Medical ethics and law for doctors of tomorrow: the 1998 Consensus Statement updated.

Knowledge of the ethical and legal basis of medicine is as essential to clinical practice as an understanding of basic medical sciences. In the UK, the General Medical Council (GMC) requires that medical graduates behave according to ethical and legal principles and must know about and comply with the GMC's ethical guidance and standards. We suggest that these standards can only be achieved when the teaching and learning of medical ethics, law and professionalism are fundamental to, and thoroughly integrated both vertically and horizontally throughout, the curricula of all medical schools as a shared obligation of all teachers. The GMC also requires that each medical school provides adequate teaching time and resources to achieve the above. We reiterate that the adequate provision and coordination of teaching and learning of ethics and law requires at least one full-time senior academic in ethics and law with relevant professional and academic expertise. In this paper we set out an updated indicative core content of learning for medical ethics and law in UK medical schools and describe its origins and the consultative process by which it was achieved.

Immunohistology of normal and ovarian cancer tissue with a monoclonal antibody to placental alkaline phosphatase.

A monoclonal antibody, designated NDOG2, has been shown to react with placental alkaline phosphatase. It does not bind to liver, kidney, bone, or intestinal alkaline phosphatase enzymes and has shown a positive reaction with all of over 50 placentae. Immunohistological studies have shown (a) a reaction with respiratory bronchiolar epithelium of lung, endocervical gland epithelium, the epithelium of fallopian tube, and certain reticular cells in the thymic medulla; (b) no detectable staining with ten other normal tissues including testis and tonsil; and (c) a significant reaction with nine of 13 ovarian cystadenocarcinomas and little or no staining with four malignant ovarian tumors of other histopathological types. The NDOG2 antibody may be of value as a marker in patients with ovarian cystadenocarcinoma.

The biological activity of the corticotropin-releasing hormone receptor-adenylate cyclase complex in human myometrium is reduced at the end of pregnancy.

We recently suggested that placentally derived CRH might influence human parturition via specific receptor mechanisms. We identified a human myometrial CRH receptor that changes to a high affinity state in the later stages of pregnancy and becomes coupled to the adenylate cyclase system. The purpose of this study was to investigate the functional capacity of this receptor in myometrial tissue obtained from women being delivered electively by cesarian section at term (38-40 weeks gestation) and preterm (30-35 weeks gestation) before the onset of labor. Myometrial membrane suspensions were prepared by differential centrifugation, and the production of cAMP after stimulation with various test substances was measured by RIA. In preterm myometrium, both human CRH and cholera toxin stimulated cAMP production. This effect was significantly reduced in term myometrium. The adenylate cyclase was functionally active in term myometrium, as demonstrated by the use of forskolin. Furthermore, pertussis toxin pretreatment of term myometrial membranes did not increase the response to CRH. These results suggest that in human pregnant myometrium at term, there is a modification in the coupling mechanisms between CRH receptors and the catalytic component of adenylate cyclase, resulting in a reduction of CRH-stimulated cAMP production.

A terminal-labelling microcytotoxicity assay with 125I-iododeoxyuridine as a label for target cells.

The development of a terminal-labelling microcytotoxicity assay is described in which target cells (fetal fibroblasts) were labelled with 125I-iododeoxyuridine after effector (lymphoid) cells had been incubated with them for 24 h. The time-course for the development of cell-mediated cytotoxicity was assessed following allogeneic skin grafting. 'Non-specific' cytotoxicity detracts from the sensitivity of all microcytotoxicity assays and the terminal-labelling assay using 125I is no exception. The non-specific effects can be reduced but not eliminated by the removal of adherent cells. The optimum target cell/effector cell ratio would seem to be between 1:100 and 1:250. Residual lymph node cells did not appear to incorporate enough label to affect the test results. In vivo correlates of in vitro findings are still not easy to determine.

Abnormal expression of class II MHC antigens in placentae from patients with pemphigoid gestationis: analysis of class II MHC subregion product expression.

Abnormal expression of class II MHC antigens was consistently observed in an immunohistological study on placentae from patients with pemphigoid gestationis. The area affected in all the placentae was the chorionic villi adjacent to the maternal decidua. The villous stroma, and in some cases the chorionic fetal endothelium, had abnormal expression of class II MHC antigens. Monoclonal antibodies specific for the class II MHC subregion products (DR, DP and DQ) were used to analyse the class II MHC antigen expression. Differential expression of the class II MHC subregion products was observed on the villous stroma and chorionic fetal endothelium; DR and DP were always expressed but DQ in some cases was heterogeneous. This abnormal expression of class II MHC antigens may reflect an immunological attack on the placenta in pemphigoid gestationis.

