Multicentre randomised controlled trials in obstetrics and gynaecology: an analysis of trends over three decades.

To assess the trend in multicentre randomised controlled trials (RCTs), a database of 670 RCTs was assembled from four generic obstetric and gynaecological journals (Acta Obstetricia et Gynecologica Scandinavica, British Journal of Obstetrics & Gynaecology, Obstetrics & Gynecology and American Journal of Obstetrics & Gynecology) for 1975, 1980, 1985, 1990, 1995, 2000 and 2005. During this period, there was an inflationary trend with the proportion of published multicentre RCTs (from 12.9% in 1975 of all RCTs to 23.8% in 2005; P = 0.008). Multicentre RCTs had multiauthored publications (OR = 2.90; 95% CI 1.99-4.22) and more often received external funding (OR = 2.41; 95% CI 1.70-3.48) than single centre RCTs. The inflationary trend in multicentre RCTs requiring funding and collaboration represents the increasing complexity of medical research necessary to underpin evidence-based practice.

Randomised controlled trial comparing the efficacy of same-day administration of mifepristone and misoprostol for termination of pregnancy with the standard 36 to 48 hour protocol.

OBJECTIVE: To determine the efficacy of oral mifepristone followed by vaginal misoprostol 6 hours later compared with the standard 36- to 48-hour regimen for medical termination of pregnancy. DESIGN: Single centre, two arm, parallel, open randomised controlled trial. SETTING: Medical termination service at a teaching hospital. SAMPLE: Four hundred and fifty women undergoing medical termination of pregnancy at up to 63 days of gestation. METHODS: Eligible women were randomised to receive mifepristone 200 mg orally followed by vaginal misoprostol 800 micrograms either 6 hours (n=225) or 36-48 hours (n=225) later. All participants were invited to attend for a follow-up pelvic ultrasound scan within 7 days following the misoprostol administration. For those women in whom products of conception remained at the follow-up ultrasound scan, expectant management ensued with weekly follow-up ultrasound scans until the termination was complete. They could elect to undergo an evacuation of uterus at any stage following the scan. Those women with a nonviable gestation sac at the follow-up scan were offered a further dose of vaginal misoprostol 800 micrograms or suction termination of pregnancy. Women with a continuing pregnancy were managed with surgical termination. MAIN OUTCOME MEASURE: Successful medical abortion defined as no requirement for medical or surgical intervention beyond the initial dose of misoprostol. RESULTS: One hundred and sixty-five women (79%) in the 6-hour group and 197 women (92%) in the 36- to 48-hour group had a successful termination at first follow-up ultrasound or presumed on the basis of other considerations (those not seen for ultrasound but deemed successful by negative pregnancy test, products passed on ward or long-term assessment of notes). Twenty-two women (10%) in the 6-hour regimen required up to three further ultrasound scans after 7 days following the mifepristone administration in order to ensure that the termination process was complete. None of these women required a suction evacuation of uterus. In the 36- to 48-hour regimen, ten (5%) women had up to two further ultrasound scans to confirm a complete termination without the need for a surgical evacuation of uterus. Therefore, the overall successful termination rate in the 6-hour regimen was 89% (187/210) compared with 96% (207/215) in the 36- to 48-hour regimen (relative risk=0.92, 95% CI 0.84-0.98). Repeat administration of misoprostol or surgical treatment was required in 23 women (11%) in the 6-hour group and 8 women (4%) in the 36- to 48-hour group. A viable pregnancy was found in five women (2%) in the 6-hour group and in three women (1%) in the 36- to 48-hour group. CONCLUSIONS: Oral mifepristone 200 mg followed by vaginal misoprostol 800 micrograms after 6 hours is not as effective at achieving a complete abortion compared with the 36- to 48-hour protocol.

The reliability and validity of three dimensional ultrasound volumetric measurements using an in vitro balloon and in vivo uterine model.

