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Objective: To survey lead colposcopists to explore the extent to which patients are currently being invited to discuss the results of their invasive cervical cancer review, the reasons why this might not be happening and the clinician experience., Methods: An online survey was sent to lead colposcopists across England. They were asked whether they offered the review to patients, if they did how they did so and what their experience was and if they did not, why not., Results: There was a 68.5% (N = 122) response rate, with 53% of respondents currently offering the review meetings. Patients were predominantly invited to the review meeting face to face and clinicians' experiences were mixed with a variety of positive and negative aspects of the meetings given. For those clinicians not currently offering a review meeting, there were a variety of reasons: 25% cited a lack of awareness of the guidelines, 19% time constraints, 12% a fear of causing additional distress and 2% a fear of litigation. Open-ended responses demonstrated a considerable amount of misunderstanding about the process., Conclusion: Despite National Health Service Cervical Screening Programme guidelines, not all clinicians offer review meetings to patients and those who do offer them do not always offer them to all women. Patient research needs to be conducted to explore the value of the meetings further, and there is a need to do more to engage clinicians in the process., (© 2015 John Wiley & Sons Ltd.)

Objectives: Vaginal vault cytology sampling following hysterectomy is recommended for specific indications in national guidelines. However, clinical governance issues surround compliance with guidance. Our first study objective was to quantify how many patients undergoing hysterectomy at the University Hospital of North Staffordshire (UHNS) had vault cytology advice in their histology report and, if indicated, whether it was arranged. The second was to devise a vault cytology protocol based on local experience and national guidance., Methods: The local cancer registry was searched. Clinical, clerical and histological data for all patients undergoing hysterectomy were collected., Results: In total, 271 patients were identified from both the gynae-oncology and benign gynaecology teams. Of these, 24% (65/271) were gynae-oncology patients with a mean age of 69 years. The benign gynaecology team had 76% (206/271) of patients with a mean age of 55 years. Subsequently, 94% (256/271) had cytology follow-up advice in their histopathology report. Ultimately, from both cohorts, 39% (18/46) had follow-up cytology performed when indicated., Conclusion: A high proportion of cases complied with national guidance. However, a disappointingly high number did not have vault cytology sampling when this was indicated. This is probably a result of the complex guidance that is misunderstood in both primary and secondary care. Vault follow-up of patients after hysterectomy rests with the team performing the surgery. Vault cytology, if indicated, should be performed in secondary care and follow-up should be planned. The protocol set out in this article should be followed to avoid unnecessary clinical governance failings., (© 2014 John Wiley & Sons Ltd.)

An audit of the screening history of all new cervical cancer cases has been a requirement since April 2007. While NHS cervical screening programmes (NHSCSP) guidance requires that women diagnosed with cervical cancer are offered the findings of the audit, as yet there has been no research to investigate the psychological impact that meeting to discuss the findings might have on patients. This is in spite of the fact that cytological under-call may play a role in as many as 20% of cervical cancer cases. This review draws on the literature concerning breaking bad news, discussing cancer and disclosing medical errors, in order to gain insight into both the negative and positive consequences that may accompany a cervical screening review meeting. We conclude that while patients are likely to experience some distress at disclosure, there are also likely to be positive aspects, such as greater trust and improved perception of care., (© 2013 Blackwell Publishing Ltd.)

Objective: To audit the process and outcome of case reviews performed for invasive cervical cancers diagnosed between 2003 and 2007, and the timely disclosure of results to the respective patients., Methods: Invasive cervical cancer reviews were performed on all cases of cervical cancer diagnosed between 2003 and 2007. Following the review, women were classified into two categories: a group who developed invasive cancer despite adherence to the screening programme or in whom a management or diagnostic decision was determined to have been a principal factor in the development of their disease (Group A), and a second group who either had never undergone a cervical smear or had been established defaulters from the screening programme (Group B)., Results: Ninety-seven of the 98 cases of invasive cervical cancer diagnosed in the 4-year study period were reviewed. Sixty of the 61 women in Group A were sent an invitation to discuss the results of their case review. Thirty-six (37%) were classified as Group B, and it was deemed neither appropriate nor possible to invite the patients for a review consultation. Of the women sent an invitation, only 24 (40%) chose to attend., Conclusion: A policy of selective invitation for the disclosure of invasive review results is feasible. Less than one-half of patients diagnosed with cervical cancer appear to want to know how they developed cervical cancer despite previously participating in a screening programme., (© 2012 Blackwell Publishing Ltd.)

Objective: To investigate the diagnosis, review and management of women identified as having a cytology/histology discrepancy., Methods: A review of all patients diagnosed with a discrepancy between referral smear and cervical histology was performed between January 2003 and December 2004. Cases were followed for a minimum of 4 years and patient management and outcome reviewed., Results: A significant discrepancy was identified in 79 cases, 0.1% of all smears (n = 80,926) analysed during the study period. A discrepancy between cytology and histology, obtained from large loop excision of the transformation zone (LLETZ), was confirmed by multidisciplinary review in 42 cases (53.2%). In 37 cases (46.8%) the cytological and/or histological diagnosis was revised; the cytology was significantly more likely than the histology to be amended (chi square P = 0.005), most often because cytology had been overcalled. Of the confirmed discrepancy cases, 33 (78.6%) were due to high-grade squamous cell or glandular abnormalities on cytology with a negative, inflammatory or human papillomavirus (HPV) infection on histology (HGC/NH). HGC/NH cases were managed by cytological follow-up in 29 (87.9%), of which 72.4% of the smears were negative when performed at least 6 months post-excision. During the 4-year follow-up period six women with a confirmed HGC/NH underwent a repeat cervical excision (hysterectomy or LLETZ), and of these, HPV effect was seen in two cases but no cervical intraepithelial neoplasia was detected in any of the histological specimens., Conclusion: Cytology overcall was responsible for the majority of cytology/histology discrepancies. A confirmed discrepancy is not an indication for a further excisional biopsy but follow-up is essential because a small percentage of patients may have disease that has been missed., (© 2010 Blackwell Publishing Ltd.)