The expression of major histocompatibility antigens by human chorionic villi.

Frozen sections of human placentae taken at selected stages throughout gestation were stained with monoclonal antibodies to HLA-A, B, C and DR antigens, using an indirect immunoperoxidase technique. No staining of villous trophoblastic tissue was detected. Antibody to HLA-A, B, and C antigens clearly stained membranous elements of the villous stroma. Antibody to HLA-DR antigens stained rare, elongated cells of the villous stroma in the term placenta. Monoclonal antibodies to syncytiotrophoblast membrane were used as a control. This antigen distribution was confirmed by absorption of these monoclonal antibodies in an indirect radioimmunoassay. Adult spleen homogenate gave much stronger absorption than a trophoblast membrane preparation with antibodies to HLA-A, B, C or DR antigens. The opposite absorption pattern was observed with the anti-trophoblast monoclonal antibodies. Detergent solubilisation did not affect the absorption capacity of trophoblast membrane for HLA-A, B, C or DR antigens. Maternal antibody could be eluted from trophoblastic areas of term placental sections by washing at physiological pH, but this did not effect the binding of monoclonal antibodies. Thus the HLA antigens were not masked by preformed maternal alloantibody. These observations confirm that chorionic villous trophoblast does not express detectable HLA antigen. This may be the principal reason for the lack of rejection of the fetal allograft.

Immunohistological and biochemical evidence for a role for hyaluronic acid in the growth and development of the placenta.

A monoclonal antibody, designated NDOG1, has been used to stain a series of human and monkey placentae as well as several adult human tissues using immunoperoxidase techniques. In early placentae, NDOG1 was found to stain extracellular material associated with proliferating, extravillous cytotrophoblast cell columns and with the cytotrophoblast shell at the feto-maternal junction. The immunohistology suggests that NDOG1 antigen may be secreted by the anchoring cytotrophoblast into the immediately adjacent maternal tissues. NDOG1 antibody also shows extracellular staining in the stroma of early human placentae and reacted with the apical villous syncytiotrophoblast plasma membrane throughout pregnancy. Biochemical experiments demonstrated that extracts of this latter membrane contained NDOG1 antigenic activity which was susceptible to digestion with bovine testicular hyaluronidase. Hyaluronic acid was the only glycosaminoglycan found in this membrane, thereby implying a reaction between NDOG1 antibody and hyaluronic acid. Whilst no such direct interaction could be demonstrated in vitro, NDOG1 was shown to compete with two other antibodies which themselves demonstrated specificity for hyaluronic acid. The proposed identity between the NDOG1 antigen and hyaluronic acid is discussed particularly in terms of placentation where the distribution of NDOG1 staining may confirm the role of hyaluronic acid in providing an open matrix structure during stages of cell proliferation, migration and invasion.

Abnormal expression of HLA-DR antigen in the placenta of a patient with pemphigoid gestationis.

The villous stroma and fetal endothelium in chorionic villi adjacent to maternal decidua in a placenta of a woman suffering from pemphigoid gestationis were found to have abnormal expression of HLA-DR antigen. This aberrant DR expression may be a reflection of an immune attack on the placenta.

Radioimmunoassay of thyroxine and 3,3',5'-triiodothyronine (reverse T3) in human amniotic fluid.

Measurement of amniotic fluid iodothyronine concentrations may enable antenatal detection of fetal thyroid abnormalities; however, the delineation of normal ranges is complicated by methodological problems associated with strong and highly variable protein-binding, and specificity of antisera. Improved radioimmunoassays of thyroxine (T4) and 3,3',5-triiodothyronine (reverse T3, rT3) have been developed to overcome these problems. In normal pregnancy, mean rT3 concentrations at less than 17 weeks, 17-22 weeks and 35-42 weeks gestation were 3.6 nmol/l (n = 21), 6.1 nmol/1 (n = 14) and 0.66 nmol/1 (n = 39) respectively; corresponding mean T4 concentrations were 2.4 nmol/1, 6.5 nmol/1 and 3.6 nmol/1. rT3 concentrations showed a strong positive correlation with T4 concentration in each age range; however, the molar ratio of rT3:T4 decreased progressively with gestational age, from 1.69 at less than 17 weeks to 0.19 at 35-42 weeks. In both mid- and late gestation, rT3 and T4 concentrations were strongly correlated with total amniotic fluid protein concentrations.

