Ménière's disease clinical subtypes in a population from the USA.

OBJECTIVE: To ascertain the distribution of Ménière's disease phenotype subgroups in a US-based cohort, based on a recently introduced classification scheme utilising a Spanish and Portuguese cohort. METHODS: A retrospective, cross-sectional, single-institutional chart review was conducted. The electronic medical records of Ménière's disease patients were identified using International Classification of Diseases codes at a tertiary referral centre and reviewed to extract subgroup-defining features. Patients with definite Ménière's disease as per American Academy of Otolaryngology-Head and Neck Surgery criteria were categorised into one of five subgroups, for unilateral and bilateral Ménière's disease. RESULTS: Eighty-one patients with definite Ménière's disease were identified. Seventy-two cases of unilateral Ménière's disease were observed: 52.8 per cent were type 1, 20.8 per cent were type 2, 4.2 per cent were type 3, 18.1 per cent were type 4, and 4.2 per cent were type 5. This cohort differed significantly in distribution to a comparison Mediterranean cohort (p < 0.01). Nine cases of bilateral Ménière's disease were observed. CONCLUSION: The distribution of unilateral Ménière's disease subtypes in this US population was different from that observed in a European population.

Prevalence of high-grade cervical intraepithelial neoplasia in women with persistent high-risk HPV genotypes and negative cytology.

INTRODUCTION: Primary HPV screening will be implemented into the English Cervical Screening Programme by 2019. Its impact upon women referred to colposcopy, with negative cytology but persistently positive high-risk HPV (hrHPV), remains unreported from UK Sentinel sites. HPV primary screening was introduced in Sheffield, UK in April 2013; this paper reports its impact on the service. METHODS: A retrospective cohort study was performed from June 2014 to July 2016 at the Jessop Wing Colposcopy Unit, Sheffield. UK. Data were obtained from the pathology and colposcopy databases and cross-referenced with case-notes and pathology results for women referred with persistently positive hrHPV, cytology negative samples. Patient demographics, hrHPV genotype, biopsy rates, histological diagnoses, management, and outcomes were collected and baseline statistics performed. RESULTS: During the study 1076 women were seen. Most frequent hrHPV genotypes were: hrHPV other, 41%; and HPV16, 33%. The majority (72%) were found to have normal colposcopy; 28% had an abnormal colposcopic assessment (11% low-grade; 11% high-grade; 6% inadequate). The majority were discharged (83%) and only 5% underwent LLETZ. No cancers were detected. High-grade cervical intraepithelial neoplasia (CIN) was found in 7%; overall risk of CIN2 was 1/29; 1/30 for CIN3. Presence of HPV16 was associated with a significantly higher risk of high-grade CIN; 1/9. CONCLUSION: This is the first study to report results for women referred to colposcopy with cytology negative, persistently positive hrHPV. Disease prevalence is low, although women with HPV16 have a significantly higher likelihood of high-grade disease compared to other HPV subtypes.

A review of the use of human papilloma virus (HPV) in cervical screening.

Using key words online databases were searched to identify relevant publications to review the use of Human papilloma virus (HPV) in cervical screening. The mode of cervical screening in the UK has been decided but implementation plans have yet to be announced. The protracted uncertainty surrounding the initial announcement to move to HPV primary screening together with the lack of a national steer has resulted in a flight of staff which threatens the provision of the current and future service. The transition will be a challenging time but analysis of data from more than 176,000 women has shown clear evidence of a reduction in the incidence of cancer where HPV testing is used. There will however, be a population of women who are cytologically negative but high-risk HPV positive and the management of these women will be key to maximising the benefits of HPV primary screening. As cervical cytology becomes increasingly rare its effectiveness and role in cervical screening will come under scrutiny and we must ensure the specificity of reporting is maintained in order for it to survive.

Does LLETZ excision margin status predict residual disease in women who have undergone post-treatment cervical cytology and high-risk human papillomavirus testing?

