Anaesthetic management of two different modes of delivery in patients with dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa is an inherited severe bullous condition characterised by extreme skin fragility and blistering in response to minor trauma. We present two obstetric cases with recessive dystrophic epidermolysis bullosa, one who underwent elective caesarean section, the other who delivered vaginally. The key points in the anaesthetic management of the obstetric patient with dystrophic epidermolysis bullosa include multidisciplinary preassessment, airway management strategies and the role of regional anaesthesia.

Placental ABCA1 expression is reduced in primary antiphospholipid syndrome compared to pre-eclampsia and controls.

The ATP binding cassette transporter A1 (ABCA1) mediates cellular cholesterol and phospholipid efflux, and is implicated in phosphatidylserine translocation and apoptosis. Loss of functional ABCA1 in null mice results in severe placental malformation. This study aimed to establish the placental localisation of ABCA1 and to investigate whether ABCA1 expression is altered in placentas from pregnancies complicated by pre-eclampsia and antiphospholipid syndrome. ABCA1 mRNA and protein localisation studies were carried out using in situ hybridization and immunohistochemistry. Comparisons of gene expression were performed using real-time PCR and immunoblotting. ABCA1 mRNA and protein was localised to the apical syncytium of placental villi and endothelia of fetal blood vessels within the villi. ABCA1 mRNA expression was reduced in placentas from women with APS when compared to controls (p<0.001), and this was paralleled by reductions in ABCA1 protein expression. There were no differences in ABCA1 expression between placentas from pre-eclamptic pregnancies and controls. The localisation of ABCA1 in human placenta is consistent with a role in cholesterol and phospholipid transport. The decrease in ABCA1 protein in APS may reflect reduced cholesterol transport to the fetus affecting the formation of cell membranes and decreasing the level of substrate available for steroidogenesis.

Coelomic fluid leptin concentration in normal first-trimester pregnancies and missed miscarriages.

OBJECTIVE: Investigation of the possible role of leptin in early pregnancy failure. METHODS: Leptin concentration was measured in maternal serum, coelomic fluid and amniotic fluid from 15 singleton pregnancies with live fetuses and 7 missed miscarriages at 7-10 weeks of gestation. RESULTS: In the pregnancies with live fetuses, the median leptin concentration was significantly higher in coelomic fluid (median 33.1 ng/ml) than in maternal serum (median 8.1 ng/ml) or amniotic fluid (median 0.5 ng/ml). In the pregnancies with missed miscarriage, compared to those with live fetuses, the median leptin concentration in coelomic fluid was higher (median 45.3 ng/ml), but in maternal serum it was not significantly different (median 5.5 ng/ml). CONCLUSIONS: The high coelomic fluid leptin concentration suggests that embryonic death may be preceded by impaired oxygenation of the placenta that stimulates production of leptin.

Uterine artery Doppler and mid-trimester maternal plasma homocysteine in subsequent pre-eclampsia.

OBJECTIVE: To investigate whether mid-trimester maternal plasma homocysteine concentration is elevated in women who develop pre-eclampsia and in those women identified at high risk by abnormal uterine artery Doppler examination. METHODS: This was a multicenter study involving healthy women undergoing screening for pre-eclampsia by uterine artery Doppler velocimetry at 22-24 weeks' gestation. Abnormal uterine artery blood flow was defined as a mean pulsatility index (PI) above the 95th centile (1.6). Controls (mean PI < 1.6) were matched for gestational age and date of blood sample collection. Maternal plasma homocysteine concentration was measured retrospectively using a chemiluminescent immunoassay. RESULTS: In total, 683 women were recruited. Maternal plasma homocysteine concentration did not vary with gestation. Maternal plasma homocysteine concentration in women who subsequently developed pre-eclampsia (n = 80, 12%) was not significantly different from women with uncomplicated pregnancies (n = 536, 78%) (median 5.1, range 2.7-14.1 micromol/l vs. median 5.5, range 1.9-27.9 micromol/l, p = 0.44). There were no significant differences in the maternal plasma homocysteine concentration in women with abnormal uterine artery Doppler findings (n = 275) compared with controls (n = 408), (median 5.6, range 2.6-17.7 micromol/l vs. median 5.4, range 1.9-27.9 micromol/l, p = 0.13). CONCLUSION: Mid-trimester maternal plasma homocysteine concentration is not elevated in women who developed pre-eclampsia even in those at high risk defined by abnormal uterine artery Doppler velocimetry.

The basement membrane zone in patients with systemic lupus erythematosus: immunofluorescence studies in the skin, kidney and amniochorion.