Objective: To assess the usefulness of a leaflet distributed to women before colposcopy designed to reduce their anxiety and psychosexual morbidity by providing information., Design: Prospective randomised study., Setting: Colposcopy clinic of a large district general hospital., Sample: Two hundred consecutive women undergoing colposcopy for the first time for a cervical cytological abnormality of severity no greater than moderate dyskaryosis., Methods: Women were randomised into one of two groups (leaflet or control). Those in the leaflet group were sent an information leaflet prior to attending the clinic. In the colposcopy clinic all the women completed a State/Trait Anxiety Inventory (StAI/TrAI) and a modified psychosexual questionnaire before undergoing colposcopy. This was repeated at the six-month follow up visit. Women in the leaflet group also completed a further questionnaire on the leaflet., Main Outcome Measures: Differences of anxiety and psychosexual scores between leaflet and control groups., Results: The leaflet was well received. There were no statistical differences in StAI and TrAI scores between the study group and the control group at either visit, although in the whole study population StAI and TrAI scores were reduced at the second visit. The leaflet group had significantly more psychosexual problems but by the second visit, the scores had improved and the two groups were similar. When the mean differences in anxiety and psychosexual scores at the initial and second visits were compared between the groups, the reduction in negative sexual feelings and deterioration of TrAI scores experienced by the leaflet group was significant., Conclusions: This study suggests that the provision of sending an information leaflet prior to colposcopy is not beneficial in isolation. Other approaches need to be considered.

Objectives: Using magnetic resonance spectroscopy (MRS) to measure phosphorus-containing metabolites in the liver, this study aimed to investigate non-invasively whether or not women with haemolysis, elevated liver enzymes and low platelets (HELLP) have detectable abnormalities of hepatic energetics., Setting: John Radcliffe Hospital, Oxford., Design: Prospective study., Methods: After giving informed consent, patients with HELLP syndrome (n = 7) and controls with severe pre-eclampsia (n = 3), were studied by 31P MRS of the liver as soon as possible after delivery (range 2-4 days) and compared with normal nonpregnant controls (n = 6). Haematological and biochemical tests were performed serially and on the day of the MRS in all pregnant patients., Results: The severity of HELLP varied as follows: peak aspartate aminotransferase (range 129-2574), peak gamma glutamyl transferase (range 28-96), peak lactate dehydrogenase (range 305-2820), nadir platelets (range 25-114), peak international normalised ratio for prothrombin time (before fresh frozen plasma) (range 0.9-1.9). One pregnancy was terminated but all others resulted in live births and all mothers made uneventful, rapid recoveries. MRS-determined relative hepatic concentrations of phosphorus-containing metabolites and absolute concentrations of adenosine triphosphate did not differ significantly between groups. One patient with the most clinically severe HELLP syndrome (by laboratory criteria) exhibited magnetic resonance spectra which showed a relative increase in phosphomonoester and an absolute decrease in hepatic adenosine triphosphate (to 62% of control)., Conclusions: Enthusiasm for the conservative management of HELLP syndrome that develops remote from term has been tempered by the inability to identify patients at risk for progression to hepatic necrosis. We found that most patients with HELLP syndrome had normal liver metabolism as assessed by MRS. However, clinically severe HELLP syndrome can be associated with disturbed hepatic metabolism consistent with that seen in hepatic ischaemia and/or granulocytic infiltration of the liver.

Objective: To analyse activation of maternal peripheral blood leukocytes by flow cytometric measurements of intracellular free-ionised calcium of lymphocytes, granulocytes and monocytes, separately., Design: Case-control study., Setting: High risk pregnancy service in a regional centre., Material: Samples from 10 women with pre-eclampsia, 10 appropriately-matched women with normal pregnancy, nine multigravid normal women at mid-gestation selected as being least likely to demonstrate any tendencies towards pre-eclampsia, and 11 healthy nonpregnant women of reproductive age were studied., Methods: Using flow cytometry, intracellular free ionised calcium ([Ca2+]i) was estimated by loading the cells with Fluo-3 and measuring the changes in fluorescence intensity induced by free ionised calcium. After the basal levels were measured, the response of phagocytes to stimulation with n-formylmethionyl-leucyl-phenylalanine (fMLP) was determined., Main Outcome Measures: Basal [Ca2+]i of peripheral blood leukocytes., Results: Median basal [Ca2+]i was significantly increased in all three subsets of leukocytes--lymphocytes, granulocytes and monocytes in pre-eclampsia--compared with the three control groups. Samples from both groups of women with normal pregnancy did not differ from those from nonpregnant women. The peak responses of monocytes to stimulation with 10 nmol fMLP were greater in samples from pre-eclamptic women, giving evidence of priming., Conclusions: Peripheral blood leukocytes are activated in pre-eclampsia in terms of basal changes in the intracellular second messenger--free ionised calcium. Peripheral blood monocytes are primed to give greater responses after stimulation with fMLP.

