HLA-C antibodies in women with recurrent miscarriage suggests that antibody mediated rejection is one of the mechanisms leading to recurrent miscarriage.

HLA-C is the only polymorphic classical HLA I antigen expressed on trophoblast cells. It is known that higher incidence of C4d deposition on trophoblast cells is present in women with recurrent miscarriage. C4d is a footprint of antibody-mediated classical complement activation. Therefore, this study hypothesize that antibodies against HLA-C may play a role in the occurrence of unexplained consecutive recurrent miscarriage. Present case control study compared the incidence of HLA-C specific antibodies in 95 women with at least three consecutive miscarriages and 105 women with uneventful pregnancy. In the first trimester of the next pregnancy, presence and specificity of HLA antibodies were determined and their complement fixing ability. The incidence of HLA antibodies was compared with uni- and multivariate logistic regression models adjusting for possible confounders. Although in general a higher incidence of HLA antibodies was found in women with recurrent miscarriage 31.6% vs. in control subjects 9.5% (adjusted OR 4.3, 95% CI 2.0-9.5), the contribution of antibodies against HLA-C was significantly higher in women with recurrent miscarriage (9.5%) compared to women with uneventful pregnancy (1%) (adjusted OR 11.0, 95% CI 1.3-89.0). In contrast to the control group, HLA-C antibodies in the recurrent miscarriage group were more often able to bind complement. The higher incidence of antibodies specific for HLA-C in women with recurrent miscarriage suggests that HLA-C antibodies may be involved in the aetiology of unexplained consecutive recurrent miscarriage.

Systolic blood pressure and fatty acid-binding protein 4 predict pregnancy-induced hypertension in overweight nulliparous women.

INTRODUCTION: The insulin-sensitivity regulator adipocyte fatty acid-binding protein 4 (FABP4) integrates metabolic and inflammatory responses. We hypothesize that there is relationship between FABP4 and factors related to metabolic syndrome in pregnancy-induced hypertension (PIH). METHODS: In this prospective observational study, among the 72 relatively overweight (BMI ≥24 kg/m2) nulliparous women, 14 developed non-proteinuric PIH and 12 developed proteinuric PIH (preeclampsia), whereas 46 had normotensive pregnancies. Insulin sensitivity was assessed via the whole-body insulin sensitivity index (ISI) and the homeostatic model of assessment - insulin resistance (HOMA-IR) at 24 weeks of gestation. Maternal serum levels of FABP4, high-sensitive C-reactive protein (hs-CRP), total testosterone, and non-protein-bound calculated free testosterone (cfT) were determined at 24 and 32 weeks. RESULTS: Measures of ISI, HOMA-IR, hs-CRP, testosterone and lipids did not differ at 24 and/or at 32 weeks in women who were subsequently hypertensive. SBP was higher at all time points and FABP4 levels tended to be higher at 24 and 32 weeks in patients compared to controls. In logistic regression analysis, baseline FABP4 (OR [95% CI] 1.069 [1.020-1.121], P = 0.006) and SBP after 10 min standing (OR [95% CI] 1.087 [1.029-1.149], P = 0.003) were associated with the development of PIH. FABP4 levels at 24 weeks did not correlate with insulin sensitivity. Neither was correlation seen between FABP4 levels at 24 and 32 weeks, vs. those of hs-CRP and testosterone. DISCUSSION AND CONCLUSIONS: Serum FABP4 concentration and SBP after 10 min standing in an orthostatic test at 24 weeks are associated with subsequent development of PIH.

Effects of sympatholytic therapy on postmenopausal symptoms in hypertensive postmenopausal women.

