Bjørg Lorentzen

Fatty acid pattern of esterified and free fatty acids in sera of women with normal and pre-eclamptic pregnancy

Objective To determine the composition of esterified and free fatty acids in sera of women with normal and pre‐eclamptic pregnancy.

Increased lipolytic activity and high ratio of free fatty acids to albumin in sera from women with preeclampsia leads to triglyceride accumulation in cultured endothelial cells

OBJECTIVE The null hypothesis of this study was that the triglyceride accumulation in endothelial cells exposed to sera from preeclamptic women was determined by the presence of triglyceride-rich lipoproteins in the sera. STUDY DESIGN The accumulation of triglycerides in cultured endothelial cells was studied using incorporation of tritiated glycerol. RESULTS Triglyceride-rich lipoproteins in the patient sera contributed little to the endothelial triglyceride accumulation. However, sera from preeclamptic women were found to have a higher molar ratio of free fatty acids to albumin compared with sera from women with normal pregnancies (1.6 +/- 0.5 vs 0.9 +/- 0.4, respectively, p less than 0.025). In addition, sera from preeclamptic women, compared with sera from normal pregnancies, showed enhanced lipolytic activity (release of free fatty acids 0.85 +/- 0.29 vs 0.17 +/- 0.16 mmol/ml per 24 hours, respectively; p less than 0.025) that further increased the free fatty acids/albumin ratio. CONCLUSION Sera from preeclamptic women have both a higher ratio of free fatty acids to albumin and increased lipolytic activity, resulting in enhanced endothelial uptake of free fatty acids, which are further esterified into triglycerides.

Glucose intolerance in women with preeclampsia

BACKGROUND We have previously shown that women with proteinuric hypertension of pregnancy (preeclampsia) have increased circulating levels of triglycerides and free fatty acids. Preeclampsia has, therefore, several features in common with the insulin resistance syndrome. The objective of the present study was to investigate the glucose tolerance and insulin response of women with preeclampsia compared to women with normal pregnancy. METHODS Oral glucose tolerance test was performed in ten women with preeclampsia and eight healthy women with normal pregnancy. The glucose, insulin, C-peptide and free fatty acid responses were calculated. RESULTS The mean fasting glucose concentration was significantly lower in preeclamptic women (3.3 vs 3.7 mmol/l; p = 0.02). Fasting serum triglycerides were increased in women with preeclampsia compared to normal pregnancy (3.3 vs 1.9 mmol/l; p = 0.003). Women with preeclampsia had also increased serum free fatty acids, 0.52 vs 0.36 mmol/l for normal pregnancy; p = 0.056). Log s-insulin and cholesterol were not different. The incremental area under the curve for the glucose (p = 0.001) and insulin (p = 0.02) responses to oral glucose tolerance test showed higher values for preeclampsia as compared to women with normal pregnancy. For free fatty acids the total area under the suppression curve was higher in women with preeclampsia (p = 0.03). CONCLUSIONS These results support the concept that preeclampsia is associated with metabolic aberrations found in insulin resistance syndrome.

Thrombin-inhibitor complexes in the blood during and after delivery

Activation of coagulation leads to generation of thrombin which in turn is inactivated by the formation of thrombin-antithrombin (TAT) complexes, and thrombin-heparin cofactor complexes (T-HCII). These complexes were measured in plasma by ELISA methods. During normal delivery, the median TAT level in ten women increased from 4.1 to 7.8 times the median normal reference level. There was great individual variation, and levels 42 and 56 times normal median were found in two women shortly after normal delivery. The median T-HCII levels increased only moderately from 2.3 to 3.1 times median normal reference. D-dimer values were elevated in 28 out of the 30 samples. In blood sampled 1-2 days after delivery, the median TAT level was 2.5 times the median normal reference. The median T-HCII level was now 5.6 times the median normal reference value. The values were stable during the first 4 days post partum, and there was little difference between those delivered vaginally or by Caesarean section (C-section). D-dimer values were above normal reference in all women, and higher in women delivered by C-section. In conclusion, increasing TAT levels during labour and delivery indicated generation of thrombin which was mainly inactivated by antithrombin. The T-HCII levels increased less during delivery. In the early post partum period, the T-HCII levels were relatively more increased than the TAT levels. These results suggest that intravascularly generated thrombin is preferably inactivated by antithrombin, even in parturient women. In the post partum period, formation of T-HCII complexes was more evident, possibly reflecting extravascular inactivation of thrombin.

