Elevated serum levels of visfatin in gestational diabetes: a comparative study across various degrees of glucose tolerance.

AIMS/HYPOTHESIS: Concentrations of visfatin are increased in insulin-resistant conditions, but the relationship between visfatin and insulin and/or insulin resistance indices in pregnancy remains unclear. Insulin resistance in pregnancy is further accentuated in women with gestational diabetes mellitus (GDM). Thus we assessed serum levels of visfatin in pregnant women with varying degrees of glucose tolerance. MATERIALS AND METHODS: Fasting visfatin levels were measured at 28 weeks of gestation in 51 women divided according to their response to a 50-g glucose challenge test (GCT) and a 75-g OGTT: control subjects (n = 20) had normal responses to both a GCT and an OGTT; the intermediate group (IG; n = 15) had a false-positive GCT, but a normal OGTT; the GDM group (n = 16) had abnormal GCTs and OGTTs. RESULTS: There were no age or BMI differences between analysed groups. Across the subgroups there was a progressive increase in glucose and insulin at 120 min of the OGTT (p < 0.01). This was accompanied by an increase in visfatin, from 76.8 +/- 14.1 ng/ml in the control subjects, to 84.0 +/- 14.7 ng/ml in the IG group and 93.1 +/- 12.3 ng/ml in the GDM group (p < 0.01 for GDM vs control subjects). There was a positive correlation between visfatin and fasting insulin (r = 0.38, p = 0.007) and insulin at 120 min of the OGTT (r = 0.39, p = 0.006). CONCLUSIONS/INTERPRETATION: An increase in fasting visfatin, the levels of which correlate with both fasting and post-glucose-load insulin concentrations, accompanies worsening glucose tolerance in the third trimester of pregnancy. However, the significance of these findings, and in particular the role of visfatin in the regulation of insulin sensitivity during pregnancy, remains to be elucidated.

Pregnancy in renal transplant recipients: the Royal Free Hospital experience.

BACKGROUND: For women with end-stage renal failure of child-bearing age, renal transplantation offers a chance to start a family. Pregnancies in renal transplant recipients involve risks for graft and fetus, and need to be carefully managed. AIM: To identify graft, fetal and maternal outcomes in our patients, and compare our results with those of the large national transplant registries. DESIGN: Retrospective case-note review. METHODS: We assessed the outcomes of 48 pregnancies in 24 renal transplant recipients. Obstetric data and renal parameters were examined in 27-30 pregnancies that progressed to delivery. RESULTS: Mean time from transplantation to pregnancy was 6.5 years, with an unfavourable outcome in patients who conceived within 1 year. There was a 41% incidence of fetal growth restriction (FGR), and 33% of infants were small for gestational age. FGR was associated with maternal hypertension, a pre-pregnancy serum creatinine (SCr) >/= 133 micro mol/l (1.5 mg/dl), calcineurin inhibitors and the use of cardioselective beta blockers. Two patients with pre-pregnancy SCr > 200 micro mol/l lost their grafts within 3 years of delivery. A permanent significant decline in graft function occurred in 20%, by 6 months post delivery. DISCUSSION: FGR with SGA infants occurs frequently. Atenolol should be avoided in pregnancy and Metoprolol should not be combined with calcineurin inhibitors. Pregnancy appeared to have a deleterious effect on graft function in patients with SCr > 155 micro mol (1.75 mg/dl). Patients with pre-pregnancy SCr 200 micro mol/l are at greatest risk.

Markers of platelet activation, thrombin generation and fibrinolysis in women with sickle cell disease: effects of differing forms of hormonal contraception.

OBJECTIVE: To examine laboratory markers of platelet activation, thrombin generation and fibrinolysis in women with sickle cell disease (SCD) using the combined oral contraceptive pill (COCP), progestogen only (PO) contraception and non-hormonal contraception. DESIGN: A prospective observational study set in two teaching hospitals in the London region. METHOD: Forty-four women with SCD in steady haematological state using differing hormonal contraception were recruited and venesection was performed at standardised times for the measurements of markers of platelet activation, thrombin generation and fibrinolysis. OUTCOME MEASURES: Prothrombin fragment1+2, plasmin alpha2 antiplasmin complexes, platelet factor 4 (PF-4), beta-thromboglobulin and free protein S antigen (PS-Ag). RESULTS: PS-Ag was decreased and PF-4 increased in all women while the other haemostatic variables were within normal reference ranges. However, there was no statistically significant differences in the measurements of all the haemostatic variables between the three groups of sickle cell women (Kruskal-Wallis, P > 0.05). CONCLUSION: There is anxiety about prescribing the COCP in women with SCD based on the assumption that risk of venous thromboembolism may be compounded by the underlying disease process that occurs with these women. The observed data suggest that SCD women who use the COCP have haemostatic markers which are not statistically different compared with similar women who use PO contraception or non-hormonal contraception. However, a randomized interventional trial would be necessary to evaluate further the safety aspect of COCP use in this group of women.