Objective: To determine whether circulating markers of oxidative stress are elevated in pre-eclampsia when appropriate precautions are taken to prevent in vitro oxidation, Design: A prospective study., Setting: Nuffield Department of Obstetrics and Gynaecology, Oxford and The William Harvey Institute, London., Sample: Three groups of women: those with pre-eclampsia (n = 19), control pregnant women (n = 19) matched for gestation, age and parity and a group of non pregnant individuals of reproductive age (n = 7)., Methods: Citrated plasma was stored at -80 degrees C with 20 micromol beta hydroxytoluene to prevent auto-oxidation. Plasma samples were assayed for levels of 8 epi-prostaglandin F2alpha, lipid hydroperoxides, malondialdehyde and also the lipid soluble antioxidant vitamin E., Results: There were no differences in 8 epi-prostaglandin F2alpha, lipid peroxide or malondialdehyde levels between the groups of women with pre-eclampsia and those acting as pregnant controls. However, lipid hydroperoxides and malondialdehyde were significantly raised in both pre-eclampsia and normal pregnancy, compared with nonpregnant women. Vitamin E levels were similar in women with pre-eclampsia and those with a normal pregnancy, but in both groups levels were significantly higher than in nonpregnant women., Conclusion: Circulating markers of oxidative stress are raised in normal pregnancy and pre-eclampsia.

Objective: To evaluate whether routinely giving an antibiotic after loop diathermy excision of the cervical transformation zone reduced post-operative vaginal loss., Design: Prospective, randomised, double-blind placebo controlled parallel study., Participants: Five hundred women undergoing loop diathermy excision in a colposcopy clinic., Intervention: Administration of either ofloxacin 400 mg (2x200 mg) once daily for 5 days or an identical placebo., Main Outcome Measure: Vaginal loss, assessed using a pictorial chart., Results: No significant difference in post-operative vaginal loss was found., Conclusion: Routine antibiotic prophylaxis after loop diathermy excision is not justified.

Objective: To investigate whether syncytiotrophoblast microvilli (STBM) are shed into the maternal circulation in increased amounts in pre-eclamptic pregnancies as a possible cause of maternal vascular endothelial dysfunction., Design: A time-resolved fluoroimmunoassay was developed to measure STBM levels in peripheral and uterine venous plasma from normal pregnant and pre-eclamptic women. Three colour flow cytometry was used to assess the microparticulate nature of the STBM in pregnancy plasma. The effects of these plasmas on endothelial cell proliferation was compared and a correlation with the levels of STBM detected was sought., Setting: A laboratory investigation using clinical samples obtained from an obstetric practice in a teaching hospital., Samples: Peripheral venous plasma from 20 women with established pre-eclampsia, 20 normal pregnant women matched for age, gestation and parity, and 10 nonpregnant women of reproductive age. Paired uterine and peripheral venous plasma taken at caesarean section from 10 women with pre-eclampsia and 10 unmatched normal pregnant women., Results: STBM were detected in the plasma of pregnant women by both flow cytometry and time-resolved fluoroimmunoassay. Significantly higher levels of STBM were found in women with established pre-eclampsia (P=0.01). STBM concentrations were higher in uterine venous plasma than in concurrently sampled peripheral venous plasma, confirming their placental origin. A significant correlation was found between the amount of STBM in the plasma and endothelial cell inhibitory activity., Conclusions: STBM are shed into the maternal circulation (microvillous deportation) and are present in significantly increased amounts in pre-eclamptic women. They may contribute to the endothelial dysfunction underlying the maternal syndrome of pre-eclampsia.

Objective: To compare the effects of maternal administration of betamethasone and dexamethasone on fetal heart rate, using computerised numerical analyses, and to examine the association between changes in short term variation and the timing and indication for delivery., Setting: John Radcliffe Hospital, Oxford., Sample: Fifty-nine women with singleton pregnancies, who were at risk of delivery before 34 weeks of gestation, had received no steroids in the preceding week and could give informed consent., Methods: Women were randomised on a double-blind basis to receive either betamethasone or dexamethasone. The fetal heart rate was recorded (60-minute duration at similar times of day) before steroid administration and on each of the following two days; changes were measured by computerised analyses., Main Outcome Measures: Changes in short term variation and long term variation of fetal heart rate or the number of fetal movements. Statistical analysis was nonparametric., Results: Betamethasone and dexamethasone had no differential effects on the computerised cardiotocography. However, both steroids decreased baseline fetal heart rate, increased long term variation, increased short term variation, and decreased fetal movements on the first day after steroid administration, and decreased high fetal heart rate variation and decelerations on the second day. Among 13 women who were delivered within one week of steroid administration, smaller rises in short term variation on day one were associated with delivery for fetal indications., Conclusions: Both betamethasone and dexamethasone produced transient, unexplained changes in the fetal heart rate over the two days following steroid administration. Larger changes in short term variation were associated with fetal wellbeing. It is important to recognise that such changes are a physiological response of the human fetus to steroid administration.

Objective: To study changes throughout gestation and the puerperium of middle cerebral artery flow velocity waveforms obtained by transcranial Doppler ultrasound., Design: Prospective, observational study., Setting: John Radcliffe Maternity Hospital, Oxford, UK., Participants and Methods: Middle cerebral artery velocities were measured by transcranial Doppler ultrasound in 25 nonpregnant women, 22 women longitudinally followed throughout pregnancy and 21 women serially studied from delivery until the late puerperium., Main Outcome Measures: Transcranial Doppler changes in pregnancy and the puerperium., Results: The transcranial Doppler ultrasound measurements showed good reproducibility. Signals from one middle cerebral artery could not be obtained in 4.6% of the examinations, but otherwise readings were similar on both sides. Women in the second half of pregnancy had lower middle cerebral artery mean velocities than nonpregnant women. Velocities decreased with advancing gestation but increased in the immediate puerperium to levels comparable to those found in nonpregnant women., Conclusions: Transcranial Doppler ultrasound is a noninvasive technique suitable for studying maternal cerebral haemodynamics in pregnancy and postpartum. Middle cerebral artery mean velocity decreased with advancing gestation and increased to nonpregnant values in the immediate puerperium. These physiological changes need to be considered when comparing data with measurements taken in abnormal pregnancy states.