OBJECTIVE: To evaluate the reliability and validity of two and three dimensional ultrasound volumetric measurements using balloon and uterine models. DESIGN: Prospetive observational study. SETTING: Obstetric ultrasound department at a university teaching hospital. METHOD: Two and three dimensional ultrasound volumetric measurements (with 5, 10 and 15 ultrasonic slices) were performed on 30 different sets of ultrasound images obtained from 15 water filled balloons with volumes ranging from 19 to 697mL. The measurements were performed independently by two observers who were blinded to the true volumes of the balloons. For the uterine model, only three dimensional ultrasonic volume measurements were performed independently on 16 uteri by two observers who were again unaware of the definitive uterine volumes. OUTCOME MEASURE: For the assessment of intra-and inter-rater reliability, the intraclass correlation coefficient was used. The index of concordance between the ultrasonic volumes and those obtained by the reference standard (validity) was assessed with the conventional Pearson's correlation coefficient, limits of agreement method and the intra-class correlation coefficient. RESULTS: High levels of reliability and validity were obtained for both two and three dimensional ultrasound balloon volume measurements. For two dimensional ultrasonic volume measurements, the intra-class correlation coefficient ranged from 0.992 to 0.998 for reliability and validity whereas the Pearson's correlation coefficient for validity was 0.996. With three dimensional ultrasonic volume measurements, the intra-class correlation coefficient ranged from 0.991 to 0.999 for reliability and validity whereas the Pearson's correlation coefficient for validity was 0.999. Both two and three dimensional ultrasonic measurements tended to underestimate the true balloon volume with the largest observed mean difference obtained with three dimensional ultrasound measurements using five ultrasonic slices and the smallest value obtained with three dimensional ultrasound measurements employing 15 ultrasonic slices. The mean difference in volume measurement for two dimensional ultrasound was intermediate between these two values. However, two dimensional ultrasound volume measurement generated the largest range between the limits of agreement whereas the smallest range was obtained with three dimensional ultrasound using 10 ultrasonic slices. The intra-class correlation coefficient for reliability and validity with three dimensional ultrasonic uterine volume estimation ranged from 0.956 to 0.996 whereas the Pearson's correlation coefficient for validity ranged from 0.993 to 0.999). The use of three dimensional ultrasound also consistently under-estimated the actual uterine volumes. The larger the number of ultrasonic slices employed for three dimensional ultrasound, the smaller was the mean difference between the ultrasonic and true uterine volume measurements and the smaller the limits of agreement. CONCLUSIONS: The reliability and validity of balloon and uterine volume measurement by three dimensional ultrasound is high. This allows further research on three dimensional ultrasound for measuring pelvic organ volumes in the prediction of pelvic pathology.

Primary peripheral T cell lymphoma of the endometrium.

A case of a primary peripheral T cell lymphoma arising in the endometrium is presented. Primary lymphomas of the female genital tract are rare, with endometrial lymphomas and those of T cell type being rarer still. Extensive investigations revealed no other sites of disease and the patient was treated by hysterectomy and chemotherapy. She remains well 33 months later. We believe that this case is exceptionally unusual.

The development and validation of an algorithm for real-time computerised fetal heart rate monitoring in labour.

OBJECTIVE: To develop and validate a computerised algorithm for the interpretation of the characteristics of fetal heart rate monitoring in labour. DESIGN: Prospective observational study. SETTING: Labour ward in a tertiary hospital. SAMPLE: Intrapartum cardiotocograms from 24 pregnancies. METHODS: A computerised algorithm was developed to assess the fetal heart baseline rate, variability, the number of accelerations and the number of decelerations. Twenty five minute segments of cardiotocograms were interpreted by the algorithm and also by seven expert reviewers independently. The reviewers were unaware of the outcome of labour. The reliability of the characteristics of cardiotocography and the validity of the computerised algorithm were assessed using the intraclass correlation coefficient and weighted kappa statistic for continuous and ordinal variables respectively. RESULTS: The inter rater reliability of the baseline fetal heart rate and the number and type of decelerations was good (intraclass correlation coefficient 0.93, 0.93 and 0.79, respectively). The reliability of baseline variability (kappa = 0.27) and accelerations (intraclass correlation coefficient = 0.27) was poor. The computerised algorithm had good agreement with the reviewers for the baseline fetal heart rate (intraclass correlation coefficient 0.91 to 0.98) and the number of decelerations (intraclass correlation coefficient 0.82 to 0.91), but was less valid as regards the number of late decelerations (intraclass correlation coefficient 0.68 to 0.85) and the number of accelerations (intraclass correlation coefficient 0.06 to 0.80), and was invalid as regards baseline variability (kappa 0.00 to 0.34). CONCLUSIONS: The high level of validity of the computerised algorithm for the estimation of the baseline fetal heart rate and the number of decelerations justifies its further technical development.