Menstrual pattern in women with sickle cell anaemia and its association with sickling crises.

This was a prospective observational study based on 6-month menstrual diaries in women with sickle cell anaemia (SCA). The aim was to evaluate the natural menstrual pattern and to establish if there was an association between menses and painful crises in these women. The main outcome measures included length of cycle, duration of loss and the occurrence of painful crises in relation to menses. Eighty-two women were recruited initially and 42 returned completed menstrual diaries. A total of 213 continuous natural cycles were evaluated. The mean cycle length was 28.9 (+/- 5.95) days, while the mean duration of menstrual loss was 4.69 (+/- 4.65) days. Thirty-seven per cent of the women had definite cyclical painful crises with each menses and in this group, 61.5% of crises occurred with menstrual flow. An additional 21% had at least three cyclical crises documented in the 6-month period. In 42%, there was no association between menses and crises. In summary, 58% of women had some form of cyclical crises (albeit not severe) in association with menstrual cycles. In severe cases, the use of a continuous combined contraceptive pill regime or Depo-Provera to induce amenorrhoea (as well as to provide contraception) should be considered.

Red cell deformability in oral contraceptive pill users with sickle cell anaemia.

The use of the combined oral contraceptive pill (COCP) in women with sickle cell anaemia (SCA) is controversial, as contraceptive steroids are thought to adversely affect erythrocyte deformability. This observational study was performed to investigate whether hormonal contraception influenced erythrocyte deformability in women with SCA. 30 women with SCA using various contraceptive modalities: COCP (n = 10); progestogen only (PO) contraception (n = 10) and non-hormonal contraception (n = 10) were recruited. Erythrocyte deformability was assessed using the clogging rate (CR) and red cell transit time (RCTT). There was no statistical difference in the mean CR and RCTT between the three groups of women (one-way ANOVA). Current contraceptive steroids do not appear to impair red cell deformability in women with SCA.

The effect of ovarian steroids on sickle cell deformability.

Sickle cell disease (SCD) is an incurable debilitating disease affecting the Afro-Caribbean population. The combined oral contraceptive pill (COCP), an effective and popular method of contraception, is often denied to women with SCD for fear that the disease process may have a synergistic effect on the coagulation changes associated with contraceptive steroids. In this study red cell deformability was assessed in 10 women with SCD and 10 comparable women with normal AA haemoglobin. Neither group was on exogenous hormones. The red cells were taken in the follicular phase of the menstrual cycle when women have low endogenous levels of oestradiol and progesterone. The effect of the steroids contained in the COCP on red blood cells was simulated by incubation with therapeutic concentrations of oestradiol and progesterone. Red cell deformability is a measure of the ease with which erythrocytes flow through small capillaries and was assessed using the parameters red cell transit time (RCTT) and clogging rate (CR). Therapeutic concentrations of oestradiol and progesterone did not appear to influence red cell deformability in women with SCD or normal AA haemoglobin.

Pregnancy management and outcomes in women with thalassaemia major.

The health background, management and outcomes of 25 pregnancies in 18 women with transfusion dependent beta thalassaemia are described with particular consideration of appropriate preconceptual guidance for such women. This is an observation study of women attending three collaborating London hospitals. Nine of the pregnancies required induction of ovulation. Two pregnancies were complicated by diabetes and three by hepatitis C. One patient was hepatitis B positive. Two pregnancies were in women with cardiac problems, one of whom died of cardiac failure nine months after delivery of a live child. Two of the pregnancies miscarried and three were terminated, with the others resulting in 21 live children (including one set of twins). 14 of the pregnancies were delivered by caesarean section. After pregnancy five women developed secondary amenorrhoea, two developed cardiac problems and two developed diabetes.

High prevalence of low bone mass in thalassaemia major.