Fetal Doppler shift waveforms in intrauterine growth retardation: laplace transform analysis technique.

An approach to the analysis of fetal blood flow velocity/time waveforms is described using a Doppler shift flowmeter. The waveform shape is described in terms of its Laplace transform. Variations in the value of the dominant coefficient in the Laplace transform in the descending thoracic aorta appear to distinguish growth retarded from normally grown fetuses early in pregnancy. Growth retardation was defined by an index of size specifically aimed at detecting the disproportionately grown fetus. Simpler methods of waveform shape description fail to detect the growth retarded fetus early in the second trimester.

Assessment and management of hypertensive disorders in pregnancy by health professionals in the Avon district.

A questionnaire based survey was carried out in the Avon health districts to investigate the assessment and management of hypertensive disorders in the third trimester of pregnancy by health professionals. A total of 673 responses were analysed from 310 general practitioners, 48 hospital doctors, 214 hospital midwives, 81 community midwives and 120 student midwives. The study revealed a wide variation in the criteria used for the diagnosis of a hypertensive disorder in pregnancy and some outmoded recommendations for management. The importance of continuing education is stressed, in order to ensure that current research and the consensus of expert opinion is being relayed to the personnel involved in antenatal care.

Mortality and morbidity associated with early-onset preeclampsia.

OBJECTIVE: To examine the management of early-onset preeclampsia and its maternal and fetal morbidity and mortality. DESIGN: Retrospective cohort study of 49,812 births at a university teaching hospital between June 1986 and March 1997. Seventy-one women were identified with a diagnosis of preeclampsia with an onset at less than 30 completed weeks of gestation. RESULTS: The incidence of very preterm preeclampsia was 1 in 682 total births. The mean diagnosis to delivery interval (range) was 14 days (0-49 days). There were no maternal deaths. Fifteen women (21%) had developed HELLP/ELLP syndrome, 9 (13%) had renal failure, 1 (1.4%) had eclampsia, and 11 (15%) had an abruption. Five women (7%) had a termination of pregnancy, 57 (80%) were delivered by cesarean section, and 4 (5%) required a classical incision. There were 12 intrauterine deaths (16%), 9 neonatal deaths (12%), and 52 neonatal survivors (72%). Two of the survivors were known to have neurological impairment at the 2-year follow-up. CONCLUSIONS: A conservative approach to the management of early-onset preeclampsia results in a good obstetric outcome for the majority of fetuses, but this must be balanced against the significant risk of morbidity to the mothers.

Abu Dhabi third stage trial: oxytocin versus Syntometrine in the active management of the third stage of labour.

OBJECTIVE: To compare the effect of oxytocin and Syntometrine when used as part of active management of third stage of labour on postpartum haemorrhage, hypertension, nausea/vomiting and retained placenta. STUDY DESIGN: A randomised double blind trial was conducted in the Obstetric Unit of Corniche Hospital, Abu Dhabi in the United Arab Emirates. Between 1 January 1991 and 30 June 1991, 2040 women were randomly allocated either to the oxytocin (n = 1017) or the Syntometrine (n = 1023) group. Twelve patients had to be excluded from the trial (oxytocin, 5; Syntometrine, 7) after randomisation because they no longer fulfilled the inclusion criteria. All women in the trial received either oxytocin 10 units or Syntometrine 1 ml (oxytocin 5 units+ergometrine (ergonovine) 0.5 mg) by intramuscular injection with delivery of the anterior shoulder of the baby. Relative risk with 95% confidence intervals was calculated for each variable. RESULTS: Oxytocin (10 units) alone was as effective as Syntometrine (1 ml) in preventing post-partum haemorrhage without an increase in the incidence of retained placenta. Median blood loss was similar in both groups. The incidences of nausea, vomiting and headache were significantly lower in the oxytocin group, as was the occurrence of a mean rise in diastolic and systolic blood pressures of 20 and 30 mmHg or more, respectively. CONCLUSION: Prophylactic administration of oxytocin 10 U in the third stage of labour, as part of active management, reduces the incidence of maternal nausea, vomiting, headache and rise in blood pressure than does Syntometrine 1 ml without adversely affecting the rate of post partum haemorrhage.