Validity of ultrasound estimation of fetal weight.

OBJECTIVE: To assess the validity of ultrasound estimation of fetal weight at term. METHODS: We conducted a prospective observational study whereby all ultrasonic biometric measurements were done by a single observer. Fifty pregnant women at term had ultrasonic measurement of various fetal biometric parameters performed within a week of delivery. Fetal weight was estimated by the use of four reported methods (Aoki, Campbell, Shepard, and Hadlock formulas). We compared estimated weight with the birth weight after the estimated fetal weight was adjusted by adding 25 g for each day between the ultrasound measurements and delivery. RESULTS: The adjusted estimated fetal weight obtained from all four formulas tended to be lower than measured birth weight. The smallest mean difference was obtained with the Shepard and Aoki formulas (51.4 g and 60.5 g, respectively), whereas the Campbell and Hadlock formulas produced larger mean differences (141.8 g and 190.7 g, respectively). The Aoki formula generated the smallest range between the limits of agreement (-324.2 to 445.2 g) whereas the Campbell formula produced the largest range (-286.5 to 570.1 g). The range between the limits of agreement generated with the Shepard and Hadlock formulas were intermediate between those produced by the Aoki and Campbell formulas. The intraclass correlation coefficients generated with the Aoki and Shepard formulas were identical (0.90). The intraclass correlation coefficients obtained with the Hadlock (0.84) and Campbell formulas (0.85) were lower. CONCLUSION: The validity of ultrasonic estimation of fetal weight at term with all four formulas was high.

How useful is uterine artery Doppler flow velocimetry in the prediction of pre-eclampsia, intrauterine growth retardation and perinatal death? An overview.

OBJECTIVE: To evaluate the clinical usefulness of Doppler analysis of the uterine artery velocity waveform in the prediction of pre-eclampsia and its associated complications of intrauterine growth retardation and perinatal death. DESIGN: Quantitative systematic review of observational diagnostic studies using online searching of the MEDLINE database coupled with scanning of the bibliographies of primary and review articles including known unpublished studies. MATERIAL: Twenty-seven studies involving 12,994 subjects stratified into population subgroups at low and high risk of developing pre-eclampsia and its complications. OUTCOME MEASURES: The outcome measures studied were: 1. the development of pre-eclampsia; 2. intrauterine growth retardation; and 3. perinatal death. The main meta-analyses were the flow velocity waveform ratio +/- diastolic notch derived by transabdominal Doppler ultrasound as the measurement parameter. The analyses were conducted using likelihood ratio as a measure of diagnostic accuracy. A likelihood ratio of 1 indicates that the test has no predictive value for the outcome. Prediction for the outcome event is considered conclusive with likelihood ratios of > 10 or < 0 x 1 for a positive and negative test result, respectively. Moderate prediction can be achieved with likelihood ratios of 5-10 and 0 x 1-0 x 2 whereas likelihood ratios values of 1-5 and 0 x 2-1 would generate only minimal prediction. RESULTS: In the low risk population a positive test result, predicted pre-eclampsia with a pooled likelihood ratio of 6 x 4 (95% CI 5 x 7-7 x 1), while a negative test result had a pooled likelihood ratio of 0 x 7 (95% CI 0 x 6-0 x 8). For intrauterine growth retardation the pooled likelihood ratio was 3 x 6 (95% CI 3 x 2-4 x 0) for a positive test result and 0 x 8 (95% CI 0 x 8-0 x 9) for a negative test result. Using perinatal death as outcome measure, the pooled likelihood ratio was 1 x 8 (95% CI 1 x 2-2 x 9) for a positive test result and 0 x 9 (95% CI 0 x 8-1 x 1) for a negative test result. In the high risk population a positive test result predicted pre-eclampsia with a pooled likelihood ratio of 2 x 8 (95% CI 2 x 3-3 x 4), while a negative test had a likelihood ratio of 0 x 8 (95% CI 0 x 7-0 x 9). For intrauterine growth retardation the pooled likelihood ratio was 2 x 7 (95% CI 2 x 1-3 x 4) for a positive test result and 0 x 7 (95% CI 0 x 6-0 x 9) for a negative result. For perinatal death the pooled likelihood ratio was 4 x 0 (95% CI 2 x 4-6 x 6) for a positive test result and 0 x 6 (95% CI 0 x 4-0 x 9) for a negative result. CONCLUSION: Uterine artery Doppler flow velocity has limited diagnostic accuracy in predicting pre-eclampsia, intrauterine growth retardation and perinatal death.