Cooley's original description of beta-thalassaemia major included marked bone deformities as a characteristic feature. These were thought to be due to expansion of haemopoiesis attempting to compensate for the congenital anaemia. Regular blood transfusions from infancy prevents these skeletal problems. Nevertheless, symptoms due to bone disease frequently occur in adult patients. Osteoporosis has not previously been reported as a cause of severe morbidity in thalassaemia major. The present study shows a high prevalence of low bone mass among thalassaemia major patients and analyses the predisposing causes. Bone density scans were performed in 82 patients with transfusion-dependent beta thalassaemia. Factors known to be associated with low bone mass such as gender, endocrine disorders and lifestyle activities, together with factors specific to the thalassaemia and its management, were included in a series of univariate analyses to ascertain any significant associations. 42 (51%) of the patients had severely low bone mass and a further 37 (45%) had low bone mass. The three factors showing a statistically significant association with severely low bone mass were male sex, 24/38 (63%) males had severely low bone mass, compared with 18/44 (41%) females, the lack of spontaneous puberty, 22/32 (69%) who required therapeutic induction of pubertal development had severely low bone mass, compared with 19/47 (40%) with spontaneous puberty and diabetes, 8/10 (80%) diabetic patients had severely low bone mass, compared with 23/56 (41%) with normal glucose tolerance. There was no association between the bone mineral density measurements and the haematological characteristics or treatment details of these patients. Severely low and low bone mass are common findings in patients with beta-thalassaemia major despite optimal transfusion and iron chelation. The associated features suggest that the severely low bone mass is due to endocrine abnormalities, in contrast to the haematological causes of bone disease characteristically seen in untreated thalassaemics.

Incidence of endocrine complications and clinical disease severity related to genotype analysis and iron overload in patients with beta-thalassaemia.

The incidence of endocrine dysfunction in relation to the detailed genotype of beta-thalassaemia is investigated in this study. In addition, the association of genotype to specific clinical features of beta-thalassaemia is examined, together with the relationship between serum ferritin levels and endocrine complications. Ninety-seven patients were included, all with transfusion dependent beta-thalassaemia. Patients were divided into 2 categories; group 1 consisted of patients with a beta0/beta0 genotype with or without a concomitant alpha-globin gene deletion as well as patients with beta0/beta+ or beta+/beta+ genotype and normal alpha-globin chain synthesis. Group 2 included patients with beta+/beta+ or beta+/beta0 genotype and one alpha-globin chain deletion and those with a moderate amount of beta-globin chain synthesis (beta++) and normal alpha-globin chain synthesis. The results showed that group 1 patients were more likely to have severe clinical disease (p=0.005). Sixty-four patients (66%) had at least 1 endocrine disorder and 39 (40%) had multiple endocrinopathies; the most common abnormality was hypogonadotrophic hypogonadism (HH). There was a significant association between patients with group 1 genotypes and the presence of HH and impaired glucose tolerance or diabetes. A positive correlation was demonstrated between serum ferritin concentrations and the presence of thyroid or parathyroid dysfunction.

Sperm concentrations and quality in beta-thalassaemia major.

We report semen analyses in eight patients with beta-thalassaemia major, with poor results in all but the youngest. The causation is multi-factorial, with iron deposition in the pituitary gland resulting from life-long dependence on blood transfusions being a major factor. We speculate on other contributing causes, but further research is required to elucidate these. Improving haematological care means that these men are increasingly surviving to adult life. Relevant techniques to enable them to achieve their desire for fatherhood are considered.

Pregnancy in sickle cell disease in the UK: results of a multicentre survey of the effect of prophylactic blood transfusion on maternal and fetal outcome.

OBJECTIVE: To determine the outcome of pregnancies complicated by sickle cell disease in the UK during 1991-1993 and the effect of prophylactic blood transfusion programmes on maternal and fetal outcome. DESIGN: A multicentre study. SUBJECTS: Eighty-one pregnancies complicated by sickle cell disease and 100 pregnancies from women of black African descent without haemoglobinopathies to act as a comparative group. Pregnancies complicated by sickle cell disease were divided by the type of haemoglobinopathy and also by transfusion regimen. MAIN OUTCOME MEASURES: Antenatal and postnatal complications of sickle cell disease, proteinuric hypertension, preterm delivery, emergency delivery by caesarean section, fetal distress, birthweight, perinatal and maternal mortality. RESULTS: There were two maternal deaths in the 81 pregnancies and the perinatal mortality rate was 60/1000. Antenatal sickling complications occurred in 46.2% of pregnancies and postnatal sickling complications occurred in 7.7% of pregnancies. Pregnancies complicated by sickle cell disease were significantly more likely to be associated with anaemia, preterm delivery, proteinuric hypertension, birthweight below the 10th centile and caesarean section as an emergency procedure than the comparative group. Severe sickling complications occurred more commonly in the third trimester and there was some evidence that a prophylactic transfusion programme reduced the risk of this. Prophylactic transfusion did not improve obstetric outcome when compared with those pregnancies that were untransfused. CONCLUSIONS: Sickle cell disease remains a severe complicating factor to pregnancy and perinatal mortality and maternal mortality rates in the UK have increased since last reported. A policy of exchange transfusing all women with homozygous sickle cell disease (HbSS) from 28 weeks gestation is recommended to reduce the risk of maternal complications in the third trimester and puerperium. There remains a role for earlier prophylactic blood transfusion programmes in women with poor obstetric and haematological histories.