Objectives: Nitric oxide released from vascular endothelial cells is a potent vasodilator and inhibits platelet adhesion. It has been suggested that decreased nitric oxide production from dysfunctional endothelial cells is implicated in the pathophysiology of pre-eclampsia. In this study evidence was sought for abnormal production of nitric oxide in pre-eclamptic women., Participants: Blood was collected from 20 women presenting with pre-eclampsia, from 20 matched healthy pregnant controls and from 12 nonpregnant women of childbearing age., Methods: Serum nitrate, the stable end metabolite of nitric oxide, was measured by vanadium III chloride reduction and chemiluminescence., Results: Sera from women with pre-eclampsia had significantly higher nitrate concentrations (mean 47.4 mumol/L [SD 13.6]) compared with healthy pregnant (mean 31.2 mumol/L [SD 9.14]) and nonpregnant (mean 32.1 mumol/L [SD 10.0]) controls., Conclusions: These results do not support the hypothesis that decreased endothelial cell nitric oxide production may be important in the pathophysiology of pre-eclampsia. On the contrary, serum nitrate levels are increased which may reflect either increased production of nitric oxide from an unidentified source or decreased elimination through the kidneys.

Objective: To study how the treatment of severe gestational hypertension affects maternal middle cerebral artery velocimetry., Design: Prospective, clinical, descriptive study., Setting: John Radcliffe Maternity Hospital, Oxford, England., Participants: Pregnant and puerperal women who required acute or chronic antihypertensive treatment with nifedipine (n = 46) or methyldopa (n = 26), respectively., Methods: Transcranial Doppler ultrasound examinations of maternal middle cerebral arteries were performed before and 45 min after nifedipine; and before and 48 hours after the onset of methyldopa therapy. Blood pressure and heart rate were also recorded., Main Outcome Measures: Clinical and transcranial Doppler changes induced by the antihypertensive medication., Results: Blood pressure and middle cerebral artery velocities decreased significantly following both short- and long-acting antihypertensive therapy. Nifedipine-induced changes were more pronounced and uniform than those found after methyldopa (16.7% and 6.4% decrease in middle cerebral artery mean velocity, respectively). The middle cerebral artery mean velocity decrease was independent of changes in the blood pressure or heart rate., Conclusions: Maternal cerebral haemodynamics are influenced by antihypertensive treatment. The reduction of middle cerebral artery flow velocities following administration of nifedipine and methyldopa may suggest that cerebral vasodilatation is occurring, which is consistent with the concept that cerebral vasospasm is present in women with pre-eclampsia. The cerebral vasodilatation could result from a direct effect of the medication on the arteries in question.

Objective: To investigate the hypothesis that, should there be an increase in deported syncytiotrophoblast microvillous membrane fragments in pre-eclampsia, it may cause maternal vascular endothelial dysfunction., Design: Syncytiotrophoblast microvillous membrane (STBM) vesicles, prepared from normal term placentae, were perfused through small subcutaneous arteries isolated from fat biopsies obtained at caesarean section. Endothelial function of these arteries was studied by determining acetylcholine-induced relaxation after preconstriction with noradrenaline. As controls, physiological buffer or red blood cell membranes in physiological buffer were used and endothelial function similarly estimated. Transmission electron microscopy was performed on arteries after perfusion., Sample: STBM vesicles, isolated from the placentae of three healthy women undergoing elective caesarean section for reasons unrelated to pre-eclampsia, were suspended in physiological buffer. Subcutaneous fat arteries were obtained from a separate group of 13 normotensive pregnant women, also undergoing elective caesarean section at term., Results: Perfusion with red blood cell membranes or physiological buffer had no significant effect on the concentration dependent relaxation in arteries preconstricted with noradrenaline. However, after 2 h perfusion with STBM vesicles, arteries showed a significant reduction in relaxation to acetylcholine, indicative of altered endothelial function. Transmission electron microscopy of arteries perfused with STBM vesicles confirmed endothelial disruption., Conclusions: STBM vesicle perfusion specifically altered the relaxation response of preconstricted maternal subcutaneous fat arteries to acetylcholine, suggesting an alteration in endothelial dependent relaxation. Deported microvilli may therefore be capable of producing endothelial cell damage and endothelial dysfunction observed in the maternal syndrome of pre-eclampsia.

Objective: To determine the relation between the inactive urinary kallikrein: creatinine ratio (IUK:Cr) and the angiotensin sensitivity test (AST) at 28 weeks of gestation and to assess each as a screening test for pre-eclampsia., Design: Prospective interventional study., Subjects: Four hundred and fifty-nine normotensive nulliparous women recruited from hospital antenatal clinics., Setting: John Radcliffe Maternity Hospital, Oxford, and Queen Charlotte's and Chelsea Hospital, London., Interventions: A urine sample for IUK:Cr measurement was provided before performing the AST at 28 weeks of gestation. Those women who demonstrated increased sensitivity to angiotensin II were entered into a randomised placebo controlled trial of low dose aspirin for the prevention of pre-eclampsia (CLASP)., Main Outcome Measures: The development of pre-eclampsia., Results: The IUK:Cr ratio was significantly lower in those women who showed increased sensitivity to angiotensin II (P < 0.0001 Student's t test). The sensitivity and specificity for detecting pre-eclampsia were, respectively, 22% and 85% for the AST and 67% and 75% for the IUK:Cr. Low-dose aspirin (60 mg) had no effect on the pregnancy outcome., Conclusion: There appears to be some relation between the IUK:Cr and AST tests in pregnancy. However, in this population, the IUK:Cr ratio was a better screening test for pre-eclampsia than the AST, but overall neither test was a powerful predictor for the syndrome.

