9 research outputs found

    Metabolic pathways in normal and pre-eclamptic pregnancies

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    Maternal metabolism undergoes dramatic changes in pregnancy in order to sustain and nourish the developing fetus. During healthy pregnancy the mother goes from an anabolic state in early pregnancy to a state of catabolism in late pregnancy with increased lipolysis together with a significant reduction in insulin sensitivity. Pre-eclampsia (PE) characterised by hypertension and proteinuria is a major cause of maternal and perinatal morbidity. There is acute ‘atherosis’ in PE placenta, and lipid accumulation within glomerular cells and liver. PE women have an early, excessive triglyceride and free fatty acid (FFA) rise and greater cardiovascular disease (CVD) risk in later life. The cause of these lipid abnormalities in PE is unknown but disordered adipocyte function including exaggerated lipolysis and aberrant release of adipokines (such as IL-6 and TNF alpha) is a major candidate pathway. Elevations in FFAs, and pro-inflammatory adipokines could underpin the oxidative stress, endothelial dysfunction, inflammation, and insulin resistance - characteristic features of PE. The aims of this thesis were to acquire a better understanding of lipid metabolism and function in normal pregnancy, to determine if adipocyte function was altered in PE and, if so, to establish mechanisms. In addition I planned to corroborate epidemiological evidence of increased future CVD risk and to establish which risk factors accounted for this increased risk. I collected subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) biopsies in non-labouring pregnant healthy (n=31) and PE (n=14) women who underwent caesarean section. Maternal blood was collected prior to delivery and phenotyping of the mother was performed including plasma assay for cholesterol, triglyceride, HDL-cholesterol, IL-6, TNF-α, leptin, adiponectin, high sensitivity CRP, glucose and insulin concentrations. Maternal BMI at booking, standardised blood pressure measurements and birth weight centile were also recorded. I determined ex vivo lipolytic activity (basal, isoprotenerol stimulated and insulin suppression of lipolysis) and adipokine production in response to lipopolysaccharide (LPS) stimulation from these biopsies. The gene expression of relevant target genes and macrophage densities in each adipose depot by immunocytochemistry (ICC) was also performed. In addition I performed carotid ultrasound assessment of women with a previous history of PE (n=31) and matched controls (n=29). Ethical approval was obtained from Glasgow Royal Infirmary LREC and all patients gave their informed consent. I found that in normal pregnancy, adipocyte lipolytic function is independent of maternal BMI. Adipocyte lipolytic function of SAT and VAT are also independent of each other. Adipose tissue is very metabolically flexible and the rate of whole body lipolysis is still insulin sensitive in late gestation. VAT is more closely related to markers of maternal insulin resistance (IR) and is more sensitive to catecholamine stimulation and less sensitive to insulin suppression of lipolysis than SAT, the basis of the “portal paradigm”. Increasing BMI is associated with an increase in VAT cell size, with increased lipolysis and an increase in pro-inflammatory adipokines, a potential mechanism through which increasing obesity could predispose to metabolic complications of pregnancy. In contrast SAT cell size is not closely related to BMI and this may reflect the adaptation of this depot to increasing fat mass through both hypertrophy and hyperplasia, a metabolically advantageous response. TNF alpha is an important correlate of basal lipolysis in SAT. In PE there is decreased insulin sensitivity of both SAT and VAT compared to controls as calculated by the fat cell insulin sensitivity index (or responsiveness to insulin once the tissue is stimulated by isoproterenol). This would potentially make a significant impact on total circulating FFA as almost 60% of circulating FFA are from these adipose depots. The rise in FFA in PE occurs early in pregnancy and contributes significantly to IR. Therefore the IR of adipose tissue could lead to a vicious cycle of increased lipolysis, increased FFA and further exacerbation of IR. In contrast to controls, SAT cell size is intimately related to BMI suggesting that adaptation to increasing fat mass is mainly through adipocyte hypertrophy which could lead to increased endoplasmic reticulum stress, increased IR and increased release of inflammatory adipokines. I have shown that SAT cell size does relate to adipokine release in PE, with increased release of leptin, CRP and PAI-1 and paradoxical increase in the anti-inflammatory IL-10. I had hypothesised that in addition to an inherent defect in adipocyte function there was an additional factor present in maternal serum of women with PE released from the placenta which excessively stimulated lipolysis. I failed to demonstrate any effect of maternal serum on adipocyte lipolysis in either controls or PE. I also found that after stimulation with LPS, there was increased release of TNF alpha and IL-6 in VAT in PE but not in controls, with higher gene expression of these adipokines. TNF alpha release also correlated negatively with the fat cell insulin sensitivity index (FCISI) of VAT implicating a paracrine effect in this tissue. I also demonstrated an increase in gene expression of cfms (activated macrophages) relative to control gene, and increased density of cfms+ macrophages/adipocytes in the VAT of PE women implicating activated adipose tissue macrophages as a potential source of the increased release of inflammatory adipokines. Lastly I attempted to corroborate epidemiological evidence for the increase future risk of CVD women with a history of PE by assessing two surrogate markers for atherosclerosis - carotid IMT and carotid plaque scores. Both were found to be increased, with plaque scores significantly so. Classic risk factors such as age, lipids, BP and smoking did not attenuate this effect and BMI only marginally attenuated it, therefore only partially explaining this increased risk. In summary the data presented in this thesis provides further evidence that PE is a “metabolic syndrome of pregnancy” with disordered adipocyte function and metabolism, with an increased future risk of CVD in later life. Further studies on adipose accumulation, function and composition in normal and complicated human pregnancy are warranted

