Women's experiences of being invited to participate in a case-control study of stillbirth - findings from the Midlands and North of England Stillbirth Study.

BACKGROUND: The Midlands and North of England Stillbirth Study (MiNESS) was a case-control study of women who had a stillbirth or who had an ongoing pregnancy. During the set up phase questions were raised about whether interviewing women within six weeks of a stillbirth and recruiting women who were still pregnant into a "stillbirth" study was acceptable. This led to the research questions "whether it is appropriate to ask women who have recently experienced a stillbirth to participate in research?" and "whether it is appropriate to ask pregnant women to participate in a research project looking at factors associated with stillbirth." This nested study aimed to describe the opinions of women approached to participate in MiNESS to explore their views and experiences of a research project focussed on stillbirth. METHODS: Semi- structured interviews were conducted at a single study site involved in MiNESS. Purposive sampling was used to obtain a sample of women who were approached following a stillbirth (case n = 6) and those who were approached during pregnancy who gave birth to a live born baby (control n = 6). These two groups of women were divided equally according to whether they participated in the main MiNESS questionnaire study and those who declined to do so (n = 3 in each group). Interview data were transcribed and analysed using thematic analysis to identify the most important factors in determining whether women participated in MiNESS. RESULTS: The following themes emerged from the analysis: participants' understanding of research; approach by researcher; wanting to help; stillbirth taboo. These themes are explored individually in the manuscript. Participants reported positive views about research and previous participation in research studies. Respondents valued an initial approach from a member of staff already known to them. The taboo around stillbirth was a barrier to participation for some women with ongoing pregnancies. CONCLUSIONS: Experiences and views regarding research differed between participants and non-participants in the MiNESS study. Participants reported a greater understanding of the importance and implications of clinical research. When designing future studies, the timing of approach, clarity of information and the person approaching potential participants should be considered to optimise recruitment. TRIAL REGISTRATION: NCT02025530 date registered: 01/01/2014.

Alterations in maternally perceived fetal movement and their association with late stillbirth: findings from the Midland and North of England stillbirth case-control study.

OBJECTIVE: To report perception of fetal movements in women who experienced a stillbirth compared with controls at a similar gestation with a live birth. DESIGN: Case-control study. SETTING: 41 maternity units in the UK. PARTICIPANTS: Cases were women who had a late stillbirth ≥28 weeks gestation (n=291) and controls were women with an ongoing pregnancy at the time of the interview (n=733). Controls were frequency matched to cases by obstetric unit and gestational age. METHODS: Data were collected using an interviewer-administered questionnaire which included questions on maternal perception of fetal movement (frequency, strength, increased and decreased movements and hiccups) in the 2 weeks before the interview/stillbirth. Five fetal movement patterns were identified incorporating the changes in strength and frequency in the last 2 weeks by combining groups of similar pattern and risk. Multivariable analysis adjusted for known confounders. PRIMARY OUTCOME MEASURE: Association of maternally perceived fetal movements in relation to late stillbirth. RESULTS: In multivariable analyses, women who reported increased strength of movements in the last 2 weeks had decreased risk of late stillbirth compared with those whose movements were unchanged (adjusted OR (aOR) 0.18, 95% CI 0.13 to 0.26). Women with decreased frequency (without increase in strength) of fetal movements were at increased risk (aOR 4.51, 95% CI 2.38 to 8.55). Daily perception of fetal hiccups was protective (aOR 0.31, 95% CI 0.17 to 0.56). CONCLUSIONS: Increased strength of fetal movements and fetal hiccups is associated with decreased risk of stillbirth. Alterations in frequency of fetal movements are important in identifying pregnancies at increased risk of stillbirth, with the greatest risk in women noting a reduction in fetal activity. Clinical guidance should be updated to reflect that increase in strength and frequency of fetal movements is associated with the lowest risk of stillbirth, and that decreased fetal movements are associated with stillbirth. TRIAL REGISTRATION NUMBER: NCT02025530.

Outcomes of pregnancy in patients with known Budd-Chiari syndrome.