Objective: To measure the plasma levels of corticotrophin-releasing hormone and corticotrophin-releasing hormone binding protein in normal pregnancy and in pregnancies complicated by pre-eclampsia., Setting: John Radcliffe Hospital, Oxford and St Thomas's Hospital, London., Subjects: One hundred and twenty pregnant women sampled prospectively throughout gestation, of whom 91 experienced a normal pregnancy and eight developed pre-eclampsia; in a second study, 10 women with severe pre-eclampsia, presenting at a range of gestational ages, were sampled once and compared with appropriately matched normal pregnant women., Main Outcome Measure: Plasma levels of corticotrophin-releasing hormone determined by immunoradiometric assay. Plasma levels of corticotrophin-releasing hormone binding protein measured by direct radioimmunoassay., Results: In the prospective study, plasma samples from women with pre-eclampsia exhibited higher (390.2 versus 292.7 pmol/l at 36 weeks) levels of corticotrophin-releasing hormone and significantly lower (5.24 versus 8.14 nmol/l at 36 weeks, P < 0.002) levels of corticotrophin-releasing hormone binding protein than normal controls. In the second, single time point study a significant elevation in CRH (P < 0.002) and reduction in CRH-BP (P < 0.001) was found in pre-eclamptic pregnancies compared with controls., Conclusions: In human pregnancies complicated by pre-eclampsia there is an elevated level of corticotrophin releasing hormone whilst there is less corticotrophin-releasing hormone binding protein; therefore there is a net increase in free potentially bioactive hormone which may play a role in the pathology of the disease.

Objectives: Generalised maternal endothelial cell dysfunction appears to be an underlying problem in pre-eclampsia presumed to be caused, directly or indirectly, by one or more circulating factors derived from the placenta. Recently it has been suggested that tumour necrosis factor (TNF) may play an important role in pre-eclampsia and contribute to endothelial activation. This study was designed to investigate this proposal., Design: Plasma TNF-alpha, IL-6 and both forms of soluble TNF receptors (p55 and p75 TNF-R) have been measured by ELISA in 31 pre-eclamptic patients and 31 pregnant controls matched for age, parity and gestational age., Results: Levels of IL-6, TNF-alpha and soluble TNF-R (p55 and p75) were significantly higher in pre-eclamptic patients, compared with age and gestation matched controls with a wide variation in levels between pre-eclamptic individuals. There was a correlation between levels of IL-6 and TNF or TNF-R and between TNF and TNF-R levels. However, when the pre-eclamptic patients were subdivided on the basis of the severity of their disease, the median values of plasma concentrations of IL-6, TNF-alpha and TNF-R were all higher in the group with lower platelet counts., Conclusions: These new findings are consistent with the concept that the maternal syndrome of pre-eclampsia is associated with endothelial dysfunction and provide evidence that at least part of this dysfunction could arise from excessive release of TNF-alpha into the circulation.

Objective: To determine the effect of maternal administration of dexamethasone on fetal heart rate and its variation., Design: Retrospective analysis of computerised data derived from cases studied over three years., Setting: High risk pregnancy unit, John Radcliffe Hospital, Oxford., Subjects: Twenty-eight pregnant women, at 27 to 32 weeks of gestation, to whom dexamethasone was given to accelerate pulmonary maturation in the expectation of preterm delivery., Methods: Dexamethasone (two doses of 12 mg intramuscularly, 12 h apart) was given on 51 occasions at weekly intervals (one to four occasions per patient). Complete data were available for cardiotocograph analysis from computerised measurement of fetal heart rate variables for two days before and four days after dexamethasone and, in 19 women, measurements of umbilical arterial flow velocity waveforms before and after dexamethasone., Results: In 10 pregnancies without fetal distress there was a highly significant (P < 0.01) transient rise in short term fetal heart rate variation after dexamethasone administration, from means (SE) 6.4 (0.28) to 9.8 (0.4) ms. In 18 pregnancies with subsequent delivery for fetal distress (abnormal fetal heart rate pattern) and high umbilical arterial resistance index [mean 0.93 (0.06 SE)], the rise in short term fetal heart rate variation was less (P < 0.01), from mean (SE) 5.4 (0.26) to 6.1 (0.48) ms. In a further case of discordant twin pregnancy, the larger twin continued to respond to dexamethasone administrations with a rise in fetal heart rate variation for five weeks; the smaller twin, with maintained tachycardia and reduced umbilical arterial end-diastolic flow velocity, failed to respond after the first two weeks., Conclusion: The results show that maternal dexamethasone administration normally causes a rise in fetal heart rate variation for up to a day. This rise is reduced in pre-eclampsia or intrauterine growth retardation, associated with a reduction in umbilical flow, perhaps because of a consequential lower concentration of steroid in the fetus. The results contrast with those for betamethasone which has been reported to reduce fetal heart rate variation.

