Sequential testing strategies in prenatal screening for down's syndrome

Down’s syndrome is a classic chromosomal disorder with an incidence rate of one in every 750 live births. Early detection of Down’s syndrome pregnancies through screening will provide the option of early termination of pregnancy and better obstetric care to women with affected pregnancies. Some of the screening policies which have been implemented in the UK are second trimester double, triple or quadruple marker tests, first trimester combined ultrasound and biochemical (CUB) screening, and integrated screening. Screening performance can be optimized by applying appropriate correction factors for variables such as maternal smoking, ethnicity and assisted conception. Typical screening performance is around 70% detection of Down’s syndrome pregnancies at a 5% false positive rate for second trimester quadruple marker screening, 90% detection at a 5% false positive rate for CUB screening and 90% detection at a 1-2% false positive rate for integrated screening. The NHS Fetal Anomaly Screening Programme Committee has set a current performance target for Down’s syndrome screening of at least 75% detection at a 3% or lower false positive rate and this can be achieved by CUB or integrated testing by setting a threshold (cut-off) risk of 1 in 150 at term. However, further improvements in performance proposed by the Committee to meet a detection rate of 90% at a false positive rate of 2% or less are unlikely to be reached by single stage testing, and protocols which include some element of sequential testing are required. The Health Technology Assessment Programme is currently reviewing two new approaches to screening, namely, repeated measure and cross trimester testing to evaluate their potential to meet the more challenging standard. In the present study, using various combinations of maternal serum marker and ultrasound measurements, several screening strategies and refinements are explored to establish their potential for improving detection rates and reducing false positive rates in Down’s syndrome screening. Extensive use has been made of routinely collected screening data from the west of Scotland Regional Screening programme for retrospective analysis using standard Gaussian methods, statistical modeling and SPSS and S-PLUS statistical software. The performance of within- and across-trimester contingent screening programmes have been evaluated and the effects of ethnicity, maternal smoking habit and assisted reproductive technology (ART) on screening markers has been assessed using first and second trimester samples. Screening within the first trimester The standard approach to CUB screening is to carry out maternal serum marker measurements (PAPP-A and fβhCG) and ultrasound Nuchal Translucency measurements at 11-13+6 weeks of gestation. This study had also shown that in the CUB screened population in the west of Scotland, adopting a within-trimester contingent screening protocol where all women have serum marker testing but only those women with intermediate risks from the serum markers are offered NT, would have achieved a detection rate of 88.7% at a false positive rate of 5.8% with 29% of women requiring an NT measurement. Using LMP based gestational age this screening protocol would have achieved a detection rate of 83.3% at a false positive rate of 7.4% with 25.9% of women requiring an NT measurement. When analysis was performed only on pregnancies with certain LMP dates, the contingent screening protocol would have achieved a detection rate of 88.9% at a false positive rate of 7.0% with 25.3% of women requiring an NT measurement. Where ultrasound resources are scarce within-trimester contingent screening has the potential to maintain screening performance whilst reducing the number of NT scans required. Across –trimester screening Evidence suggests that sequential testing strategies can improve screening performance. This has been explored in this study by statistical modelling using S-PLUS. Various combinations of markers were tested. It was estimated that optimal performance could be achieved by a cross-trimester contingent screening protocol with repeat measures of PAPP-A (NT, PAPP-A, fβhCG in the first trimester followed by AFP, hCG, InhA, uE3, PAPP-A in the second trimester in a sub-set of women with intermediate risks). This could achieve a detection rate of 92.2% at a false positive rate of 1.4% but with only 9.7% of women requiring a second trimester screening test. This meets the aspirational performance standard proposed by the UK NSC. Without NT measurements (i.e. serum only screening), the model indicates that this screening protocol would achieve a detection rate of 86.2% at a false positive rate of 3.0% with 22.3% of women requiring a second trimester screening test. Therefore, the inclusion of NT measurement at the first stage of testing is necessary to achieve the desired performance. The Effects of Smoking and Ethnicity Many maternal and pregnancy factors are known to affect serum marker concentrations and small but useful improvements in screening performance can be made by correcting for these. Changes however, vary between trimesters and in this study paired first and second trimester samples have been used to measure the changes in serum marker levels in smokers and between different ethnic groups at each stage of pregnancy. In this study, the AFP level in smokers was increased in the first trimester by 16.3% when compared with the non-smokers. The hCG level in smokers was decreased by 27.6% and 30.5% in the first and second trimesters respectively. The fβhCG level was decreased in smokers in the second trimester by 17.1% when compared with non-smokers. The PAPP-A level was decreased by 14% and 22.8% in first and second trimesters respectively when compared with non-smokers. These results demonstrate that the effect of smoking is gestation dependant and without appropriate correction factors being applied, these serum marker changes would result in inappropriate risks being estimated for individual women. The study on the effect of ethnicity on screening markers has shown that South Asian women had higher hCG levels in the first trimester compared with Caucasian women. They also had lower fβhCG and PAPP-A in the second trimester. Oriental women had higher first and second trimester hCG levels when compared with Caucasian women. They also had higher fβhCG and PAPP-A levels in the first trimester. Middle East women had lower first trimester AFP when compared with Caucasian women. Black women had higher hCG in the first trimester when compared with Caucasian women. In Black women, the PAPP-A level was also elevated in both trimesters. While this study confirms that correction for ethnicity is clearly indicated, appropriate correction factors are difficult to derive as there is likely to be some variation in the classification of ethnicity between studies. Assisted Reproductive Technology The growing use of ART in developed countries and the variety of different methods employed make accurate correction factors desirable but difficult to derive. In this study, women pregnant after ART had larger NT measurements compared with women who had conceived spontaneously. The PAPP-A level was lower in the IVF or ICSI with fresh eggs group when compared with the controls. Among the ART treatment groups, the NT was higher in the IVF or ICSI with fresh eggs group when compared with the controls. The AFP level was higher in the IVF with donor’s egg group when compared with the controls. The hCG level was higher in the ART group overall when compared with the controls. Women pregnant after IVF or ICSI with fresh eggs and frozen eggs had higher hCG level. Smoking frequency, birthweight and prematurity In addition to its effects on serum marker concentrations, smoking in pregnancy is known to be associated with low birth weight and prematurity. It is important therefore that maternal smoking is accurately recorded on screening request forms and in this study, the accuracy of self reported smoking status was assessed by analysis of cotinine in serum. Results showed that the percentage of self-reported smokers (24.1%) at booking was significantly lower than the cotinine-validated estimate of 30.1%. Also, smoking was associated with low birth weight, delivery prior to 39 weeks, increased AFP level (3.1%) and reduced hCG level (28.7%) in the second trimester. An increasing AFP level (but not hCG level) was associated with lower birth weight and delivery prior to 39 weeks in both smokers and non smokers but the effect was most marked in smokers. The difference in birth weight between the highest and the lowest AFP category for non-smokers was 448.3g and for smokers was 619.2g, suggesting that smoking exacerbates the effect of an elevated AFP on birth weight. Overall the difference in birth weight between the lowest AFP category in non smokers and the highest AFP category in smokers was 931.6g. Summary In summary, this study has shown that a cross-trimester contingent screening protocol with repeat measures has the potential to meet the UK NSC aspirational standard of 90% detection of Down’s syndrome pregnancies with a screen positive rate of less than 2%. Around 90% of women would complete screening in the first trimester without the need for a second stage sequential test. Correcting for factors such as maternal smoking habits, ethnicity and ART would further improve screening performance. Also it has been shown that where ultrasound resources are scarce, within-trimester and across-trimester protocols can reduce the need for NT measurement in all women and still deliver excellent screening performance although this falls short of the higher performance standard. The potential of these new screening protocols now need to be tested in prospective multicentre trials to confirm their performance in prospective practice