    How to assess and manage hypertension during and after pregnancy.

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    Hypertensive disorders of pregnancy are increasingly important complications of which clinicians should have an up-to-date knowledge to facilitate prompt recognition, diagnosis and management. These disorders affect a growing number of pregnancies worldwide, with incidence rates likely to increase in the future commensurate with increasing maternal age and maternal comorbidities independent of age, with consequent effects on maternal and fetal/neonatal morbidity and mortality rates. This article mainly focuses on management within the UK of these disorders, examining their current working definitions, detection methods and recent developments in screening tool development. The current NICE-recommended strategies for treating these disorders and minimizing their occurrence in pregnancy are also explored. In addition, the association between adverse pregnancy outcome and increased risk of future maternal and offspring cardiovascular disease is described, with comments on future strategies to help minimize these potential risks

    In preeclampsia, maternal third trimester subcutaneous adipocyte lipolysis is more resistant to suppression by insulin than in healthy pregnancy

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    Obesity increases preeclampsia risk, and maternal dyslipidemia may result from exaggerated adipocyte lipolysis. We compared adipocyte function in preeclampsia with healthy pregnancy to establish whether there is increased lipolysis. Subcutaneous and visceral adipose tissue biopsies were collected at caesarean section from healthy (n=31) and preeclampsia (n=13) mothers. Lipolysis in response to isoproterenol (200 nmol/L) and insulin (10 nmol/L) was assessed. In healthy pregnancy, subcutaneous adipocytes had higher diameter than visceral adipocytes (<i>P</i><0.001). Subcutaneous and visceral adipocyte mean diameter in preeclampsia was similar to that in healthy pregnant controls, but cell distribution was shifted toward smaller cell diameter in preeclampsia. Total lipolysis rates under all conditions were lower in healthy visceral than subcutaneous adipocytes but did not differ after normalization for cell diameter. Visceral adipocyte insulin sensitivity was lower than subcutaneous in healthy pregnancy and inversely correlated with plasma triglyceride (<i>r</i>=−0.50; <i>P</i>=0.004). Visceral adipose tissue had lower <i>ADRB3, LPL,</i> and leptin and higher insulin receptor messenger RNA expression than subcutaneous adipose tissue. There was no difference in subcutaneous adipocyte lipolysis rates between preeclampsia and healthy controls, but subcutaneous adipocytes had lower sensitivity to insulin in preeclampsia, independent of cell diameter (<i>P</i><0.05). In preeclampsia, visceral adipose tissue had higher <i>LPL</i> messenger RNA expression than subcutaneous. In conclusion, in healthy pregnancy, the larger total mass of subcutaneous adipose tissue may release more fatty acids into the circulation than visceral adipose tissue. Reduced insulin suppression of subcutaneous adipocyte lipolysis may increase the burden of plasma fatty acids that the mother has to process in preeclampsia

