk factor benefits of metformin treatment were not observed in the morbidly obese subgroup of patients (body mass index > 37). No change in fasting glucose concentrations, fasting insulin, or insulin responses to glucose challenge was recorded after 14-wk metformin or placebo therapy. There was an inverse relationship between body mass and treatment efficacy. We show in a large randomized placebo-controlled trial that metformin treatment improves ovulation frequency in women with abnormal ovarian function and polycystic ovaries significantly but to a modest degree, and protracted treatment improves cardiovascular risk factors. These data support a beneficial effect of metformin in improving ovarian function in women with oligomenorrhea and polycystic ovaries.
Adult↗
Hypercoagulable states and pregnancy.
Pulmonary thromboembolism is a major cause of maternal death in the developed world. Underlying this condition is the problem of deep venous thrombosis. These problems often reflect an underlying hypercoagulable state. Growing evidence implicates congenital and acquired thrombophilias in the pathophysiologic processes underlying not only venous thrombosis, but also miscarriage, intrauterine growth restriction, and preeclampsia, raising new possibilities for intervention.
Anticoagulants↗
Elimination of electrically induced iontophoretic artefacts: implications for non-invasive assessment of peripheral microvascular function.
Iontophoretic assessment of skin microvascular function is complicated by the occurrence of electrically induced hyperaemia, especially at the cathode. Studies were performed to identify means of reducing such effects. Skin vasodilator responses were measured using a laser Doppler imager that controlled iontophoretic current delivery. A novel feature involved monitoring voltage across the iontophoresis chambers. Comparison between responses to vehicle (distilled H(2)O), acetylcholine (ACh) and sodium nitroprusside (SNP) showed electrically induced hyperaemia at the cathode associated with the vehicle, whose time course overlapped with that of the SNP response. Voltage across the chambers containing drugs dissolved in H(2)O was significantly (p = 0.018, n = 7) lower than the voltage profile of H(2)O alone. H(2)O iontophoresis was associated with cathodal hyperaemic responses in most subjects, whereas a 0.5% NaCl vehicle produced lower voltages and eliminated this artefact. Voltage.time integral rather than charge was the prime determinant of electrically induced hyperaemic responses. No significant correlation was found between skin fold thickness and either calculated skin resistance (r(2) = 0.0002) or vascular response to ACh (r(2) = 0.13). Smaller chamber size led to higher voltages and greater electrically induced hyperaemic responses. These appear to be prostaglandin dependent as they were ablated by cyclooxygenase inhibition. Use of a low-resistance vehicle combined with larger chamber sizes and lower currents can prevent such artefacts, thereby increasing the robustness of this methodology for clinical assessment of endothelial function.
Acetylcholine↗