OBJECTIVE: This study looks at the importance of large loop excision of the transformation zone (LLETZ) excision margins and residual cervical intraepithelial neoplasia (CIN) in women undertaking high-risk human papillomavirus (hrHPV) test of cure (TOC). METHODS: A retrospective cohort study with interval analysis performed June 2007 and June 2012 on all women undertaking treatment for CIN and subsequent hrHPV TOC 6 months post LLETZ. RESULTS: Final analysis group comprised 2093 women treated by LLETZ (1396 completely excised; 697 incompletely excised). 298 out of 1794 women (13%) were hrHPV positive at TOC. Thirty-six women who failed TOC and attended colposcopy had residual CIN. No statistically significant difference existed between the completely and incompletely excised groups with regards to the detection of residual CIN at 6 months post-treatment. There was no correlation of margins of excision with hrHPV status at TOC. The overall cure rate at TOC was 98%. CONCLUSIONS: TOC pathways recommend subsequent follow-up in primary care. This study identified no safety issues with TOC pathways. We can no longer assess histological failure rates at 12 months; we, therefore, recommend that this measure of treatment failure be redefined for post TOC women. It seems time to question the benefits of routine excision margins reporting, in the absence of invasion, for treated CIN. Future reporting needs to be reconsidered by the Royal College of Pathologists.

Development of a technical external quality assurance scheme in non-gynaecological cytology in UK.

Technical external quality assurance (EQA) schemes are well established for histopathology and cervical cytology but, to date, sadly lacking for diagnostic cytology (DC). This timely review redresses the balance by describing the development and evaluation of a technical EQA scheme for DC available to the UK, Europe and beyond.

High-risk HPV platforms and test of cure: should specific HPV platforms more suited to screening in a 'test of cure' scenario be recommended?

OBJECTIVE: When the Sheffield screening laboratory changed the high-risk human papillomavirus (hrHPV) platforms from hybrid capture 2(®) (HC2; Digene Ltd) and to cobas 4800(®) (Roche) an unexpected and substantial increase in the number of cytology-negative/hrHPV-positive test-of-cure (ToC) samples after large loop excision of the transformation zone (LLETZ) was noted. We explore the potential reasons for these increased rates and discuss the implications this may have on the English NHS cervical screening programme (CSP). METHODS: A retrospective cohort study with interval analysis between June 2007 and June 2012. RESULTS: ToC was performed on 1530 women with HC2 and 396 with cobas 4800: 95.1% and 92.4% of women had negative cytology at ToC in the HC2 and cobas4800 testing period, respectively. Of these 13.9% and 27.8% tested positive for hrHPV in the HC2 and cobas 4800 group, respectively (P = <0.0001). No clinically significant increase in the number of cases of cervical intraepithelial neolpasia (CIN) was detected by the cobas4800 test in spite of doubling the number of cytology-negative/hrHPV-positive ToC samples. CONCLUSIONS: As far as we are aware, this is the first study reporting potential differences between different HPV platforms currently available in the English programme. The immediate impact of this increase in rates of hrHPV detection with cobas4800 is an increased number of colposcopy referrals to our service. The NHSCSP needs to assess whether this increase is acceptable and, if not, whether specific HPV platforms more suited to screening in a ToC scenario should be recommended.

Can I leave the theatre? A key to more reliable workplace-based assessment.

BACKGROUND: The value of workplace-based assessments such as the mini-clinical evaluation exercise (mini-CEX), and clinicians' confidence and engagement in the process, has been constrained by low reliability and limited capacity to identify underperforming trainees. We proposed that changing the way supervisors make judgements about trainees would improve score reliability and identification of underperformers. Anaesthetists regularly make decisions about the level of trainee independence with a case, based on how closely they need to supervise them. We therefore used this as the basis for a new scoring system. METHODS: We analysed 338 mini-CEXs where supervisors scored trainees using the conventional system, and also scored trainee independence, based on the need for direct, or more distant, supervision. As supervisory requirements depend on case difficulty, we then compared the actual trainee independence score and the expected trainee independence score obtained externally. RESULTS: Compared with the conventional scoring system used in previous studies, reliability was very substantially improved using a system based on a trainee's level of independence with a case. Reliability improved further when this score was corrected for case difficulty. Furthermore, the new scoring system overcame the previously identified problem of assessor leniency and identified a number of trainees performing below expectations. CONCLUSIONS: Supervisors' judgements on trainee independence with a case, based on the need for direct or more distant supervision, can generate reliable scores of trainee ability without the need for an onerous number of assessments, identify trainees performing below expectations, and track trainee progress towards independent specialist practice.