Objective: To study whether intervention debulking surgery improves survival in patients with advanced ovarian cancer who have bulky (> 2 cm) residual disease after primary surgery., Design: A prospective multicentre randomised study., Setting: Hospitals in the West Midlands., Subjects: Ovarian cancer patients with bulky residual disease after primary surgery who are considered well enough to receive cis-platinum based chemotherapy and further surgery., Methods: Eligible patients were randomised to receive combination chemotherapy alone or combined with intervention debulking surgery., Main Outcome Measure: Survival was assessed using product limit method and log-rank test., Results: Seventy-nine patients were entered into the study. Thirty-seven patients were randomised to intervention debulking surgery, 25 (67%) of whom underwent intervention debulking surgery, which was performed a median of 13 weeks after primary surgery. The median survival for the intervention debulking surgery group was 15 months (95% CI 10-20 mo) and that of those randomised to chemotherapy alone, which was 12 months (95% CI 8-16 mo), were not significantly different (hazard ratio = 0.71; 95% CI 0.44-1.13)., Conclusion: Intervention debulking surgery may not improve survival in patients with advanced ovarian cancer.

Objective: To assess the effectiveness of second trimester 24-hour ambulatory blood pressure measurement as a screening test for pre-eclampsia., Design: Prospective interventional study., Setting: John Radcliffe Maternity Hospital, Oxford, and Queen Charlotte's and Chelsea Hospital, London., Subjects: One hundred and sixty-two normotensive nulliparous women recruited at hospital booking clinics., Intervention: Ambulatory blood pressure was measured at 18 and 28 weeks gestation using the TM2420 monitor., Main Outcome Measure: The development of pre-eclampsia., Results: Awake systolic and mean arterial pressures were significantly increased (P < 0.02) at 18 weeks in those who later developed pre-eclampsia. Those differences were more apparent at 28 weeks at which time the diastolic pressure was also increased (P < 0.01). At both stages of gestation the higher readings were sustained during sleep so that the awake-sleep differences were similar in relation to each outcome. The group with incipient pre-eclampsia had a significantly faster heart rate at both 18 and 28 weeks (P < 0.002) The sensitivity in predicting pre-eclampsia for a mean arterial pressure of 85 mmHg or greater at 28 weeks was 65%, with a positive predictive value of 31%. The sensitivity and positive predictive value for a test combining a mean arterial pressure of 85 mmHg or greater and a heart rate of 90 bpm or greater were 53% and 45%, respectively., Conclusion: Although second trimester ambulatory blood pressure is significantly increased in women who later develop pre-eclampsia, the predictive values for blood pressure alone are low. The efficiency of the test is increased by combining the awake ambulatory heart rate and blood pressure measurement together. If an effective method for preventing pre-eclampsia becomes available (commencing at 28 weeks gestation), then awake ambulatory blood pressure and heart rate may have some clinical value as a screening test.

Objectives: To determine if placental syncytiotrophoblast microvillous (STBM) membranes contain factors which could cause the maternal endothelial cell disturbance thought to be central to the pathophysiology of the maternal syndrome of pre-eclampsia., Design: STMB membranes isolated from pre-eclamptic or normal placentae were added to cultures of endothelial cells and their effect on the proliferation (measured by 3H-thymidine incorporation), viability (measured by 51Cr release) and growth as a monolayer of these cells was determined. Membranes prepared from red blood cells, and non-endothelial adherent and nonadherent cell lines were used as specificity controls., Subjects: STBM membranes were isolated from the placentae of primigravid women, 10 having caesarean sections for breech presentations and 10 for pre-eclampsia., Results: STBM membranes from the placentae of normal and pre-eclamptic women suppressed endothelial cell proliferation to a similar extent and disrupted the cell monolayer to form a honeycomb-like pattern. This change in morphology was seen before significant endothelial cell death occurred. Red blood cell membranes had no effect on either endothelial cell proliferation, viability or monolayer integrity. Endothelial cells from human umbilical arteries and bovine adrenal capillaries were similarly suppressed, but comparable concentrations of STBM membranes had no effect on non-endothelial cell lines., Conclusions: Syncytiotrophoblast microvillous membranes specifically interfered with endothelial cell growth in vitro. Our results demonstrate that there are trophoblast products which could cause the maternal syndrome of pre-eclampsia through endothelial cell damage.

Objective: To compare assisted vaginal delivery by forceps with delivery by vacuum extractor, where a new vacuum extractor policy was employed which dictated the cup to be used in specific situations., Design: Multicentre randomised controlled trial., Setting: Four district general hospitals in the West Midlands., Subjects: Six hundred-seven women requiring assisted vaginal delivery, of whom 296 were allocated to vacuum extractor delivery and 311 to forceps., Main Outcome Measures: Delivery success rate, maternal perineal and vaginal injuries, maternal anaesthetic requirements, neonatal scalp and facial injuries., Results: Of the vacuum extractor group, 85% were delivered by the allocated instrument compared to 90% in the forceps group (odds ratio (OR) 0.64; 95% confidence intervals (CI) 0.4-1.04). However, more women in the vacuum extractor group were delivered vaginally (98%) than in the forceps group (96%). There were significantly fewer women with anal sphincter damage or upper vaginal extensions in the vacuum extractor group (11% vs 17%, OR 0.6; 95% CI, 0.38-0.97). There were significantly fewer women in the vacuum extractor group requiring epidural or spinal anaesthetics (25.4% vs 32.7%, OR 0.69; 95% CI 0.49-0.99) or general anaesthetics (1% vs 4%, OR 0.17; 95% CI 0.04-0.76). Although there were significantly more babies in the vacuum extractor group with cephalhaematomata (9% vs 3%, OR 3.3; 95% CI 1.4-7.4) there were fewer babies in the vacuum extractor group with other facial injuries. There were three babies in the forceps group with unexplained neonatal convulsions., Conclusions: Assisted vaginal delivery using the new vacuum extractor policy is associated with significantly less maternal trauma than with forceps. Further studies are required to assess neonatal morbidity adequately.