Histological studies suggest that the basement membrane zone (BMZ) is the main target of tissue pathology in cutaneous lupus erythematosus (LE). The BMZ is characteristically thickened and is the site of deposition of autoantibodies in LE. Alteration of some (BMZ) macromolecules is implicated in the pathology of several bullous skin diseases. A major component of BMZ is heparan sulphate proteoglycan (HSPG) which was found reduced in the skin of some patients with systemic lupus erythematosus (SLE) and in the kidney of mice with lupus nephritis. Similar to the skin, amnion is derived from the ectodermal germ layer during embryogenesis and expression of BMZ components of amniochorion was not previously studied in SLE. The aim of the present study was to investigate the expression of major BMZ macromolecules in the skin, kidney and amnioplacentae obtained from patients with SLE and compare these findings with organ biopsies from unaffected individuals. In addition, determining whether the differences in composition and distribution of BMZ macromolecules in these organs correlate with certain patterns of deposition of immunoreactants could contribute to our understanding of the mechanism of deposition of immunoreactants in SLE. In some patients with SLE, reduced expression of HSPG in nonlesional skin was reported previously. These changes of heparan sulphate might be important in the pathogenesis of LE. Therefore, the aims of this study are to confirm the previous finding and to compare HSPG expression between lesional and nonlesional LE skin. The unique features of each BMZ could contribute to the deposition or binding of positively charged immune complexes and explain the different patterns of immunofluorescence. Frozen sections of skin, kidney and amniochorion obtained from patients with SLE were investigated by indirect immunofluorescence technique using monoclonal antibodies (Moab) to determine the expression of major components of the BMZ. Heparan sulfate expression is reduced in the skin and, to a lesser extent, in the kidney in patients with SLE. There was no correlation between the kidney and skin heparan sulfate expression within the same patient. The BMZ composition in amniochorionic membrane ofplacentae from women with SLE was normal. Heparan sulfate may be one of the major targets for immunoglobulin deposition in the skin of patients with SLE. The processes of immunoglobulin deposition in SLE may be more complex in that there was no correlation between heparan sulfate expression in the skin and kidney of the same patient.

Fetal programming for adult disease: where next?

The Barker hypothesis of fetal programming for adult cardiovascular and metabolic diseases has attracted much interest over the past few years. In this review, we summarize the main studies in this field, give a brief outline of some of the laboratory models used to investigate this hypothesis and discuss potential mechanisms underlying these clinical observations that are amenable to future research.

Uterine artery function in pregnant rats fed a diet supplemented with animal lard.

We hypothesised that maternal uterine artery vascular dysfunction could contribute to cardiovascular dysfunction in offspring of rats fed a diet rich in fat. Sprague-Dawley rats were fed for 10 days prior to pregnancy and throughout gestation either: (a) a control breeding diet, or (b) the same diet supplemented with 20 % w/w lard, vitamins, essential micronutrients and protein to control values. At 20 days gestation vascular function was assessed in uterine arteries and third-order mesenteric arteries. Vascular reactivity in response to application of potassium, noradrenaline, the thromboxane analogue U46619, acetylcholine and nitric oxide was assessed. Maternal plasma concentrations of factors likely to contribute to endothelial dysfunction were measured. Maximum acetylcholine-induced relaxation was impaired in the mesenteric arteries of the lard-fed dams (max % relaxation: lard-fed, 69.7 +/- 6.48; control, 85.37 +/- 2.69, P = 0.03). Uterine artery vascular function was similar in the two groups (max % acetylcholine-induced relaxation: lard-fed, 73.7 +/- 4.01; control, 77.5 +/- 4.72, P = 0.98). Concentrations of plasma lipids, 8-epi-PGF(2alpha) and leptin were normal, whereas insulin and corticosterone concentrations were raised in the lard-fed group (insulin (ng ml(-1)): lard-fed, 8.04 +/- 0.47; control, 1.35 +/- 0.37, P < 0.0001; corticosterone (ng ml(-1)): lard-fed, 1164.0 +/- 170.9; control, 541.9 +/- 96.3, P = 0.005). Fetal and placental weights were reduced in lard-fed dams (fetus (g): lard-fed, 4.27 +/- 0.38; control, 2.96 +/- 0.40, P = 0.025; placenta (g): lard-fed, 0.72 +/- 0.06; control, 0.57 +/- 0.04, P = 0.05). Cardiovascular dysfunction in offspring is not associated with reduced uterine artery endothelial function but is associated with activation of the hypothalamic-pituitary-adrenal axis, hyperinsulinaemia and fetoplacental growth retardation.

Contraceptive practices in women with systemic lupus erythematosus and/or antiphospholipid syndrome: what advice should we be giving?