Factors contributing to false-negative and potential false-negative cytology reports in SurePath™ liquid-based cervical cytology.

OBJECTIVES: The characteristics of false-negative conventional cervical cytology smears have been well documented, but there is limited literature available for liquid-based cytology (LBC), especially SurePath™ samples. We aimed to assess the characteristics of false-negative SurePath LBC samples. METHODS: Over a period of 5 years, an audit of false-negative reports in SurePath cervical cytology was undertaken. In a workload of 183, 112 samples, 481 (0.3%) false negatives were identified using two routes: those detected by routine laboratory internal quality control (rapid pre-screening) (n = 463) and those reported as normal (true false negatives) with concurrent high-grade cervical histology (n = 18). Ninety-five false-negative cases with a subsequent biopsy reported as at least cervical intraepithelial neoplasia grade 2 (CIN2+) were reviewed for a number of different cytomorphological features. RESULTS: Of 95 samples with subsequent CIN2+, 30.5% predominately contained microbiopsies/hyperchromatic crowded cell groups (HCGs), 27.3% sparse dyskarytotic cells, 4.2% pale cell dyskaryosis, 6.3% small dyskaryotic cells; 3.2% were misinterpreted cells, 8.4% contained other distracting cells, 7.4% were low contrast, 5.3% were unexplained and 7.4% were true negatives. The mean number of microbiopsies/HCGs in that category was 4.6. The mean number of abnormal cells in the sparse dyskaryotic cell category was 13.8. CONCLUSIONS: Microbiopsies/HCGs were the commonest reason for false negatives. They were usually present in sufficient numbers to be detected but interpretation could be problematic. Dispersed single abnormal cells were usually not identified because of their scarcity or the presence of distracters.

Outcome of SurePath™ cervical samples reported as borderline nuclear change by cytological subtype and high-risk HPV status.

BACKGROUND: The average borderline rate in cervical cytology samples for English laboratories was 3.8% with the range being 2.0-6.8% at the time of the present study, which was undertaken in order to determine the association between different subtypes of borderline nuclear change (BNC), high-grade cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus (hrHPV) status. MATERIALS AND METHODS: Of 68,551 SurePath(TM) cervical samples reported in one laboratory over a period of 2 years, 2335 (3.4%) were reported as BNC. hrHPV status was known in 1112 cases (47.6%). The outcome was known only for women with hrHPV-positive BNC, who were recommended for colposcopy under the National Health Service Cervical Screening Programme sentinel site protocol. Women with hrHPV-negative BNC were returned to 3-yearly recall. The cases were subdivided into BNC, high-grade dyskaryosis cannot be excluded (B-HG; 105 cases); BNC with koilocytosis (B-K; 421 cases); BNC with other features of HPV (B-HPV; 160 cases); and BNC, not otherwise specified (B-NOS; 426 cases) and were correlated with the histological outcome where available. RESULTS: The study population age ranged from 23 to 65 years. Cases that tested positive for hrHPV by Qiagen HCII assay comprised 78.1%, 81.0%, 73.1% and 67.8% of B-HG, B-K, B-HPV and B-NOS categories, respectively. CIN2 or worse (CIN2+) was found in 64.6%, 10.0%, 19.7% and 20.1% of hrHPV-positive cases of B-HG, B-K, B-HPV and B-NOS, respectively, which was significantly higher in the B-HG category (P < 0.001) and lower in the B-K category compared with B-NOS (p < 0.001) and B-HPV (p = 0.006) respectively. CIN3+ comprised 55.6%, 6.3%, 26.3% and 19.1% of biopsies in the same categories, respectively. CONCLUSIONS: Subtyping BNC is useful, especially B-K and B-HG, which, respectively, had the lowest and highest rates of detection of both CIN2+ and CIN3+, confirming that koilocytosis is likely to be associated with transient HPV infection. Women with B-HG should be referred to colposcopy in the absence of HPV triage.