    Visceral adipose tissue activated macrophage content and inflammatory adipokine secretion is higher in pre-eclampsia than in healthy pregnancy

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    Obesity increases preeclampsia risk. Adipose tissue inflammation may contribute to the clinical syndrome of pre-eclampsia. We compared adipose tissue macrophage infiltration and release of pro-inflammatory adipokines in pre-eclampsia and healthy pregnancy. Subcutaneous and visceral adipose tissue biopsies were collected from healthy (n=13) and preeclampsia (n=13) mothers. Basal and lipopolysaccharide stimulated adipocyte TNFα, IL-6, CCL-2 and CRP release was measured. Adipose tissue cell densities of activated (cfms(+)) and total (CD68(+)) macrophages were determined. In pre-eclampsia only, visceral adipose tissue TNFα release was increased after lipopolysaccharide stimulation (57 [76] vs 81 [97] pg/mL/ug DNA, p=0.030). Basal TNFα release was negatively correlated insulin sensitivity of visceral adipocytes (r=-0.61, p=0.030) in pre-eclampsia. Visceral adipocyte IL-6 release was increased after lipopolysaccharide stimulation in pre-eclampsia only (566 [696] vs 852 [914] pg/mL/ugDNA, p=0.019). Visceral adipocyte CCL-2 basal (67 [61] vs 187 [219] pg/mL/ugDNA, p=0.049) and stimulated (46 [46] vs 224 [271] pg/mL/ugDNA, p=0.003) release was greater than in subcutaneous adipocytes in pre-eclampsia only. In pre-eclampsia, median TNF mRNA expression in visceral adipose tissue was higher than controls (1.94 [1.13-4.14] vs 0.8 [0.00-1.27] TNF / PPIA ratio, p=0.006). In visceral adipose tissue, CSF1R (a marker of activated macrophages) mRNA expression (24.8[11.0] vs 51.0[29.9] CSF1R/PPIA ratio, p=0.011) and activated (cfms+) macrophage count (6.7[2.6] vs 15.2[8.8] % cfms+/adipocyte, p=0.031) were higher in pre-eclampsia than in controls. In conclusion, our study demonstrates dysregulation of inflammatory pathways predominantly in visceral adipose tissue in pre-eclampsia. Inflammation of visceral adipose tissue may mediate many of the adverse metabolic effects associated with pre-eclampsia

    Impact of maternal obesity on perinatal and childhood outcomes

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    Maternal obesity is of major consequence, affecting every aspect of maternity care including both short- and long-term effects on the health of the offspring. Obese mothers are at a higher risk of developing gestational diabetes and pre-eclampsia, potentially exposing the foetus to an adverse intrauterine environment. Maternal obesity is linked to foetal macrosomia, resulting in increased neonatal and maternal morbidity. Foetal macrosomia is a result of a change in body composition in the neonate with an increase in both percentage fat and fat mass. Maternal obesity and gestational weight gain are associated with childhood obesity, and this effect extends into adulthood. Childhood obesity in turn increases chances of later life obesity, thus type 2 diabetes, and cardiovascular disease in the offspring. Further clinical trials of lifestyle and, potentially, pharmacological interventions in obese pregnant women are required to determine whether short- and long-term adverse effects for the mother and child can be reduced

    Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial

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    Background: tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy.Methods: we performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930.Findings: between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference –0·01, 95% CI –0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group.Interpretation: in women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. Funding: National Institute of Health Research.</p

    Short and long term strategies for the management of hypertensive disorders of pregnancy

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    The hypertensive disorders of pregnancy include gestational hypertension and preeclampsia, both de novo and superimposed on chronic hypertension. These disorders occur frequently among pregnant woman and are important contributors to maternal and perinatal mortality and morbidity worldwide. In this review, we will focus on recent developments in the prediction and pathogenesis of these disorders, prevention of preeclampsia and current strategies for the treatment of hypertension in pregnancy. We also explore the evidence relating adverse pregnancy outcome to an increased future risk of cardiovascular disease and potential strategies to minimize this risk
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