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune oestrogen-mediated disease. Antiphospholipid syndrome (APS) is an autoimmune acquired thrombophilia. These two conditions may co-exist and are most frequently diagnosed in young women. Hormonal contraception may promote lupus activity and thromboses. Medical practitioners may not know what advice to give these women regarding contraception. OBJECTIVES: To determine the past and present contraceptive practices of women with SLE and/or APS, and to establish the incidence of complications related to use of various contraceptives. Also, the contraceptive information given to women following diagnosis was evaluated. STUDY DESIGN: Observational questionnaire-based study of 86 women with SLE and/or APS attending the Lupus/Thrombophilia Clinics at St. Thomas' Hospital. RESULTS: One of the 19 (5%) women with SLE using the combined oral contraceptive pill (COCP) at the time of diagnosis reported a severe lupus 'flare'. Seven of the 32 (22%) women with APS using the COCP suffered from thromboses during use. There were no problems specific to women with SLE and/or APS using any other form of contraception. Thirty-nine (45%) women received no contraceptive information following their diagnosis, 37 (46%) were told to avoid the COCP due to the increase in lupus 'flare' and/or thromboses. CONCLUSION: There is no clinically significant association between COCP use and lupus 'flare'. The high incidence of thromboses in women with APS using the COCP containing either second or third generation progestogens suggests that these women should be advised against using this form of contraception. Women with SLE and/or APS should be given more information about contraceptive issues.

Normal expression of cell adhesion molecules in placentae from women with systemic lupus erythematosus and the antiphospholipid syndrome.

Pregnant women with active systemic lupus erythematosus (SLE) and/or the antiphospholipid syndrome (APS) are prone to recurrent miscarriage, pre-eclampsia, intrauterine growth restriction and premature delivery. Placental dysfunction may account for these complications yet the mechanisms remain uncertain. Amongst these, an inflammatory response in the placental vasculature could play a role, involving recruitment of neutrophils and platelets and the increased endothelial expression of cell adhesion molecules (CAM), central to the recruitment process. The aim of this study was primarily to investigate CAM expression in the fetoplacental vasculature in women with SLE/APS. Circulating maternal concentrations of soluble CAM were also elucidated. There were no differences in CAM immunostaining in placentae from patients with SLE and/or APS compared with controls. In both patients and controls moderate immunostaining for the intercellular adhesion molecule-1 (ICAM-1) was observed in placental vascular endothelium and mild immunostaining was present in the placental villous stroma. Strong immunostaining for platelet endothelial CAM (PECAM) occured in the placental vascular endothelium whereas P-selectin was mildly expressed in the stem vessel endothelium only. Vascular CAM-1 (VCAM-1) and E-selectin were undetectable in either study or control placentae. In contrast, ICAM-1 and VCAM-1 but not E-selectin, as assessed by immunoassay (ELISA), were elevated in maternal serum from SLE/APS patients compared with controls. This study suggests that upregulation of CAM expression and subsequent activation of neutrophil and/or platelet activity within the placental villous tree is unlikely to be a mechanism by which the adverse pregnancy outcome arises in SLE/APS pregnancies. However, maternal endothelial cell activation (ECA) may play a more important role.

Normal expression of tissue factor, thrombomodulin, and annexin V in placentas from women with antiphospholipid syndrome.

OBJECTIVE: Placentas from pregnancies complicated by antiphospholipid syndrome often show thromboses and infarction, which may result from aberrations in placental coagulant pathways. We tested the hypothesis that alterations in tissue factor, thrombomodulin, and annexin V expressions contribute to poor pregnancy outcome associated with antiphospholipid syndrome. STUDY DESIGN: Frozen sections from random biopsy samples of the basal plates of placentas from patients with primary antiphospholipid syndrome (n = 9), patients with secondary antiphospholipid syndrome (n = 3), and gestational age-matched control subjects (n = 10) were immunostained for tissue factor, thrombomodulin, and annexin V. Intensity of immunostaining was assessed by means of quantitative image analysis. Annexin V protein expression was evaluated with Western blotting techniques. RESULTS: Tissue factor was expressed in the perivascular cells of the villous vasculature. Thrombomodulin and annexin V immunostaining was localized to the syncytiotrophoblast. There were no differences in the intensity of immunostaining for tissue factor, thrombomodulin, and annexin V between placentas from women with antiphospholipid syndrome and those from control subjects. Western blot analysis of annexin V expression showed no differences between study patients and control subjects. CONCLUSION: Alterations in placental coagulant pathways involving tissue factor, thrombomodulin, and annexin V do not contribute to poor pregnancy outcome associated with antiphospholipid syndrome.

Adverse pregnancy outcome in the antiphospholipid syndrome: focus for future research.

Pregnant patients with antiphospholipid syndrome (APS) may suffer from recurrent pregnancy loss, pre-eclampsia, intrauterine growth restriction and placental abruption. These conditions inevitably result in a high incidence of premature delivery with all the neonatal complications that follow. The mechanism underlying these adverse pregnancy outcomes has not yet been established. This may be primarily a maternal disease process with secondary placental maldevelopment and/or malfunction. Alternatively, there may be primary placental damage mediated directly or indirectly by antiphospholipid antibodies. The safe and successful treatment of pregnant women with APS lies in the understanding of the aetiology of this condition and the mechanism by which complications in pregnancy may arise. In this article we highlight areas in which research may be targeted such that our understanding of the pathogenesis of adverse pregnancy outcome may be enhanced.