Fetal heart rate (FHR) records should be presented as measurements derived from numerical analysis. Such analysis requires computerized systems. The Oxford system is the longest established and most tested of the systems available. It could provide the basis for a standardized approach to the numerical analysis of antepartum FHR records. Intrapartum FHR monitoring is of uncertain clinical value. It is premature to recommend standards for numerical analysis to upgrade the present methods of data presentation during labour. Once the patterns of abnormality are better defined numerically such standards will be mandatory because intrapartum FHR records cannot be interpreted reliably by eye.

Objective: To establish reference ranges for the human fetal middle cerebral artery pulsatility index (MCA PI) for the local obstetric population, and to compare computerised antenatal fetal heart rate (FHR) analysis with the MCA PI as indicators of fetal compromise., Design: Prospective data collection for selected patients., Setting: High risk pregnancy unit of a teaching hospital., Subjects: Group 1 consisted of 18 healthy women with uncomplicated singleton pregnancies. Group 2 consisted of 27 women admitted to the high risk pregnancy unit over a 9 month period with intrauterine growth retardation and other related problems; all these women were delivered by prelabour caesarean section., Intervention: Serial Duplex sonography to determine fetal MCA PI in Groups 1 and 2. Serial FHR analysis using computerised numerical techniques in Group 2 only., Main Outcome Measures: Serial MCA PI values from 24 to 39 completed weeks of gestation in Group 1. Comparison of serial MCA PI values with FHR analysis in relation to fetal outcome in Group 2., Results: In Group 1 the MCA PI diminished significantly as gestation advanced from 1.73 (SD 0.25) at 24 weeks to 1.38 (SD 0.26) at 39 weeks (P < 0.01). In Group 2 eleven babies were hypoxaemic at delivery: all had low MCA PI values while only nine had an abnormal FHR prior to delivery., Conclusion: In normal pregnancy, there is a fall in the fetal MCA PI with advancing gestation which probably reflects a decreasing vascular resistance to fetal cerebral blood flow. Hypoxaemia at delivery appeared to be better recognised by the fetal MCA flow velocity waveform than the FHR analysis. This increased sensitivity, however, was achieved at the expense of a reduced specificity. Larger studies are needed to confirm the findings of this preliminary investigation.

Objective: To examine the relationship between experimentally induced increments in blood pressure and maternal middle cerebral artery flow velocity patterns measured by transcranial Doppler ultrasound (TCD)., Design: Prospective experimental study., Setting: John Radcliffe Maternity Hospital, Oxford., Intervention: Middle cerebral artery flow velocity waveforms were measured using 2 MHz pulsed Doppler ultrasound via the temporal cranial approach at 28 weeks gestation before, during and 10 min following an angiotensin II infusion., Subjects: 101 normotensive primiparous women at 28 weeks gestation., Results: A significant rise in blood pressure and fall in heart rate were demonstrated between pre-infusion and maximum angiotensin II infusion (maximum blood pressure) recordings. Simultaneous changes were observed in all flow velocity indices, shown as a decrease in systolic velocity and pulsatility index, and an increase in diastolic and mean velocity (P < 0.0001). These values all returned to baseline levels 10 min post infusion (P < 0.0001). Statistical analysis suggested that the change in flow velocity is related to the rise in blood pressure rather than the direct effect of angiotensin II on the cerebral circulation., Conclusion: Transcranial Doppler can detect changes in the cerebral circulation associated with alterations in blood pressure during pregnancy. The technique needs to be evaluated further in hypertensive disease.

Objective: To observe the spontaneous resolution of pre-eclampsia-related thrombocytopenia., Design: A retrospective study., Setting: High Risk Pregnancy Unit, John Radcliffe Maternity Hospital, Oxford., Subjects: Thirty women with pre-eclampsia complicated by the HELLP/ELLP syndrome who did not receive any specific treatment for their thrombocytopenia., Intervention: Serial platelet counts throughout labour and the puerperium until the platelet counts returned to levels above 100 x 10(9)/l., Main Outcome Measures: Time taken from delivery and platelet nadir for platelet counts to return to levels above 100 x 10(9)/l. The rate of recovery from the platelet nadir was measured by the slope of the serial platelet counts plotted against time., Results: The mean time until platelet count exceeded 100 x 10(9)/l was 67 h (SD 25) after delivery and 44 h (SD 17) from the platelet nadir. All women had counts above 100 x 10(9)/l by 111 h after delivery, and by 88 h after the platelet nadir. Although the time to recovery appeared to depend on the degree of thrombocytopenia, the rate of resolution did not., Conclusion: These data can be used as a guide by clinicians as to the expected time course for postpartum resolution of pre-eclampsia-related thrombocytopenia.

Objective: To test the application in practice of computerized fetal heart rate (FHR) analysis in pregnancy., Design: Randomized distribution of subjects with computerized analysis automatically revealed or concealed., Setting: A district general hospital and a teaching hospital outside London., Subjects: 2869 pregnant women studied within a year., Outcome Measures: Quality and duration of the cardiotocogram; quantitative measurement of FHR variation; number of stillbirths., Results: With interactive advice to the operator, records were of improved quality (up to 28% without signal loss) with potentially much reduced recording time. The short-term FHR variation measured in the last records before intervention is reported for the first time., Conclusion: The benefits of using the computers include improvement in record quality and saving of time. In addition, where interpretation depended on estimation of FHR variation there was prima facie evidence of observer misinterpretation; visual analysis was unreliable. A larger trial is now required with more rigorous constraints on intervention.