Risk of postoperative acute kidney injury in patients undergoing orthopaedic surgery—development and validation of a risk score and effect of acute kidney injury on survival:observational cohort study

Funding: This study was funded by Tenovus Tayside, Chief Scientist Office, Scotland and a travelling fellowship from the Royal College of Physicians and Surgeons of Glasgow. The funders had no role in the study design; collection, analysis, and interpretation of the data; writing of the report; or the decision to submit the article for publication. The researchers are independent of the funders.Non peer reviewedPublisher PD

Factors associated with change in objectively measured physical activity in older people:data from the Physical Activity Cohort Scotland study

Abstract Background Cross-sectional relationships between physical activity and health have been explored extensively, but less is known about how physical activity changes with time in older people. The aim of this study was to assess baseline predictors of how objectively measured physical activity changes with time in older people. Methods Longitudinal cohort study using data from the Physical Activity Cohort Scotland. A sample of community-dwelling older people aged 65 and over were recruited in 2009–2011, then followed up 2–3 years later. Physical activity was measured using Stayhealthy RT3 accelerometers over 7 days. Other data collected included baseline comorbidity, health-related quality of life (SF-36), extended Theory of Planned Behaviour Questionnaire and Social Capital Module of the General Household Survey. Associations between follow-up accelerometer counts and baseline predictors were analysed using a series of linear regression models, adjusting for baseline activity levels and follow-up time. Results Follow up data were available for 339 of the original 584 participants. The mean age was 77 years, 185 (55%) were female and mean follow up time was 26 months. Mean activity counts fell by between 2% per year (age  80, deprivation decile 5–10) from baseline values. In univariate analysis age, sex, deprivation decile, most SF-36 domains, most measures of social connectedness, most measures from the extended Theory of Planned Behaviour, hypertension, diabetes mellitus, chronic pain and depression score were significantly associated with adjusted activity counts at follow-up. In multivariate regression age, satisfactory friend network, SF-36 physical function score, and the presence of diabetes mellitus were independent predictors of activity counts at follow up after adjustment for baseline count and duration of follow up. Conclusions Health status and social connectedness, but not extended Theory of Planned Behaviour measures, independently predicted changes in physical activity in community dwelling older people