AIM: To analyse the risk of pregnancy (a prothrombotic state) in patients with Budd-Chiari Syndrome (BCS). METHODS: Retrospective study of pregnancy in women with known BCS at single center from January 2001 to December 2015. RESULTS: Out of 53 females with BCS, 7 women had 16 pregnancies. Median age at diagnosis of BCS in these women was 25 years (range 21-34 years). At least one causal factor for BCS was identified in 6 women (86%). Six women had undergone radiological decompressive treatment. All patients had anticoagulation. Six fetuses were lost before 20 wk gestation in 2 women. There were 9 deliveries over 32 wk gestation and one delivery at 27 wk. All infants did well. Seven babies were born by emergency caesarean section. There were no cases of thrombosis. Two patients had notable vaginal (PV) bleeding in 3 pregnancies. None of the patients had variceal haemorrhage. Two patients were diagnosed with pulmonary hypertension, one during pregnancy and the other in the post-partum period. There was no maternal mortality. CONCLUSION: Maternal outcomes in patients with treated BCS are favourable and fetal outcomes beyond 20 wk gestation are good. There has been increased rate of caesarean section. Pulmonary hypertension is an important finding that needs further validation. These patients should be managed in centers experienced in treating high-risk pregnancies.

An unsettled bargain? Mothers' perceptions of justice and fairness in paid work.

Mothers' return to work following childbirth is widely recognized as a key stage in establishing employment arrangements that disadvantage them in the long run. This article investigates why mothers accept these unequal arrangements using data from a qualitative study of 109 Australian mothers. It focuses on mothers' perceptions of the fairness and justice of the flexibility of arrangements they commonly enter into upon return to work. The article draws attention to the importance of different justice frameworks, distributive, procedural and interactional, in understanding women's acceptance of gender inequality in paid work. The results indicate that most mothers view their workplace arrangements as fair, consistent with a distributive justice framework. Many women also place great importance on interactional justice, particularly in their experiences in negotiating flexibility. The article also identifies differences across employment type with women in jobs with career prospects more likely to invoke interactional justice frameworks than women in jobs with few career prospects.

The benefits of paid maternity leave for mothers' post-partum health and wellbeing: Evidence from an Australian evaluation.

This paper investigates the health effects of the introduction of a near universal paid parental leave (PPL) scheme in Australia, representing a natural social policy experiment. Along with gender equity and workforce engagement, a goal of the scheme (18 weeks leave at the minimum wage rate) was to enhance the health and wellbeing of mothers and babies. Although there is evidence that leave, especially paid leave, can benefit mothers' health post-partum, the potential health benefits of implementing a nationwide scheme have rarely been investigated. The data come from two cross-sectional surveys of mothers (matched on their eligibility for paid parental leave), 2347 mother's surveyed pre-PPL and 3268 post-PPL. We investigated the scheme's health benefits for mothers, and the extent this varied by pre-birth employment conditions and job characteristics. Overall, we observed better mental and physical health among mothers after the introduction of PPL, although the effects were small. Post-PPL mothers on casual (insecure) contracts before birth had significantly better mental health than their pre-PPL counterparts, suggesting that the scheme delivered health benefits to mothers who were relatively disadvantaged. However, mothers on permanent contracts and in managerial or professional occupations also had significantly better mental and physical health in the post-PPL group. These mothers were more likely to combine the Government sponsored leave with additional, paid, employer benefits, enabling a longer paid leave package post-partum. Overall, the study provides evidence that introducing paid maternity leave universally delivers health benefits to mothers. However the modest 18 week PPL provision did little to redress health inequalities.

Timing of Return to Work and Breastfeeding in Australia.