The three mechanisms of intracellular chloride accumulation in vascular smooth muscle of human umbilical and placental arteries.

Recordings of membrane potential (Em) and intracellular [Cl-] ([Cl-]i) were made from the smooth muscle of human umbilical and placental arteries, using double-barrelled, ion-sensitive microelectrodes. In both arteries, [Cl-]i was above equilibrium with Em. In the umbilical artery, [Cl-]i was 33.8+/-0.9 mM (+/-SD, n=19) and Em -54.9+/-1.3 mV and in the placental artery respectively 35.1+/-0.7 mM (n=17) and -50.6+/-0.9 mV. In both arteries, [Cl-]i was reduced and Em hyperpolarised significantly by successive additions of 100 microM 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulphonic acid (DIDS), 10 microM bumetanide and 1 mM acetazolamide, thus revealing the presence of Cl-/HCO3- exchange, (Na+K+Cl) cotransport and "pump III". In the presence of all three inhibitors, [Cl-]i was in equilibrium with Em. As in earlier studies on rat arterial smooth and cardiac muscle, pump III was unaffected by DIDS, bumetanide, metolazone and the removal of Na+, partly inhibited by chlorothiazide and fully inhibited by ethacrynic acid. The results are discussed in terms of the possibility that of chloride accumulating systems may regulate vasomotor tone in the foetoplacental unit.

Cavaterm thermal balloon ablation for the treatment of menorrhagia.

Fifty patients due to undergo endometrial ablation as a treatment of dysfunctional uterine bleeding were recruited to assess the efficacy and safety of a new thermal balloon ablation system (Cavaterm). The patients were followed up for a mean of 14 months (range 6-24): 34 (68%) have complete amenorrhoea, 12 (24%) only have spotting, two (4%) are eumenorrhoeic, and two (4%) have had failed treatments. There were no major complications, but two patients have required oral antibiotics for suspected endometritis. Although these preliminary results are encouraging, all patients remain under review to determine long term effect of the procedure. Further evaluation is also underway in the form of a randomised trial against endometrial laser ablation.

Intrapartum umbilical artery Doppler velocimetry as a predictor of adverse perinatal outcome: a systematic review.

OBJECTIVE: To evaluate the diagnostic prediction of intrapartum umbilical artery Doppler velocimetry for adverse perinatal outcomes using systematic quantitative overview of the available literature. DESIGN: Online searching of MEDLINE database (January 1966-September 1997), scanning of bibliography of known primary and review articles, review of recent journal issues and that from personal files. Study selection, assessment of study quality and data extraction were all performed in duplicate under masked conditions. PARTICIPANTS: 2700 women (unselected, low, high, and combined low and high obstetric risk populations) included in eight studies selected for meta-analyses. MAIN OUTCOME MEASURES: Likelihood ratios (LRs) for positive and negative test results were generated for the following outcome measures: Apgar scores < 7 at 1 and 5 minute following delivery, small for gestational age fetus; intrapartum fetal heart rate abnormality, umbilical arterial acidosis at delivery; and caesarean section for fetal distress. RESULTS: For Apgar score < 7 at 1 minute following delivery, the pooled LR was 2.5 (95% CI 1.7-3.7) for a positive test and 1.0 (95% CI 0.9-1.1) for a negative test result. A positive test predicted an Apgar score < 7 at 5 minute following delivery with a pooled LR of 1.3 (95% CI 0.4-4.1) while a negative test had a pooled LR of 1.0 (95% CI 0.8-1.2). For the prediction of a small for gestational age fetus, the pooled LR was 3.4 (95% CI 2.3-5.1) for a positive test and 0.9 (95% CI 0.8-1.0) for a negative test. The prediction for fetal heart rate abnormality during labour was similarly disappointing: the pooled LR for a positive test result was 1.4 (95% CI 0.9-1.2) whereas a negative test result generated a pooled LR of 0.9 (95% CI 0.9-1.0). With umbilical acidosis at delivery, the pooled LR was 1.6 (95% CI 1.1-2.5) for a positive test and 1.1 (95% CI 1.0-1.2) for a negative test. The LRs for the prediction of caesarean section for fetal distress were 4.1 (95% CI 2.7-6.2) for a positive test result and 0.9 (95% CI 0.8-1.0) for a negative test result. CONCLUSION: Intrapartum umbilical artery Doppler velocimetry is a poor predictor of adverse perinatal outcomes.