Increased Mortality and Morbidity in Patients with Chronic Hypoparathyroidism:A population based study

A population based study was undertaken to determine the mortality and morbidity for people with hypoparathyroidism compared to the general population

Reliability of self reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study

Objective To determine what impact reliance on self reported smoking status during pregnancy has on both the accuracy of smoking prevalence figures and access to smoking cessation services for pregnant women in Scotland

Introducing NICE guidelines for intravenous fluid therapy into a district general hospital

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Photodynamic Diagnosis-guided Transurethral Resection of Bladder Tumour in Participants with a First Suspected Diagnosis of Intermediate- or High-risk Non–muscle-invasive Bladder Cancer : Cost-effectiveness Analysis Alongside a Randomised Controlled Trial

Funding/Support and role of the sponsor: The article processing charge was funded by the PHOTO project, which was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (11/142/02). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The funding body had no direct role in the study. Acknowledgments: This study is part of the PHOTO project. We thank the PHOTO team who contributed to the overall research project and are grateful to all the participants and facility staff who took part in the study.Peer reviewedPublisher PD

Provision of the progestogen-only pill by community pharmacies as bridging contraception for women receiving emergency contraception:the Bridge-it RCT

Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 27. See the NIHR Journals Library website for further project information.Peer reviewedPublisher PD

Use of effective contraception following provision of the progestogen-only pill for women presenting to community pharmacies for emergency contraception (Bridge-It):a pragmatic cluster-randomised crossover trial

BACKGROUND:Unless women start effective contraception after oral emergency contraception, they remain at risk of unintended pregnancy. Most women in the UK obtain emergency contraception from community pharmacies. We hypothesised that pharmacist provision of the progestogen-only pill as a bridging interim method of contraception with emergency contraception plus an invitation to a sexual and reproductive health clinic, in which all methods of contraception are available, would result in increased subsequent use of effective contraception. METHODS:We did a pragmatic cluster-randomised crossover trial in 29 UK pharmacies among women receiving levonorgestrel emergency contraception. Women aged 16 years or older, not already using hormonal contraception, not on medication that could interfere with the progestogen-only pill, and willing to give contact details for follow-up were invited to participate. In the intervention group, women received a 3-month supply of the progestogen-only pill (75 μg desogestrel) plus a rapid access card to a participating sexual and reproductive health clinic. In the control group, pharmacists advised women to attend their usual contraceptive provider. The order in which each pharmacy provided the intervention or control was randomly assigned using a computer software algorithm. The primary outcome was the use of effective contraception (hormonal or intrauterine) at 4 months. This study is registered, ISRCTN70616901 (complete). FINDINGS:Between Dec 19, 2017, and June 26, 2019, 636 women were recruited to the intervention group (316 [49·6%], mean age 22·7 years [SD 5·7]) or the control group (320 [50·3%], 22·6 years [5·1]). Three women (one in the intervention group and two in the control group) were excluded after randomisation. 4-month follow-up data were available for 406 (64%) participants, 25 were lost to follow-up, and two participants no longer wanted to participate in the study. The proportion of women using effective contraception was 20·1% greater (95% CI 5·2-35·0) in the intervention group (mean 58·4%, 48·6-68·2), than in the control group (mean 40·5%, 29·7-51·3 [adjusted for recruitment period, treatment group, and centre]; p=0·011).The difference remained significant after adjusting for age, current sexual relationship, and history of effective contraception use, and was robust to the effect of missing data (assuming missingness at random). No serious adverse events occurred. INTERPRETATION:Provision of a supply of the progestogen-only pill with emergency contraception from a community pharmacist, along with an invitation to a sexual and reproductive health clinic, results in a clinically meaningful increase in subsequent use of effective contraception. Widely implemented, this practice could prevent unintended pregnancies after use of emergency contraception. FUNDING:National Institute for Health Research (Health Technology Assessment Programme project 15/113/01)

Cardiovascular Effects of Switching from Tobacco Cigarettes to Electronic Cigarettes

The VESUVIUS (Vascular Effects of Regular Cigarettes Versus Electronic Cigarette Use) trial was funded by the British Heart Foundation (grant PG/15/64/31681); and supported by Immunoassay Biomarker Core Laboratory, University of Dundee, the Tayside Medical Sciences Centre, and the NHS Tayside Smoking Cessation Service. The funder had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or in the decision to submit for publication. Dr. Donnan has received research grants from AbbVie, Shire, and Gilead Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.Peer reviewedPublisher PD