OBJECTIVE: To examine the effects of timing of return to work, number of hours worked, and their interaction, on the likelihood of breastfeeding at 6 months and predominant breastfeeding at 16 weeks. METHODS: A nationally representative sample of Australian mothers in paid employment in the 13 months before giving birth (n = 2300) were surveyed by telephone. Four multivariate logistic regression models were used to analyze the effects of timing of return to work and work hours, independently and in interaction, on any breastfeeding at 6 months and on predominant breastfeeding at 16 weeks, controlling for maternal sociodemographics, employment patterns, and health measures. RESULTS: Mothers who returned to work within 6 months and who worked for ≥20 hours per week were significantly less likely than mothers who had not returned to work to be breastfeeding at 6 months. However, returning to work for ≤19 hours per week had no significant impact on the likelihood of breastfeeding regardless of when mothers returned to work. Older maternal age, higher educational attainment, better physical or mental health, managerial or professional maternal occupation, and being self-employed all significantly contributed to the increased likelihood of any breastfeeding at 6 months. Similar patterns exist for predominant breastfeeding at 16 weeks. CONCLUSIONS: The effects of timing of return to work are secondary to the hours of employment. Working ≤19 hours per week is associated with higher likelihood of maintaining breastfeeding, regardless of timing of return to work.

How do rural placements affect urban-based Australian junior doctors' perceptions of working in a rural area?

Objectives The aim of the present study was to provide qualitative insights from urban-based junior doctors (graduation to completion of speciality training) of the effect of rural placements and rotations on career aspirations for work in non-metropolitan practices. Methods A qualitative study was performed of junior doctors based in Adelaide, Brisbane and Melbourne. Individual face-to-face or telephone semistructured interviews were held between August and October 2014. Thematic analysis focusing on participants' experience of placements and subsequent attitudes to rural practice was undertaken. Results Most participants undertook rural placements in the first 2 years after graduation. Although experiences varied, positive perceptions of placements were consistently linked with the degree of supervision and professional support provided. These experiences were linked to attitudes about working outside metropolitan areas. Participants expressed concerns about being 'forced' to work in non-metropolitan hospitals in their first postgraduate year; many received little warning of the location or clinical expectations of the placement, causing anxiety and concern. Conclusions Adequate professional support and supervision in rural placements is essential to encourage junior doctors' interests in rural medicine. Having a degree of choice about placements and a positive and supported learning experience increases the likelihood of a positive experience. Doctors open to working outside a metropolitan area should be preferentially allocated an intern position in a non-metropolitan hospital and rotated to more rural locations. What is known about the topic? The maldistribution of the Australian medical workforce has led to the introduction of several initiatives to provide regional and rural experiences for medical students and junior doctors. Although there have been studies outlining the effects of rural background and rural exposure on rural career aspirations, little research has focused on what hinders urban-trained junior doctors from pursuing a rural career. What does this paper add? Exposure to medical practice in regional or rural areas modified and changed the longer-term career aspirations of some junior doctors. Positive experiences increased the openness to and the likelihood of regional or rural practice. However, junior doctors were unlikely to aspire to non-metropolitan practice if they felt they had little control over and were unprepared for a rural placement, had a negative experience or were poorly supported by other clinicians or health services. What are the implications for practitioners? Changes to the process of allocating junior doctors to rural placements so that the doctors felt they had some choice, and ensuring these placements are well supervised and supported, would have a positive impact on junior doctors' attitudes to non-metropolitan practice.

iVAX: An integrated toolkit for the selection and optimization of antigens and the design of epitope-driven vaccines.

Computational vaccine design, also known as computational vaccinology, encompasses epitope mapping, antigen selection and immunogen design using computational tools. The iVAX toolkit is an integrated set of tools that has been in development since 1998 by De Groot and Martin. It comprises a suite of immunoinformatics algorithms for triaging candidate antigens, selecting immunogenic and conserved T cell epitopes, eliminating regulatory T cell epitopes, and optimizing antigens for immunogenicity and protection against disease. iVAX has been applied to vaccine development programs for emerging infectious diseases, cancer antigens and biodefense targets. Several iVAX vaccine design projects have had success in pre-clinical studies in animal models and are progressing toward clinical studies. The toolkit now incorporates a range of immunoinformatics tools for infectious disease and cancer immunotherapy vaccine design. This article will provide a guide to the iVAX approach to computational vaccinology.

Diagnostic accuracy of routine antenatal determination of fetal RHD status across gestation: population based cohort study.