Prospective observational study to evaluate NOTSS (Non-Technical Skills for Surgeons) for assessing trainees' non-technical performance in the operating theatre.

BACKGROUND: Most surgical assessment has been aimed at technical proficiency. However, non-technical skills also affect patient safety and clinical effectiveness. The NOTSS (Non-Technical Skills for Surgeons) assessment instrument was developed specifically to assess the non-technical skills of individual surgeons in the operating theatre. This study evaluated NOTSS as a real-world assessment, with a mix of minimally trained assessors. The evaluation criteria were feasibility, validity and psychometric reliability. METHODS: In a standard evaluation of NOTSS, 56 anaesthetists, 39 scrub nurses, two surgical care practitioners and three independent assessors provided 715 assessments of 404 surgical cases of 15 index procedures across six specialties performed by 85 surgical trainees. RESULTS: The assessment was feasible, but important implementation challenges were highlighted. Most respondents considered the method valid, but with reservations about assessing cognition. The factor structure of scores, and their positive relationships with other measures of experience and performance, supported validity. Trainees' non-technical skill scores were relatively procedure-independent and achieved good reliability (generalizability coefficient 0·8 or more) when six to eight assessors observed one case each. CONCLUSION: Minimally trained assessors, who are typically present in operating theatres, were sufficiently discriminating and consistent in their judgements of trainee surgeons' non-technical skills to provide reliable scores based on an achievable number of observations.

Evaluation of procedure-based assessment for assessing trainees' skills in the operating theatre.

BACKGROUND: Procedure-based assessment (PBA) is used within most UK surgical training programmes for assessing trainees' procedural skills in the operating theatre. All postgraduate assessment methods require evidence to support their implementation. The aims were to evaluate the validity, reliability and acceptability of PBA. METHODS: Eighty-one trainees in six surgical specialties were assessed performing common procedures; 749 PBAs were provided across 348 operations by 57 clinical supervisors and four independent assessors. RESULTS: Construct validity was demonstrated by correlation of PBA scores with measures of surgical training and experience. Reliability (G exceeding 0·8) of the adjusted total item score and global summary score for a given procedure was achieved using four and three assessor judgements respectively; assessing a mix of procedures required more cases/assessors because performance is procedure specific. The acceptability of PBA for assessment and feedback within surgical training was predominantly positive among clinical supervisors and trainees. CONCLUSION: PBA demonstrated good overall validity and acceptability, and exceptionally high reliability. Trainees should be assessed adequately for each given procedure.

Assessing the surgical skills of trainees in the operating theatre: a prospective observational study of the methodology.