The challenge of evaluating surgical procedures.

All new interventions and procedures must be properly assessed in comparison to the currently accepted method(s). It is unethical not to do so. The optimum method is by Randomised Controlled Trial (RCT). This is ideally suited to the testing of drugs because the trial can usually be double blind and placebo controlled. RCTs are less commonly used for the evaluation of new surgical techniques. There are valid and invalid reasons for this and these are discussed.

Practical applications of a monoclonal antibody (NDOG2) against placental alkaline phosphatase in ovarian cancer.

A monoclonal antibody (NDOG2) against placental alkaline phosphatase (PLAP) in ovarian cancer has been used in three ways by the Bristol University Department of Obstetrics & Gynaecology. First, in an indirect immunoperoxidase technique, NDOG2 demonstrated positive standing in 64% of 56 ovarian carcinomas as well as in 25% of 44 benign tumours. The majority of these positive tumours were serous cystadenocarcinomas or serous cystadenomas and there was considerable variation in the expression of this antigen from tumour to tumour. NDOG2 was also used as the basis of two serum assays and, when labelled with 123-iodine (123I), in radioimmunoscintigraphy (RIS) to monitor patients' response to therapy. The first serum assay measures the enzymic activity of PLAP and the second recognizes the antigenicity of the molecules. Assay 2 proved more useful in that it predicted the course of the disease in 45% of patients followed up, whereas Assay 1 was only of use in 25% of cases. RIS proved to be a useful imaging technique and was at least as sensitive as conventional imaging techniques. The common causes of false-positive and false-negative results are described.

The Bristol third stage trial: active versus physiological management of third stage of labour.

OBJECTIVE: To compare the effects on fetal and maternal morbidity of routine active management of third stage of labour and expectant (physiological) management, in particular to determine whether active management reduced incidence of postpartum haemorrhage. DESIGN: Randomised trial of active versus physiological management. Women entered trial on admission to labour ward with allocation revealed just before vaginal delivery. Five months into trial high rate of postpartum haemorrhage in physiological group (16.5% v 3.8%) prompted modification of protocol to exclude more women and allow those allocated to physiological group who needed some active management to be switched to fully active management. Sample size of 3900 was planned, but even after protocol modification a planned interim analysis after first 1500 deliveries showed continuing high postpartum haemorrhage rate in physiological group and study was stopped. SETTING: Maternity hospital. PARTICIPANTS: Of 4709 women delivered from 1 January 1986 to 31 January 1987, 1695 were admitted to trial and allocated randomly to physiological (849) or active (846) management. Reasons for exclusion were: refusal, antepartum haemorrhage, cardiac disease, breech presentation, multiple pregnancy, intrauterine death, and, after May 1986, ritodrine given two hours before delivery, anticoagulant treatment, and any condition needing a particular management of third stage. INTERVENTIONS: All but six women allocated to active management actually received it, having prophylactic oxytocic, cord clamping before placental delivery, and cord traction; whereas just under half those allocated to physiological management achieved it. A fifth of physiological group received prophylactic oxytocic, two fifths underwent cord traction and just over half clamping of the cord before placental delivery. ENDPOINT: Reduction in incidence of postpartum haemorrhage from 7.5% under physiological management to 5.0% under active management. MEASUREMENTS AND MAIN RESULTS: Incidence of postpartum haemorrhage was 5.9% in active management group and 17.9% in physiological group (odds ratio 3.13; 95% confidence interval 2.3 to 4.2), a contrast reflected in other indices of blood loss. In physiological group third stage was longer (median 15 min v 5 min) and more women needed therapeutic oxytocics (29.7% v 6.4%). Apgar scores at one and five minutes and incidence of neonatal respiratory problems were not significantly different between groups. Babies in physiological group weighed mean of 85 g more than those in active group. When women allocated to and receiving active management (840) were compared with those who actually received physiological management (403) active management still produced lower rate of postpartum haemorrhage (odds ratio 2.4;95% CI1.6 to 3.7). CONCLUSIONS: Policy of active management practised in this trial reduces incidence of postpartum haemorrhage, shortens third stage, and results in reduced neonatal packed cell volume.