OBJECTIVES: To assess the accuracy of fetal RHD genotyping using cell-free fetal DNA in maternal plasma at different gestational ages. DESIGN: A prospective multicentre cohort study. SETTING: Seven maternity units in England. PARTICIPANTS: RhD negative pregnant women who booked for antenatal care before 24 weeks' gestation. INTERVENTIONS: Women who gave consent for fetal RHD genotyping had blood taken at the time of booking for antenatal care and, when possible, at other routine visits such as for Down's syndrome screening between 11 and 21 weeks' gestation, at the anomaly scan at 18-21 weeks, and in the third trimester when blood was taken for the routine antibody check. The results of cord blood analysis, done routinely in RhD negative pregnancies, were also obtained to confirm the fetal RHD genotyping. MAIN OUTCOME MEASURES: The accuracy of fetal RHD genotyping compared with RhD status predicted by cord blood serology. RESULTS: Up to four analyses per woman were performed in 2288 women, generating 4913 assessable fetal results. Sensitivity for detection of fetal RHD positivity was 96.85% (94.95% to 98.05%), 99.83% (99.06% to 99.97%), 99.67% (98.17% to 99.94%), 99.82% (98.96% to 99.97%), and 100% (99.59% to 100%) at <11, 11-13, 14-17, 18-23, and >23 completed weeks' gestation, respectively. Before 11 weeks' gestation 16/865 (1.85%) babies tested were falsely predicted as RHD negative. CONCLUSIONS: Mass throughput fetal RHD genotyping is sufficiently accurate for the prediction of RhD type if it is performed from 11 weeks' gestation. Testing before this time could result in a small but significant number of babies being incorrectly classified as RHD negative. These mothers would not receive anti-RhD immunoglobulin, and there would be a risk of haemolytic disease of the newborn in subsequent pregnancies.

The Midland and North of England Stillbirth Study (MiNESS).

BACKGROUND: The United Kingdom has one of the highest rates of stillbirth in Europe, resulting in approximately 4,000 stillbirths every year. Potentially modifiable risk factors for late stillbirths are maternal age, obesity and smoking, but the population attributable risk associated with these risk factors is small.Recently the Auckland Stillbirth Study reported that maternal sleep position was associated with late stillbirth. Women who did not sleep on their left side on the night before the death of the baby had double the risk compared with sleeping on other positions. The population attributable risk was 37%. This novel observation needs to be replicated or refuted. METHODS/DESIGN: Case control study of late singleton stillbirths without congenital abnormality. Controls are women with an ongoing singleton pregnancy, who are randomly selected from participating maternity units booking list of pregnant women, they are allocated a gestation for interview based on the distribution of gestations of stillbirths from the previous 4 years for the unit. The number of controls selected is proportional to the number of stillbirths that occurred at the hospital over the previous 4 years. DATA COLLECTION: Interviewer administered questionnaire and data extracted from medical records. SAMPLE SIZE: 415 cases and 830 controls. This takes into account a 30% non-participation rate, and will detect an OR of 1.5 with a significance level of 0.05 and power of 80% for variables with a prevalence of 57%, such as non-left sleeping position. STATISTICAL ANALYSIS: Mantel-Haenszel odds ratios and unconditional logistic regression to adjust for potential confounders. DISCUSSION: The hypotheses to be tested here are important, biologically plausible and amenable to a public health intervention. Although this case-control study cannot prove causation, there is a striking parallel with research relating to sudden infant death syndrome, where case-control studies identified prone sleeping position as a major modifiable risk factor. Subsequently mothers were advised to sleep babies prone ("Back to Sleep" campaign), which resulted in a dramatic drop in SIDS. This study will provide robust evidence to help determine whether such a public health intervention should be considered. TRIAL REGISTRATION NUMBER: NCT02025530.

Cost-effective non-surgical treatment of chronic pressure ulcers in the community.