OBJECTIVES: To compare user satisfaction and acceptability, reliability and validity of three different methods of assessing the surgical skills of trainees by direct observation in the operating theatre across a range of different surgical specialties and index procedures. DESIGN AND SETTING: A 2-year prospective, observational study in the operating theatres of three teaching hospitals in Sheffield. METHODS: The assessment methods were procedure-based assessment (PBA), Objective Structured Assessment of Technical Skills (OSATS) and Non-technical Skills for Surgeons (NOTSS). The specialties were obstetrics and gynaecology (O&G) and upper gastrointestinal, colorectal, cardiac, vascular and orthopaedic surgery. Two to four typical index procedures were selected from each specialty. Surgical trainees were directly observed performing typical index procedures and assessed using a combination of two of the three methods (OSATS or PBA and NOTSS for O&G, PBA and NOTSS for the other specialties) by the consultant clinical supervisor for the case and the anaesthetist and/or scrub nurse, as well as one or more independent assessors from the research team. OUTCOME MEASURES: Information on user satisfaction and acceptability of each assessment method from both assessor and trainee perspectives was obtained from structured questionnaires. The reliability of each method was measured using generalisability theory. Aspects of validity included the internal structure of each tool and correlation between tools, construct validity, predictive validity, interprocedural differences, the effect of assessor designation and the effect of assessment on performance. RESULTS: Of the 558 patients who were consented, a total of 437 (78%) cases were included in the study: 51 consultant clinical supervisors, 56 anaesthetists, 39 nurses, 2 surgical care practitioners and 4 independent assessors provided 1635 assessments on 85 trainees undertaking the 437 cases. A total of 749 PBAs, 695 NOTSS and 191 OSATSs were performed. Non-O&G clinical supervisors and trainees provided mixed, but predominantly positive, responses about a range of applications of PBA. Most felt that PBA was important in surgical education, and would use it again in the future and did not feel that it added time to the operating list. The overall satisfaction of O&G clinical supervisors and trainees with OSATS was not as high, and a majority of those who used both preferred PBA. A majority of anaesthetists and nurses felt that NOTSS allowed them to rate interpersonal skills (communication, teamwork and leadership) more easily than cognitive skills (situation awareness and decision-making), that it had formative value and that it was a valuable adjunct to the assessment of technical skills. PBA demonstrated high reliability (G > 0.8 for only three assessor judgements on the same index procedure). OSATS had lower reliability (G > 0.8 for five assessor judgements on the same index procedure). Both were less reliable on a mix of procedures because of strong procedure-specific factors. A direct comparison of PBA between O&G and non-O&G cases showed a striking difference in reliability. Within O&G, a good level of reliability (G > 0.8) could not be obtained using a feasible number of assessments. Conversely, the reliability within non-O&G cases was exceptionally high, with only two assessor judgements being required. The reasons for this difference probably include the more summative purpose of assessment in O&G and the much higher proportion of O&G trainees in this study with training concerns (42% vs 4%). The reliability of NOTSS was lower than that for PBA. Reliability for the same procedure (G > 0.8) required six assessor judgements. However, as procedure-specific factors exerted a lesser influence on NOTSS, reliability on a mix of procedures could be achieved using only eight assessor judgements. NOTSS also demonstrated a valid internal structure. The strongest correlations between NOTSS and PBA or OSATS were in the 'decision-making' domain. PBA and NOTSS showed better construct validity than OSATS, the year of training and the number of recent index procedures performed being significant independent predictors of performance. There was little variation in scoring between different procedures or different designations of assessor. CONCLUSIONS: The results suggest that PBA is a reliable and acceptable method of assessing surgical skills, with good construct validity. Specialties that use OSATS may wish to consider changing the design or switching to PBA. Whatever workplace-based assessment method is used, the purpose, timing and frequency of assessment require detailed guidance. NOTSS is a promising tool for the assessment of non-technical skills, and surgical specialties may wish to consider its inclusion in their assessment framework. Further research is required into the use of health-care professionals other than consultant surgeons to assess trainees, the relationship between performance and experience, the educational impact of assessment and the additional value of video recording.

Diagnosing a learning practice: the validity and reliability of a learning practice inventory.

BACKGROUND: There is an increasing literature on learning organisations as a way of fostering communication, teamwork, collaboration and collective learning, thereby promoting quality improvement and enhancing patient safety. An increasing number of instruments are being developed in an attempt to measure learning organisation characteristics. However, the majority of these tools are created for a business setting, have not been scientifically tested and have not been applied in healthcare. OBJECTIVE: To evaluate elements of the validity and reliability of an instrument (ie, learning practice inventory (LPI)) for diagnosing learning practice characteristics in primary healthcare. METHOD: Content validity was evaluated using a modified nominal group technique and a content validity rating scale. Construct validity and reliability evaluation was undertaken with 10 staff members from 10 general practices in the west of Scotland. Staff completed the inventory twice, 4-6 weeks apart. Applying generalisability theory, a variance component analysis was performed. RESULTS: The main findings present evidence that the inventory has acceptable reliability and content validity. The results also demonstrate that the inventory can reflect the consistent and uniquely different perspectives of particular designations of staff within a practice. It is possible to compare practices' overall learning environments and to identify specific areas of practice strength as well as areas for development. CONCLUSION: This study demonstrates the psychometric properties of a learning practice diagnostic inventory. It highlights the consistently different perspectives that individual staff groups have on the function of their practice, suggesting that the success of quality improvement initiatives may be compromised without the involvement and true engagement of each staff group.

Cross-trimester repeated measures testing for Down's syndrome screening: an assessment.