Objective: To determine the current management of severe pre-eclampsia and eclampsia in the United Kingdom., Design: One-page postal survey to all (1007) UK consultant obstetricians with questions about use of antihypertensive and anticonvulsant drugs in severe pre-eclampsia and eclampsia, other management strategies, definition of factors determining severity, protocol development and regional review., Results: 688 replies (69.6% response rate). The antihypertensive drugs used were mainly oral labetalol (35%), oral methyl dopa (23%) and parenteral hydralazine (29%); diuretics were not used. Diazepam was the preferred drug in eclampsia. Very few consultants used magnesium sulphate (2%). Anticonvulsants were also prescribed by 85% of consultants to prevent fits; the drugs then preferred were diazepam (41%), phenytoin (30%) and chlormethiazole (24%). Two-thirds of consultants felt there was a need for trials to study the effectiveness of antihypertensive and anticonvulsant drugs. In a woman with proteinuric hypertension, 15% of consultants did not regard the development of headache as indicating severe pre-eclampsia. Consistent management practices were not associated with agreement about protocols. Regional review does not appear to have occurred., Conclusion: Antihypertensive and anticonvulsant therapies are widely used but trials are considered necessary. Improvements in the management of women with severe pre-eclampsia or eclampsia might occur if UK obstetricians sought more collective opinion and undertook regional audit of protocols.

Objectives: To examine the deportation of trophoblast cells into the maternal blood in pre-eclamptic (gestational proteinuric hypertension) and normal pregnancy., Design: The monoclonal anti-cytokeratin antibody JMB2 was used in the APAAP technique to label trophoblast cells in cell smears of uterine vein blood obtained at caesarean section., Subjects: 10 women with proteinuric pre-eclampsia requiring caesarean section, 10 pregnant women requiring elective caesarean section for reasons other than pre-eclampsia and five control women who had never been pregnant., Results: Three populations of trophoblast cells were identified; two mononuclear cytotrophoblast types with diameters varying from 11-14 microns and 19-25 microns respectively, and multinucleated syncytiotrophoblast cells varying in size from 23-88 microns. Women with pre-eclampsia had more trophoblast cells in uterine vein blood than were found in pregnant women without pre-eclampsia. There was no correlation between the numbers of trophoblast cells and the stage of gestation or severity of the pre-eclampsia, although an acute maternal or fetal event necessitating delivery was associated with increased deportation of trophoblast. Mononuclear cytotrophoblast cells were detected in the peripheral blood of only 1 of 5 pre-eclamptic patients, despite their presence in the uterine vein blood of all 5 women., Conclusions: Trophoblast deportation is increased in pre-eclamptic pregnancy, with both cytotrophoblast and syncytiotrophoblast present in the uterine vein blood, but there is no correlation with the severity of the disease. In some cases cytotrophoblast may also enter the peripheral circulation.

Objective: To examine the maternal influences which determine large placental weight and a high ratio of placental weight to birthweight. These are known predictors of adult blood pressure., Design: Retrospective analysis of routine obstetric and haematology department records for a large cohort of pregnant women., Setting: John Radcliffe Hospital, Oxford., Subjects: 8684 pregnant women who were delivered between January 1987 and January 1989 and whose records could be linked to the results of two or more pregnancy blood counts., Main Outcome Measures: Placental weight and the ratio of placental weight to birthweight., Results: Large placental weight was associated with a low maternal haemoglobin and a fall in maternal mean cell volume during pregnancy. The highest ratio of placental weight to birthweight occurred in the most anaemic women with the largest falls in mean cell volume. Large placental weight and a high ratio of placental weight to birthweight were also independently associated with a high maternal body mass index. Maternal smoking reduced placental weight, but increased the ratio of placental weight to birthweight., Conclusions: Anaemia and iron deficiency during pregnancy are associated with large placental weight and a high ratio of placental weight to birthweight. This points to maternal nutritional deficiency as a cause for discordance between placental and fetal growth. This may have important implications for the prevention of adult hypertension, which appears to have its origin in fetal life.

Peritoneal lavage fluid cytology was performed in 87 out-patients with histologically proven epithelial ovarian cancer undergoing primary management. A total of 246 peritoneal lavages were attempted, usually with temporary cannulae (n = 229). From these, 184 samples were obtained, of which 156 (85%) were suitable for cytological analysis. The sensitivity of peritoneal lavage fluid cytology in 67 patients with known residual disease was 57% whereas serum CA 125 levels were elevated in 58 (87%). Pre- and post-treatment peritoneal lavage fluid cytology had prognostic value, but this was less than that of serum CA 125 measurements.

Large granular lymphocytes (LGL) have been shown previously to be the most abundant cell type in the first trimester human decidua. Purified populations of decidual LGL were prepared by flow cytometry of cell dispersions labelled with NKH1 (CD56), an antibody specific for peripheral blood LGL, and the functional properties of CD56-positive cells, CD56-negative and unsorted decidual cells compared. Both CD56-positive cells and unsorted decidual cells have cytotoxic activity against the natural killer (NK) cell target K562 which was weak compared with that of peripheral blood mononuclear cells (PBMC). The CD56-negative cells had no cytotoxic activity against K562. All three decidual cell populations proliferated in response to recombinant human interleukin-2 (rIL-2), but none produced detectable levels of IL-2 in culture. When unsorted decidual cells were cultured for 7 days in rIL-2 the proportion of CD56-positive cells increased and NK activity against K562 was augmented. The NK activity of purified CD56-positive decidual cells was also augmented by culturing in rIL-2. The potential role of decidual LGL in regulating the development of the semi-allogeneic placenta is discussed.