The Salisbury Pressure Ulcer Outreach Service successfully treats patients with chronic pressure ulcers that have not healed during routine community treatment. These patients have grade 4 pressure ulcers, involving extensive destruction, or damage to muscle and bone. A combination of scientific, seating and tissue viability expertise with a holistic approach results in non-surgical healing for 70% of patients. For those who still require surgery, outcomes are more successful with this approach, resulting in low recurrence rates. Prior to creation of the outreach service, patients were referred directly for surgical closure, resulting in high recurrence levels and long waiting lists. The authors compared costs of the Pressure Ulcer Outreach Service with the previous system of surgical closure. The model base case found that the Pressure Ulcer Outreach Service saved £8588 per patient, and that cost savings could be even greater if the outreach service was extended into preventative work.

Optimization of microCT imaging and blood vessel diameter quantitation of preclinical specimen vasculature with radiopaque polymer injection medium.

Vascular networks within a living organism are complex, multi-dimensional, and challenging to image capture. Radio-angiographic studies in live animals require a high level of infrastructure and technical investment in order to administer costly perfusion mediums whose signals metabolize and degrade relatively rapidly, diminishing within a few hours or days. Additionally, live animal specimens must not be subject to long duration scans, which can cause high levels of radiation exposure to the specimen, limiting the quality of images that can be captured. Lastly, despite technological advances in live-animal specimen imaging, it is quite difficult to minimize or prevent movement of a live animal, which can cause motion artifacts in the final data output. It is demonstrated here that through the use of postmortem perfusion protocols of radiopaque silicone polymer mediums and ex-vivo organ harvest, it is possible to acquire a high level of vascular signal in preclinical specimens through the use of micro-computed tomographic (microCT) imaging. Additionally, utilizing high-order rendering algorithms, it is possible to further derive vessel morphometrics for qualitative and quantitative analysis.

T cell epitope: friend or foe? Immunogenicity of biologics in context.

Like vaccines, biologic proteins can be very immunogenic for reasons including route of administration, dose frequency and the underlying antigenicity of the therapeutic protein. Because the impact of immunogenicity can be quite severe, regulatory agencies are developing risk-based guidelines for immunogenicity screening. T cell epitopes are at the root of the immunogenicity issue. Through their presentation to T cells, they activate the process of anti-drug antibody development. Preclinical screening for T cell epitopes can be performed in silico, followed by in vitro and in vivo validation. Importantly, screening for immunogenicity is complicated by the discovery of regulatory T cell epitopes, which suggests that immunogenicity testing must now take regulatory T cells into consideration. In this review, we address the application of computational tools for preclinical immunogenicity assessment, the implication of the discovery of regulatory T cell epitopes, and experimental validation of those assessments.

Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis.

BACKGROUND: Women with twin pregnancy are at high risk for spontaneous preterm delivery. Progesterone seems to be effective in reducing preterm birth in selected high-risk singleton pregnancies, albeit with no significant reduction in perinatal mortality and little evidence of neonatal benefit. We investigated the use of progesterone for prevention of preterm birth in twin pregnancy. METHODS: In this double-blind, placebo-controlled trial, 500 women with twin pregnancy were recruited from nine UK National Health Service clinics specialising in the management of twin pregnancy. Women were randomised, by permuted blocks of randomly mixed sizes, either to daily vaginal progesterone gel 90 mg (n=250) or to placebo gel (n=250) for 10 weeks from 24 weeks' gestation. All study personnel and participants were masked to treatment assignment for the duration of the study. The primary outcome was delivery or intrauterine death before 34 weeks' gestation. Analysis was by intention to treat. Additionally we undertook a meta-analysis of published and unpublished data to establish the efficacy of progesterone in prevention of early (<34 weeks' gestation) preterm birth or intrauterine death in women with twin pregnancy. This study is registered, number ISRCTN35782581. FINDINGS: Three participants in each group were lost to follow-up, leaving 247 analysed per group. The combined proportion of intrauterine death or delivery before 34 weeks of pregnancy was 24.7% (61/247) in the progesterone group and 19.4% (48/247) in the placebo group (odds ratio [OR] 1.36, 95% CI 0.89-2.09; p=0.16). The rate of adverse events did not differ between the two groups. The meta-analysis confirmed that progesterone does not prevent early preterm birth in women with twin pregnancy (pooled OR 1.16, 95% CI 0.89-1.51). INTERPRETATION: Progesterone, administered vaginally, does not prevent preterm birth in women with twin pregnancy. FUNDING: Chief Scientist Office of the Scottish Government Health Directorate.