OBJECTIVE: The short-term effects of two sympatholytic antihypertensive drug treatments, ß-blocking agent atenolol and imidazoline receptor-1 agonist moxonidine, on postmenopausal symptoms and their relationship to antihypertensive and insulin sensitivity effect were studied. DESIGN: This was a double-blind, prospectively randomized study in a multicenter, multinational setting in 112 hypertensive, overweight, postmenopausal women without hormone therapy. METHODS: Treatment was either with moxonidine, 0.6 mg/day, or with atenolol, 50 mg/day, for 8 weeks. The main outcome measures were blood pressure, insulin sensitivity by Matsuda sensitivity index and postmenopausal symptoms (hot flushes, palpitations, insomnia, irritability, depression and general impression of the symptoms (GIS) through a questionnaire. RESULTS: Both atenolol and moxonidine caused a significant reduction in diastolic blood pressure of 9.5 mmHg and 6.2 mmHg, respectively. The severity of hot flushes and palpitations were reduced significantly in both treatment groups. Relief from hot flushes was recorded in 43% of women taking atenolol and in 27% (not significant between the groups) of moxonidine-treated patients. Palpitations were relieved in 41% and 25% (not significant between the groups) of the women in the atenolol- and moxonidine-treated groups, respectively. In the atenolol group, insomnia and GIS were reduced significantly, with relief of symptoms occurring in 33% and 27% of the patients. A change in irritability was seen in blood pressure responders during the treatment in the atenolol group. There was no correlation between improvement of insulin sensitivity and relief of postmenopausal symptoms. CONCLUSIONS: In this study, two sympatholytic antihypertensives, atenolol and moxonidine, provided relief from hot flushes and palpitations, and atenolol additionally helped with insomnia and improved GIS.

Increased plasma norepinephrine levels in previously pre-eclamptic women.

A history of pre-eclampsia increases the risk of cardiovascular morbidity by mechanisms yet unknown. The aim of the present study was to assess whether plasma norepinephrine (NE) levels are increased 5-6 years after pre-eclamptic pregnancy and to investigate associations with pathophysiological mechanisms of cardiovascular disease: insulin sensitivity, vascular function and arterial pressure. A total of 28 women with previous pre-eclampsia and 20 controls were examined. Blood pressure (BP) and plasma levels of NE and endothelin-1 (ET-1) were measured at rest and after standing for 5 min. Insulin sensitivity was assessed with minimal model analysis and vascular function was assessed using venous occlusion plethysmography and pulse wave analysis. Twenty-four-hour BP measurements were carried out. Women with previous pre-eclampsia had higher levels of NE at rest (P=0.02), which did not associate significantly with insulin sensitivity or overall vasodilatory capacity. The 24-h mean of systolic and diastolic blood pressures (BPs) and heart rate did not differ between the groups (P=0.30, P=0.10 and P=0.46, respectively), and there was no significant association with NE levels. ET-1 levels were similar between the groups, but a positive correlation with systolic (P=0.04) and diastolic (P=0.03) BPs in the upright position was shown in the patient group. Increased levels of plasma NE are sustained in women with previous pre-eclampsia and may contribute to the increased risk for cardiovascular disease in these women.

Renal and vascular function in women with previous preeclampsia: a comparison of low- and high-degree proteinuria.

The degree of proteinuria during preeclampsia has been considered to be a marker of severity of the disease and of endothelial dysfunction. The aim of the study was to assess whether the degree of proteinuria in preeclamptic pregnancy is related to impairment of vascular dilatation and/or kidney function years after the index pregnancy. Thirty women with a history of severe preeclampsia divided into low (n=8, dU-prot <5 g/day) and high (n=22, dU-prot >/=5 g/day) proteinuric groups and 21 women with previous normotensive pregnancy were studied 5-6 years after index pregnancy. Renal function and blood pressure were assessed together with venous occlusion plethysmography, where changes in brachial artery blood flow, induced by intra-arterial infusions of an endothelium-independent (sodium nitroprusside) and an endothelium-dependent (acetylcholine) vasodilator, were measured. The results showed similar renal function in all groups. There was no difference in vasodilation between preeclamptic groups and controls or correlation between degree of proteinuria during index pregnancy and present vasodilation. We conclude that the degree of proteinuria during preeclampsia does not predict vascular dilatation or renal function 5-6 years after preeclamptic pregnancy.

Cord serum insulin-like growth factor binding protein-1 and -3: effect of maternal diabetes and relationships to fetal growth.