Sera of preeclamptic women are not cytotoxic to endothelial cells in culture

OBJECTIVE The null hypothesis of this study was that sera of women with preeclampsia are not cytotoxic to endothelial cells in culture. STUDY DESIGN Endothelial cells were incubated in the presence of sera (30% vol/vol) of either preeclamptic patients (n = 11) or normal pregnant women (n = 11). Release of chromium 51 from prelabeled cells was measured after exposure to the different sera. Viability of the cells was evaluated by trypan blue exclusion and plating efficiencies. Deoxyribonucleic acid and protein synthesis were studied by measuring incorporation of tritiated thymidine and leucine into deoxyribonucleic acid and proteins, respectively. Cell growth was determined by monitoring the number of cells per culture dish during a 5-day incubation period. RESULTS Release of chromium 51 from endothelial cells incubated in the presence of sera from preeclamptic women was similar to controls (26.3% +/- 4.7% vs 26.7% +/- 2.5%). There was no difference in the number of trypan blue-positive cells in cultures incubated in the presence of sera from preeclamptic women and controls. Seeding the cells in either sera from preeclamptic or control women gave the same percentage of attached cells. Similarly, preincubation of endothelial cells with either one of the two sera resulted in the same number of attached cells when they were reseeded (45% +/- 6% vs 40% +/- 15%, respectively). Incubation of endothelial cells with sera from preeclamptic or control women affected neither deoxyribonucleic acid nor protein synthesis of the endothelial cells. Furthermore, cell proliferation was similar in cultures incubated with sera from preeclamptic women and controls. CONCLUSION No evidence was found that sera of women with preeclampsia are cytotoxic to endothelial cells in culture.

Reduced soluble receptor for advanced glycation end-products (sRAGE) scavenger capacity precedes pre-eclampsia in Type 1 diabetes

Please cite this paper as: Yu Y, Hanssen K, Kalyanaraman V, Chirindel A, Jenkins A, Nankervis A, Torjesen P, Scholz H, Henriksen T, Lorentzen B, Garg S, Menard M, Hammad S, Scardo J, Stanley J, Wu M, Basu A, Aston C, Lyons T. Reduced soluble receptor for advanced glycation end‐products (sRAGE) scavenger capacity precedes pre‐eclampsia in Type 1 diabetes. BJOG 2012;119:1512–1520.

Placental glucose transfer: A human in vivo study

Objectives The placental transfer of nutrients is influenced by maternal metabolic state, placenta function and fetal demands. Human in vivo studies of this interplay are scarce and challenging. We aimed to establish a method to study placental nutrient transfer in humans. Focusing on glucose, we tested a hypothesis that maternal glucose concentrations and uteroplacental arterio-venous difference (reflecting maternal supply) determines the fetal venous-arterial glucose difference (reflecting fetal consumption). Methods Cross-sectional in vivo study of 40 healthy women with uncomplicated term pregnancies undergoing planned caesarean section. Glucose and insulin were measured in plasma from maternal and fetal sides of the placenta, at the incoming (radial artery and umbilical vein) and outgoing vessels (uterine vein and umbilical artery). Results There were significant mean (SD) uteroplacental arterio-venous 0.29 (0.23) mmol/L and fetal venous-arterial 0.38 (0.31) mmol/L glucose differences. The transplacental maternal-fetal glucose gradient was 1.22 (0.42) mmol/L. The maternal arterial glucose concentration was correlated to the fetal venous glucose concentration (r = 0.86, p<0.001), but not to the fetal venous-arterial glucose difference. The uteroplacental arterio-venous glucose difference was neither correlated to the level of glucose in the umbilical vein, nor fetal venous-arterial glucose difference. The maternal-fetal gradient was correlated to fetal venous-arterial glucose difference (r = 0.8, p<0.001) and the glucose concentration in the umbilical artery (r = −0.45, p = 0.004). Glucose and insulin concentrations were correlated in the mother (r = 0.52, p = 0.001), but not significantly in the fetus. We found no significant correlation between maternal and fetal insulin values. Conclusions We did not find a relation between indicators of maternal glucose supply and the fetal venous-arterial glucose difference. Our findings indicate that the maternal-fetal glucose gradient is significantly influenced by the fetal venous-arterial difference and not merely dependent on maternal glucose concentration or the arterio-venous difference on the maternal side of the placenta.