OBJECTIVES: To provide estimates and confidence intervals for the performance (detection and false-positive rates) of screening for Down's syndrome using repeated measures of biochemical markers from first and second trimester maternal serum samples taken from the same woman. DESIGN: Stored serum on Down's syndrome cases and controls was used to provide independent test data for the assessment of screening performance of published risk algorithms and for the development and testing of new risk assessment algorithms. SETTING: 15 screening centres across the USA, and at the North York General Hospital, Toronto, Canada. PARTICIPANTS: 78 women with pregnancy affected by Down's syndrome and 390 matched unaffected controls, with maternal blood samples obtained at 11-13 and 15-18 weeks' gestation, and women who received integrated prenatal screening at North York General Hospital at two time intervals: between 1 December 1999 and 31 October 2003, and between 1 October 2006 and 23 November 2007. INTERVENTIONS: Repeated measurements (first and second trimester) of maternal serum levels of human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and pregnancy-associated plasma protein A (PAPP-A) together with alpha-fetoprotein (AFP) in the second trimester. MAIN OUTCOME MEASURES: Detection and false-positive rates for screening with a threshold risk of 1 in 200 at term, and the detection rate achieved for a false-positive rate of 2%. RESULTS: Published distributional models for Down's syndrome were inconsistent with the test data. When these test data were classified using these models, screening performance deteriorated substantially through the addition of repeated measures. This contradicts the very optimistic results obtained from predictive modelling of performance. Simplified distributional assumptions showed some evidence of benefit from the use of repeated measures of PAPP-A but not for repeated measures of uE3 or hCG. Each of the two test data sets was used to create new parameter estimates against which screening test performance was assessed using the other data set. The results were equivocal but there was evidence suggesting improvement in screening performance through the use of repeated measures of PAPP-A when the first trimester sample was collected before 13 weeks' gestation. A Bayesian analysis of the combined data from the two test data sets showed that adding a second trimester repeated measurement of PAPP-A to the base test increased detection rates and reduced false-positive rates. The benefit decreased with increasing gestational age at the time of the first sample. There was no evidence of any benefit from repeated measures of hCG or uE3. CONCLUSIONS: If realised, a reduction of 1% in false-positive rate with no loss in detection rate would give important benefits in terms of health service provision and the large number of invasive tests avoided. The Bayesian analysis, which shows evidence of benefit, is based on strong distributional assumptions and should not be regarded as confirmatory. The evidence of potential benefit suggests the need for a prospective study of repeated measurements of PAPP-A with samples from early in the first trimester. A formal clinical effectiveness and cost-effectiveness analysis should be undertaken. This study has shown that the established modelling methodology for assessing screening performance may be optimistically biased and should be interpreted with caution.

Mini-clinical evaluation exercise in anaesthesia training.

BACKGROUND: The Mini-Clinical Evaluation Exercise (Mini-CEX) is a workplace-based assessment tool of potential value in anaesthesia to assess and improve clinical performance. Its reliability and positive educational impact have been reported in other specialities, but not, to date, in anaesthesia. In this study, we evaluated the psychometric characteristics, logistics of application, and impact on the quality of supervision of the Mini-CEX in anaesthesia training. METHODS: A Mini-CEX encounter consisted of a single specialist anaesthetist observing a trainee over a defined period of time, completing an online Mini-CEX form with the trainee, and providing written and verbal feedback. We sought trainee and supervisor perspectives on its value and ease of use and used Generalizability Theory to estimate reliability. RESULTS: We collected 331 assessments from 61 trainees and 58 assessors. Survey responses strongly supported the positive effect of the Mini-CEX on feedback, its relative feasibility, and acceptance as a potential assessment tool. In this cohort, we found variable assessor stringency and low trainee variation. However, a feasible sample of cases and assessors would produce sufficiently precise scores to decide that performance was satisfactory for each trainee with 95% confidence. To generate scores that could discriminate sufficiently between trainees to allow ranking, a much larger sample of cases would be needed. CONCLUSIONS: The Mini-CEX in anaesthesia has strengths and weaknesses. Strengths include: its perceived very positive educational impact and its relative feasibility. Variable assessor stringency means that large numbers of assessors are required to produce reliable scores.

Maternal and biochemical predictors of antepartum stillbirth among nulliparous women in relation to gestational age of fetal death.