OBJECTIVES: Insulin-like growth factor binding protein-1 and -3 (IGFBP-1 and -3) are the main insulin-like growth factor (IGF) carriers in fetal blood whose concentrations are regulated by hormonal factors such as insulin. IGFBPs may regulate fetal growth by altering the biological activity of IGF-I and IGF-II. We studied the effect of maternal diabetes on cord serum IGFBP-1 and IGFBP-3 levels, and the usability of IGFBP-1 and IGFBP-3 in the detection of birth weight variations. METHODS: Cord serum IGFBP-1 and IGFBP-3 concentrations were measured at birth by immunofluorometric assays in 67 pregnancies with type 1 diabetes and in 62 normal pregnancies. RESULTS: Concentrations of IGFBP-1 in cord serum were lower in diabetic pregnancies than in normal pregnancies (156 +/- 28 microg/l vs 266 +/- 29 microg/l, P = 0.007), whereas those of IGFBP-3 did not differ significantly (3327 +/- 158 microg/l vs 2982 +/- 105 microg/l, P = 0.076). IGFBP-1 correlated negatively and IGFBP-3 positively with birth weight z-score in diabetic pregnancies. The trend was similar in normal pregnancies. In multiple regression models, birth weight z-score was significantly associated with IGFBP-1 in diabetic and normal pregnancies, and with IGFBP-3 in diabetic pregnancies. CONCLUSION: Maternal diabetes is associated with suppressed levels of IGFBP-1 in cord serum, whereas those of IGFBP-3 do not change markedly. In diabetic pregnancies, both cord serum IGFBP-1 and IGFBP-3 correlate with fetal growth.

Effect of changes in body posture on vasoactive hormones in pre-eclamptic women.

The aim of this study was to determine the normality or otherwise of neurohormone indices, particularly the sympathetic nervous system, in pre-eclamptic patients and document whether changes in body posture magnify any differences between pre-eclamptic and normal women. We studied 11 women with pre-eclampsia and compared them with 17 matched normotensive pregnant women and eight nonpregnant women. Measurements of arterial pressure, heart rate and neurohormones were carried out with subjects in the left lateral position, then supine, left lateral, with upright posture and finally with assumption of the left lateral position again. Main outcome measures were arterial pressure, heart rate and hormones (plasma norepinephrine, renin activity, natriuretic peptides and endothelin-1). We observed that plasma norepinephrine levels were higher in pre-eclamptic than normotensive pregnant women and this was most obvious in the upright position. Plasma renin activity was likewise higher in pre-eclamptic than normotensive pregnant women, again most obvious with upright posture. Plasma natriuretic peptides and endothelin-1 levels were similar in pre-eclamptics and normotensive pregnant women. These data strengthen the premise that pre-eclampsia is associated with sympathetic overactivity as reflected by plasma norepinephrine levels, most obviously observed in the upright position.

Angiopoietic factors and retinopathy in pregnancies complicated with Type 1 diabetes.

AIMS: To evaluate the role of systemic angiopoietic factors in the progression of diabetic retinopathy during pregnancy. METHODS: In a prospective study of 26 pregnant women with diabetes and eight non-diabetic pregnant women, retinopathy was graded from fundus photographs. Plasma levels of angiopoietin-1, angiopoietin-2, human vascular endothelial growth factor A (hVEGF-A), and total soluble receptor of vascular endothelial growth factor (sVEGF) receptor-1 were measured during the first and third trimester and 3 months postpartum. RESULTS: In diabetic women, levels of angiopoietin-2 were 26.5 ng/ml (12.1-47.7) (median and range) during the first trimester, 2.9 ng/ml (0.6-3.5) during the third trimester, and 0.5 ng/ml (0.3-0.7) 3 months postpartum, compared with 44.3 (38.3-61.9), 5.7 (3.1-8.4) and 0.9 (0.6-4.9) ng/ml, respectively, in non-diabetic women (P = 0.002 between groups). Levels of angiopoietin-1 and sVEGF receptor-1 did not differ between the groups. Postpartum hVEGF-A levels were lowest in women with progression of retinopathy. In logistic regression analyses, progression of retinopathy during pregnancy was not explained by the levels of the angiopoietic factors. CONCLUSIONS: The circulating levels of angiopoietic factors in pregnant diabetic women were either lower than (Ang-2) or similar to (Ang-1, hVEGF-A, VEGFR-1) those levels observed in non-diabetic pregnant women. The levels of angiopoietic factors measured here appear not to be connected with the progression of retinopathy during pregnancy.