Trace elements as predictors of preeclampsia in type 1 diabetic pregnancy

Preeclampsia (PE) affects approximately 5% of all pregnancies, but is increased several-fold in women with pre-gestational type 1 diabetes mellitus (T1DM). Increased oxidative stress and altered maternal plasma trace elements that modulate the antioxidant system have been implicated in PE. In non-diabetic women, increased plasma copper and iron and decreased manganese, selenium, and zinc have been associated with PE in cross-sectional studies. In a longitudinal study, we hypothesized that plasma levels of trace elements differ between T1DM women with vs. without subsequent PE. Samples were collected during the first (gestation 12.2 ± 1.9 weeks, [mean ± SD]), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy, all before the onset of PE. We compared 23 T1DM women who subsequently developed PE with 24 T1DM women who remained normotensive; and we included 19 non-diabetic (non-DM) normotensive pregnant women as reference controls. Trace elements were measured using inductively coupled plasma mass spectroscopy. In T1DM women with subsequent PE vs normotensive, only plasma zinc was significantly higher at the first trimester, while copper:zinc and copper:high-density lipoprotein cholesterol ratios were higher throughout gestation (all P < .05). These findings persisted after adjustment for covariates. Higher copper:zinc ratios may contribute to oxidative stress in T1DM women who develop PE. Ratios of pro- to anti-oxidant factors may predict risk for PE in diabetic pregnancies more effectively than individual trace element levels.

Plasma Lipoproteins and Preeclampsia in Women with Type 1 Diabetes: A Prospective Study

CONTEXT In nondiabetic pregnancy, cross-sectional studies have shown associations between maternal dyslipidemia and preeclampsia (PE). In type 1 diabetes mellitus (T1DM), the prevalence of PE is increased 4-fold, but prospective associations with plasma lipoproteins are unknown. OBJECTIVES The aim of this study was to define lipoprotein-related markers and potential mechanisms for PE in T1DM. DESIGN AND SETTINGS We conducted a multicenter prospective study in T1DM pregnancy. PATIENTS We studied 118 T1DM women (26 developed PE, 92 remained normotensive). Subjects were studied at three visits before PE onset [12.2 ± 1.9, 21.6 ± 1.5, and 31.5 ± 1.7 wk gestation (means ± SD)] and at term (37.6 ± 2.0 wk). Nondiabetic normotensive pregnant women (n = 21) were included for reference. MAIN OUTCOME MEASURES Conventional lipid profiles, lipoprotein subclasses [defined by size (nuclear magnetic resonance) and by apolipoprotein content], serum apolipoproteins (ApoAI, ApoB, and ApoCIII), and lipolysis (ApoCIII ratio) were measured in T1DM women with and without subsequent PE. RESULTS In women with vs. without subsequent PE, at the first and/or second study visits: low-density lipoprotein (LDL)-cholesterol, particle concentrations of total LDL and large (but not small) LDL, serum ApoB, and ApoB:ApoAI ratio were all increased (P < 0.05); peripheral lipoprotein lipolysis was decreased (P < 0.01). These early differences remained significant in covariate analysis (glycated hemoglobin, actual prandial status, gravidity, body mass index, and diabetes duration) but were not present at the third study visit. High-density lipoprotein and very low-density lipoprotein subclasses did not differ between groups before PE onset. CONCLUSIONS Early in pregnancy, increased cholesterol-rich lipoproteins and an index suggesting decreased peripheral lipolysis were associated with subsequent PE in T1DM women. Background maternal lipoprotein characteristics, perhaps masked by effects of late pregnancy, may influence PE risk.

Maternal deaths in Norway 2005 - 2009

BACKGROUND Norway has low maternal mortality, but such deaths are underreported even in high-income countries. Our goal was to identify the exact number of maternal deaths, the causes of death and the potential for improvement through medical care in Norway. MATERIAL AND METHOD We traced maternal deaths in the period from 1 January 2005 to 31 December 2009 by linking the Medical Birth Registry and the Cause of Death Registry, supplemented with data from maternity clinics. We identified the cause of death and the lessons that could be learned by a meticulous review of each case. RESULTS We found 26 maternal deaths during the period, 14 of which were due to direct causes and 12 to indirect causes. The maternal mortality ratio was 8.7/100,000 live births. Fourteen of the deaths were registered in official statistics. Of the 12 deaths that were not included in the statistics, 11 were found through matching the registers and one had been reported directly by the hospital. The most common causes of death were hypertensive disorders during pregnancy (n = 6), thromboembolism (n = 4) and mental illness (n = 4). None of the deaths due to thromboembolism appeared in official statistics. The same applied to nine of the 12 indirect maternal deaths. We found a potential for improved medical care in 14 of 26 cases. Half of these were deaths due to hypertensive disorders during pregnancy or thromboembolism. INTERPRETATION Maternal death was considerably underreported in Norwegian official statistics during the period studied. Greater attention should be given to better blood-pressure treatment, stabilisation and timely delivery in the case of hypertension during pregnancy, and to screening for possible pulmonary embolism. The same applies to mental illness and internal medical disorders in pregnant women.