OBJECTIVE: To determine whether maternal serum levels of alphafetoprotein (alpha-FP) and human chorionic gonadotrophin (hCG) at 15-21 weeks provided clinically useful prediction of stillbirth in first pregnancies. DESIGN: Retrospective study of record linkage of a regional serum screening laboratory to national registries of pregnancy outcome and perinatal death. SETTING: West of Scotland, 1992-2001. POPULATION: A total of 84,769 eligible primigravid women delivering an infant at or beyond 24 weeks of gestation. METHODS: The risk of stillbirth between 24 and 43 weeks was assessed using the Cox proportional hazards model. Logistic regression models within gestational windows were then used to estimate predicted probability. Screening performance was assessed as area under the receiver operating characteristic (ROC) curve. MAIN OUTCOME MEASURE: Antepartum stillbirth unrelated to congenital abnormality. RESULTS: The odds ratio (95% CI) for stillbirth at 24-28 weeks for women in the top 1% were 11.97 (5.34-26.83) for alpha-FP and 5.80 (2.19-15.40) for hCG. The corresponding odds ratios for stillbirth at or after 37 weeks were 2.44 (0.74-8.10) and 0.79 (0.11-5.86), respectively. Adding biochemical to maternal data increased the area under the ROC curve from 0.66 to 0.75 for stillbirth between 24 and 28 weeks but only increased it from 0.64 to 0.65 for stillbirth at term and post-term. Women in the top 5% of predicted risk had a positive likelihood ratio of 7.8 at 24-28 weeks, 3.7 at 29-32 weeks, 5.1 at 33-36 weeks and 3.4 at 37-43 weeks, and the corresponding positive predictive values were 0.97, 0.33, 0.47 and 0.63%, respectively. CONCLUSIONS: Maternal serum levels of alpha-FP and hCG were statistically associated with stillbirth risk. However, the predictive ability was generally poor except for losses at extreme preterm gestations, where prevention may be difficult and interventions have the potential to cause significant harm.

Second-trimester levels of pregnancy-associated plasma protein-A and free beta-hCG in pregnancies with trisomy 13.

OBJECTIVE: To examine the levels of free beta-human chorionic gonadotrophin (free beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in second-trimester maternal serum from pregnancies affected by trisomy 13 and compare these with the known reduced levels of these markers in first-trimester cases in an attempt to better understand the pathophysiology of changes in marker levels in chromosomally abnormal pregnancies between the first and second trimester. METHODS: Using the Kryptor immunoassay system, we measured free beta-hCG and PAPP-A in 32 singleton pregnancies affected by trisomy 13 between 14 and 20 weeks of gestation. Using medians established in a previous study, these results were compared against 450 normal singleton pregnancies over the same gestational range. The data were combined with data from 82 cases of trisomy 13 previously examined in the first trimester (11-13 weeks) and an analysis of analyte trend was performed. RESULTS: The median free beta-hCG in multiples of the appropriate gestational median (MoM) in the second-trimester samples was not significantly different from the controls (1.15 (95% CI 0.827-1.651) vs 1.00). The median PAPP-A MoM in the second-trimester samples was significantly lower (p<0.001) than in controls (0.25 (95% CI 0.164-0.373) vs 1.00). Seventy-eight percent of cases were below the 5th centile of normal for PAPP-A. The combined cases in the first trimester had a median free beta-hCG MoM of 0.58 (95% CI 0.454-0.668) and a median PAPP-A MoM of 0.26 (95% CI 0.218-0.320). For PAPP-A, there was no significant change in median across the gestational period of 11 to 20 weeks, whilst for free beta-hCG, there was a significant increase with gestation (r=0.458, p<0.001). CONCLUSIONS: Although PAPP-A levels are reduced in trisomy 13 pregnancies in the second trimester, this isolated lower marker value is unlikely to be of value in screening for trisomy 13 in the second trimester. The aetiology of reduced levels of PAPP-A in cases with trisomy 13 may be similar to that in cases with trisomy 18, but different from that in cases with trisomy 21 since the temporal pattern in trisomies 13 and 18 are different from that in trisomy 21.