Treatment of acute pulmonary embolism during pregnancy with low molecular weight heparin: three case reports.

We report three patients who presented with acute pulmonary embolism (PE) at gestational weeks 13-19. The diagnosis was based on spiral computer tomography of the lungs. In one of the cases, PE was submassive with signs of right ventricle overload. All of the patients were treated with low molecular weight heparin enoxaparine with an initial dose of 1 mg/kg twice daily during 1 month, and therafter with a reduced dose (80%). The target anti-activated factor X levels 3 h after injection were easily kept in the therapeutic range (0.5-0.9 IU/ml). In all cases, the symptoms were relieved within 4 days and no thrombotic or bleeding complications were observed during the rest of the pregnancy. We conclude that low molecular weight heparin seems to be an efficient and practical treatment of PE during pregnancy.

Blood pressure and vasoactive hormones in mild preeclampsia and normal pregnancy.

OBJECTIVE: Changes in vasoactive hormones are reported to play an important role in the pathogenesis of preeclampsia linking placental hypoperfusion with hypertension, systemic disease, and proteinuria. We, therefore, studied diurnal patterns of vasoactive hormones in mild preeclampsia. METHODS: Venous blood samples were drawn every 2 h over 25 h for measurements of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine, renin activity, and aldosterone and two urine collections (12 h each) for stable prostaglandin metabolite measurements. The patients were nine women with mild preeclampsia and, for comparison, nine control women matched for gestation and parity. RESULTS: Women with mild preeclampsia had higher norepinephrine levels throughout 25 h, and lower systemic prostacyclin production as measured by the urinary 2,3-dinor-6-keto PGF1 alpha excretion during the daytime. Plasma endothelin and ANP and BNP concentrations tended to be higher throughout 25 h in preeclampsia, but differences between the two groups did not reach levels of statistical significance. Plasma renin activity and aldosterone did not differ between the groups. Whereas control women exhibited a diurnal variation in plasma norepinephrine, ANP, BNP, and aldosterone, and in both urinary prostacyclin and thromboxane A2 metabolites, this was less distinct or absent in patients with mild preeclampsia. CONCLUSIONS: We conclude that mild preeclampsia is associated with elevated plasma norepinephrine levels, lower systemic daytime production of prostacyclin, and blunting of the normal diurnal variation for a number of indices including plasma levels of BNP, ANP, norepinephrine, and aldosterone, and urinary prostacyclin metabolites.

Short-term metabolic effects of isradipine and metoprolol in pre-eclampsia.

OBJECTIVE: To study the effects of isradipine or metoprolol on insulin sensitivity and lipid profiles as well as on blood pressure and umbilical vascular resistance in pre-eclamptic women in the third trimester of pregnancy. DESIGN: A single-centre, prospective, randomized, double-blind, double-dummy and parallel-group study. SETTING: Helsinki University Central Hospital, a tertiary referral centre. PATIENTS: Twenty-four previously healthy pregnant women with normal findings in an oral glucose-tolerance test who were hospitalized for preeclampsia, of whom 17 completed the study. INTERVENTIONS: Between 29 and 39 weeks of gestation, measurements were made of insulin sensitivity (the minimal model), magnitude of proteinuria, and the fasting levels of serum uric acid, lipids and lipoproteins. Subsequently, treatment with isradipine 2.5 mg (n = 9) or metoprolol 50 mg (n = 8) twice daily was started, and these women were reinvestigated 5-7 days later. Blood pressure was recorded during 24 h by automated ambulatory blood pressure measurement. Umbilical artery resistance index was measured by Doppler ultrasound. MAIN OUTCOME MEASURES: Insulin sensitivity, uric acid, degree of proteinuria, lipids and lipoproteins, blood pressure, umbilical artery resistance index. sensitivity, degree of proteinuria, blood pressure, or the umbilical artery resistance index. Serum uric acid increased in both groups (P<0.05). High-density lipoprotein2 cholesterol increased 15.6% in the isradipine group (P<0.05), but no significant changes appeared in other lipids and lipoproteins in either group. CONCLUSIONS: In this study, short-term antihypertensive treatment with isradipine or metoprolol in preeclampsia had no detrimental effect on serum lipid and lipoprotein levels or insulin sensitivity.