Fertility in beta thalassaemia major: a report of 16 pregnancies, preconceptual evaluation and a review of the literature.

OBJECTIVES: To examine the pregnancies, mode of delivery and outcomes, review the literature on fertility and discuss preconceptual guidance for women with beta thalassaemia major. DESIGN: An observational study. SUBJECTS: Sixteen women with beta thalassaemia major. SETTING: Two collaborating London teaching hospitals. MAIN OUTCOME MEASURES: Pre-pregnancy assessment, pregnancy course, mode of delivery, gestational age at delivery and birthweight. RESULTS: There were 16 pregnancies in 11 women. Three of these pregnancies were terminated. Of the 13 deliveries, there were two normal deliveries, one forceps delivery and 10 caesarean sections. The main findings in a further five women seeking fertility treatment were of hypogonadotrophic hypogonadism, diabetes and cardiomyopathy. CONCLUSIONS: Pregnancy in women with beta thalassaemia major does not appear to have a deleterious effect on the course of the disease. No increased obstetric complications were encountered except for the high caesarean section rate, essentially due to cephalopelvic disproportion. A high incidence of cardiomyopathy and diabetes dictates a careful assessment before embarking on ovulation induction to treat the hypogonadotrophic hypogonadism which is common in these women.

Optimal haematocrit and haemoglobin S levels in pregnant women with sickle cell disease.

Sickle cell blood has abnormal rheological characteristics and its viscosity is determined by the level of haemoglobin S and the PCV. Rheological studies have shown that alteration of these parameters will improve oxygen delivery to the tissues. However, there is no agreed policy for optimum levels for haemoglobin S and PCV in the management of pregnancies complicated by sickle cell disease. In this study rheological measurements have been performed on pregnant women with sickle cell disease and compared with women without haemoglobinopathy. Potential oxygen delivery was not found to approach normal levels until very low levels of HbS were achieved. The optimal PCV for women with sickle cell disease was found to be 0.26 compared with 0.33 for normal women.

Blood transfusion in pregnancies complicated by maternal sickle cell disease. Effects on blood rheology and uteroplacental Doppler velocimetry.

Doppler ultrasound gives a measure of downstream resistance to blood flow. In this study it has been used to assess the change in placental vascular resistance following blood transfusion in pregnancies complicated by sickle cell disease. Eight women with homozygous sickle cell disease were followed prospectively to assess the effect of transfusion on haemoglobin S percentage, blood and plasma viscosity and uteroplacental Doppler velocimetry. Measurements were made immediately pre and post-transfusion and after several weeks when the desired improvement in haemoglobin S had been achieved. Despite significant changes in haemoglobin S levels and consequent rheological change there was found to be no change in measurements of resistance in the uteroplacental circulation as assessed by Doppler ultrasound.

Contraception and sickle cell disease.

PIP: Although women with sickle cell disease have been found to have a delay in puberty of 2.3 years, there is no evidence that they are less fertile than women without hemoglobinopathy. Women with sickle cell disease therefore need adequate family planning advice to prevent unwanted pregnancy. The need for good and comprehensive advice is particularly important given the association among these women between pregnancy and increased maternal and fetal mortality and morbidity rates. Moreover, unwanted pregnancy rates among women with sickle cell disease have been reported as being in the range of 38-64%, and one study found that only 33% of a group of women with sickle cell disease used any form of contraception compared to 66% in a control group. Sickle cell disease is listed in the manufacturers' data sheets in the UK as a contraindication to the use of the majority of combined oral contraceptive pills, but there is little good evidence to support this restriction. In fact, women with the sickle cell trait have no particular added risks and can be offered the usual range of contraceptive methods. Evidence that the use of injectable progestagens may reduce the risk of crises, however, suggests that they should be recommended as a first option of contraception for these women. Good evidence exists that the injectables are safe and effective for women with sickle cell disease despite the adverse publicity which they have received. The IUD appears to be safe as are the common barrier methods, while the combined oral contraceptive pill is a convenient, effective, and reliable form of contraception which should continue to be prescribed for these women, albeit with caution.^ieng