A controlled analysis of authorship trends over two decades.

OBJECTIVE: The purpose was to assess authorship trends over time by taking account of publication type and controlling for number of investigating centers and funding status in a multivariable analysis. STUDY DESIGN: A database of 403 randomized studies and 193 controlled observational studies was assembled by means of a combination of electronic and hand search of 4 generic obstetrics and gynecology journals for the years 1975, 1980, 1985, 1990, and 1995. A multivariable logistic regression model was built for evaluating the effect of time on authorship with multiauthored articles as the binary outcome variable (articles were classified as either those with <6 authors or those with >/=6). The analysis was performed separately for the 2 types of publications, and it was adjusted for the confounding effects of number of centers, funding status, and journal of publication. The beta coefficient (and its exponent) associated with the time term in the logistic model provided a measure of the trend in publication of multiauthored articles. RESULTS: In randomized studies the odds of publishing a multiauthored article, given the number of centers, funding status, and journal, were increased on average by 6% with every 5-year increment in time (odds ratio, 1.06; 95% confidence interval, 1.02-1. 10; P =.007). Similarly, in controlled observational studies, there was a 10% increase in the odds of publishing multiauthored articles (odds ratio, 1.10; 95% confidence interval, 1.01-1.20; P =.03). CONCLUSION: There is an inflationary trend in authorship that is not explained solely by the increased collaboration between centers and funding for research.

Misleading authors' inferences in obstetric diagnostic test literature.

OBJECTIVE: Our goal was to determine the validity of authors' inferences about the value of the cervico-vaginal fetal fibronectin test in the prediction of preterm birth and the utility of uterine artery Doppler waveform analysis in the prediction of preeclampsia. STUDY DESIGN: We evaluated all 35 diagnostic test studies (14 on fetal fibronectin and 21 on uterine artery Doppler) included in 2 meta-analyses. The information on authors' conclusions regarding the value of a positive or negative test result was independently abstracted from each article by 2 reviewers, and it was classified as definitely useful, moderately useful, slightly useful, or not at all useful. For the "gold" standard, likelihood ratios of >10 and <0. 1 were regarded as definitely useful, 5 to 10 and 0.1 to 0.2 were regarded as moderately useful, 2 to 5 and 0.2 to 0.5 were regarded as slightly useful, and 1 to 2 and 0.5 to 1 were regarded as not at all useful. The agreement between the authors and the reference standard was computed by simple percentage agreement and weighted kappa statistic. RESULTS: Among articles assessing the diagnostic value of fetal fibronectin the simple agreement between the authors and the "gold" standard was 26% (7/26) with a kappa of 0.05 (P =.83), and authors overestimated the value of the test result in 66% (17/26) of instances. Similarly, among articles assessing uterine artery Doppler the simple agreement between the authors and the "gold" standard was 31% (13/42) with a kappa of 0.28 (P =.31), and authors overestimated the value of the test result in 48% (20/42) of instances. CONCLUSION: Authors claimed more positive conclusions than could be supported by their data. When studies are reported in a misleading manner, the chance of misinterpretation on the part of the clinical reader is increased. The use of explicit criteria that are based on likelihood ratios may reduce the risk of erroneous inferences.

Logistic regression models in obstetrics and gynecology literature.