Natriuretic peptides in sheep with pressure overload left ventricular hypertrophy.

To examine tissue and plasma atrial (ANP) and brain natriuretic peptide (BNP) responses to left ventricular hypertrophy (LVH) 7 sheep underwent suprarenal aortic banding (20 mmHg initial pressure differential). Median survival time was 15 days. Proximal mean aortic pressure (MAP) increased from 65.1 +/- 5.0 mmHg (baseline) to 111.6 +/- 7.5 mmHg (day 7, p < 0.0001). Distal systolic aortic pressure fell from 85.5 +/- 8.7 mmHg (baseline) to 55.6 +/- 6.4 mmHg (day 7, p = 0.0002). Maximal plasma ANP (26.9 +/- 3.6 vs 10.1 +/- 1.2 pmol/L, p = 0.005) and BNP (15.3 +/- 3.6 vs. 3.5 +/- 1.0 pmol/L, p = 0.006) were recorded at 15 +/- 4.0 days. Coarctation induced rapid increases in PRA and plasma aldosterone and a fall in urinary sodium. Post-mortem examination of hearts confirmed LVH. Compared with controls, tissue ANP concentration was reduced in left atrium (p = 0.04) and LV (p = 0.04). BNP concentration was reduced in left atrium (p = 0.02) but tended to be higher in LV. In conclusion, suprarenal aortic coarctation leads to progressive hypertension resulting in LVH, progressive increases in plasma ANP and BNP and, in most cases, death from heart failure.

Ouabain is not detectable in human plasma.

An enzyme-linked immunosorbent assay is described for the measurement of ouabain in human plasma. This assay is specific for ouabain, strophanthidin, and ouabagenin, with other steroids, including digoxin and vasopressor hormones, exhibiting negligible cross-reactivity. Assay sensitivity was 0.06 nmol/L if 1 mL plasma was extracted and less than 0.005 nmol/L when 20 mL plasma was analyzed. Extracted plasma samples showed ouabainlike immunoreactivity that diluted in parallel with the ouabain standard curve. Repeated extraction and assay of single plasma samples, however, did not produce consistent results in the assay. Increased specificity was obtained by high-performance liquid chromatography of sample extracts before assay. When high-performance liquid chromatographic profiles of plasma spiked with ouabain standard or following bolus intravenous injections of ouabain into normal human volunteers were compared with profiles of unspiked plasma, there was no support for the immunoreactive material in the latter samples being ouabain. We propose that if ouabain is present in the human circulation, its concentration is less than 0.005 nmol/L.

Treatment of cholestasis of pregnancy with peroral activated charcoal. A preliminary study.

Elevated serum bile acid levels may play a role in the symptoms associated with cholestasis of pregnancy. Nineteen women (20 pregnancies) with cholestasis of pregnancy were randomized to receive either activated peroral charcoal (9 women, 10 pregnancies) with a dose of 50 g 3 times a day for 8 days or only normal follow-up (n = 10). Serum total bile acids, aminotransferases, alkaline phosphatase, albumin, total cholesterol, and bilirubin (total and conjugated) were evaluated after overnight fasting at the start of the study and on days 4 and 8 of follow-up. By day 8 of treatment serum total bile acid concentrations were lower in patients of the charcoal group than in the control group (P < 0.05). A decrease of total bile acids was observed in seven patients but in only one of the controls (P < 0.05). No other observations (including pruritus) were changed significantly by charcoal. The outcome of pregnancy was good in both groups. This preliminary study suggests that peroral activated charcoal may be considered an alternative in the treatment of intrahepatic cholestasis of pregnancy.