OBJECTIVE: To evaluate the reporting of multivariable logistic regression analyses and assess variations in quality over time in the obstetrics and gynecology literature. METHODS: Methodologic criteria for reporting logistic regression analyses were developed to identify problems affecting accuracy, precision, and interpretation of this approach to multivariable statistical analysis. These criteria were applied to 193 articles that reported multivariable logistic regression in the issues of four generic obstetrics and gynecology journals in 1985, 1990, and 1995. Rates of compliance with the methodologic criteria and their time trends were analyzed. RESULTS: The proportion of articles using logistic regression analysis increased over time: 1.7% in 1985, 2.8% in 1990, and 6.5% in 1995 (P < .001 for trend). Violations and omissions of methodologic criteria for reporting logistic models were common. The research question, in terms of dependent and independent variables, was not clearly reported in 32.1%. The process of variable selection was inadequately described in 51.8% of the articles. Among articles with ranked independent variables, 85.1% did not report assessment of conformity to linear gradient. Tests for goodness of fit were not given in 93.2% of articles. The contribution of the independent variables could not be evaluated in 36.2% of the articles because of a lack of coding of the variables. Interactions between variables were not assessed in 86.4% of articles. Analysis of variations in the quality of logistic regression analyses over time showed no increase in reporting of the criteria concerning variable selection and goodness of fit. However, the proportion of articles reporting one quality criterion concerning interpretation of the substantive significance of independent variables showed a trend toward improvement: 42.3% in 1985, 73.6% in 1990, and 75.4% in 1995 (P = .004 for trend). CONCLUSION: The reporting of multivariable logistic regression models in the obstetrics and gynecology literature is poor, and the time trends of improvement in quality of reporting are not particularly encouraging.

Is real-time ultrasonic bladder volume estimation reliable and valid? A systematic overview.

To assess the reliability and validity of real-time ultrasonic estimation of bladder volume we conducted an overview of the published literature identified using MEDLINE search (1966-96) and scanning of the bibliographies of known primary and review articles. Short-listed papers were classified into reliability (observer agreement) and validity (comparison of ultrasound estimation with actual bladder volume) studies. Study selection and data extraction were performed independently in duplicate. There were 81 subjects enrolled in 3 reliability studies and 504 subjects in 16 validity studies. Where reported, the index of concordance for reliability ranged from 0.923 to 1.00, while for validity it ranged from 0.914 to 0.983. However, there were several inadequacies in the design, conduct and analysis of these studies, leaving some doubt about the trustworthiness of the high levels of reliability and validity reported in the literature.

Risk of hysterectomy after 1000 consecutive endometrial laser ablations.

OBJECTIVES: To determine the hysterectomy rate after endometrial laser ablation, allowing for variable follow up times, and to evaluate the factors that might predict outcome. DESIGN: Observational cohort study. SETTING: Specialist minimal access gynaecology unit in a district general hospital. METHODS: Data were obtained from case notes, theatre records, and follow up postal questionnaires. The risk of hysterectomy following endometrial laser ablation was assessed using survival curve estimates. Proportional hazards regression analysis was used to identify the predictor(s) of this outcome. RESULTS: A single endometrial laser ablation was carried out on 746 patients (85.4%); 124 patients (14.2%) underwent one repeat procedure and three (0.4%) underwent two repeat ablative procedures. The cumulative rate of return of the postal questionnaires was 87.3% (762/873 patients). Survival curve analysis showed that the overall hysterectomy rate projected over a follow up period of 6.5 years was 21% (95% CI 16%-27%). The age of the patient at endometrial ablation, uterine cavity length, operative time, volume of fluid absorbed, the presence or absence of dysmenorrhoea, premenstrual syndrome and the method of endometrial preparation prior to surgery did not contribute significantly to the regression model. Having a repeat endometrial ablation procedure increased the risk of having a subsequent hysterectomy (RR = 2.93; 95% CI 1.59-5.40; P = 0.0015), whereas the presence of intrauterine pathology (eg, polyps, fibroids and uterine shape abnormalities) decreased the risk of this outcome (RR = 0.26; 95% CI 0.08-0.86; P = 0.0082) after adjustment for confounding due to patient's age and dysmenorrhoea prior to surgery. CONCLUSIONS: Endometrial laser ablation is a safe and effective treatment for menstrual dysfunction. Repeat ablative procedures significantly increased, and the presence of intrauterine pathology decreased, the risk of subsequent hysterectomy.