PLUTO trial protocol: percutaneous shunting for lower urinary tract obstruction randomised controlled trial.

OBJECTIVES: The primary objective is to determine whether intrauterine vesicoamniotic shunting for fetal bladder outflow obstruction, compared with conservative, noninterventional care, improves prenatal and perinatal mortality and renal function. The secondary objectives are to determine if shunting for fetal bladder outflow obstruction improves perinatal morbidity, to determine if improvement in outcomes is related to prognostic assessment at diagnosis and, if possible, derive a prognostic risk index and to determine the safety and long-term efficacy of shunting. DESIGN: A multicentre randomised controlled trial (RCT). SETTING: Fetal medicine units. POPULATION: Pregnant women with singleton, male fetus with isolated lower urinary tract obstruction (LUTO). METHODS: Following ultrasound diagnosis of LUTO in a male fetus and exclusion of other structural and chromosomal anomalies, participation in the trial will be discussed with the mother and written information given. Consent for participation in the trial will be taken and the mother randomised via the internet to either insertion of a vesicoamniotic shunt or expectant management. During pregnancy, both groups will be followed with regular ultrasound scans looking at viability, renal measurements and amniotic fluid volume. Following delivery, babies will be followed up by paediatric nephrologists/urologists at 4-6 weeks, 12 months and 3 and 5 years to assess renal function via serum creatinine, renal ultrasound and need for dialysis/transplant. MAIN OUTCOME MEASURES: The main outcome measures will be perinatal mortality rates and renal function at 4-6 weeks and 12 months measured via serum creatinine, renal ultrasound and need for dialysis/transplant. FUNDING: Wellbeing of Women. ESTIMATED COMPLETION DATE: September 2010. TRIAL ALGORITHM: [flowchart: see text].

The Birmingham Registry for Twin and Heritability Studies (BiRTHS).

In this article we present the protocol of the Birmingham Registry for Twin Heritability Studies (BiRTHS), which aims to establish a long-term prospective twin registry with twins identified from the antenatal period and subjected to detailed follow-up. We plan to investigate the concordance in anthropometrics and early childhood phenotypes between 66 monozygotic and 154 dizygotic twin pairs in the first 2 years of recruitment. In this project we plan to determine the relative contributions of heritability and environment to fetal growth, birth size, growth in infancy and development up to 2 years of age in an ethnically mixed population. Twins will be assessed with the Griffitth's Mental Development Scales, which will enable us to obtain detailed information on development. As maternal depression may have an effect on the twins' neurodevelopment, the Edinburgh Postnatal Depression Scale will be used at various stages during pregnancy and after delivery to assess maternal depressive symptoms. The increasing prevalence of obesity in both adults and children has raised concerns about the effect of maternal obesity in pregnancy on fetal growth. The prospective study design gives us the opportunity to obtain data on maternal nutrition (reflected by body mass index) and ante- and postnatal growth and development of twins.

Developing an epitope-driven tuberculosis (TB) vaccine.

Epitope-driven vaccines are created from selected sub-sequences of proteins, or epitopes, derived by scanning the protein sequences of pathogens for patterns of amino acids that permit binding to human MHC molecules. We developed a prototype tuberculosis (TB) vaccine that contains epitopes derived by (1) EpiMer mapping of previously published secreted proteins derived from Mycobacterium tuberculosis (Mtb), and (2) EpiMatrix mapping of selected Mtb genome open reading frames (ORFs). Each of the epitopes contains at least three distinct class II MHC binding motif matches. These Mtb epitope selections were validated by measuring T cell responses from peripheral blood mononuclear cells (PBMC) obtained from healthy, asymptomatic tuberculin skin test-positive donors. Twenty-four validated Mtb epitopes were selected for inclusion in a DNA plasmid vector. We immunized HLA-DR B*0101 transgenic mice with this vaccine prototype augmented by co-administration of rIL-15. Following administration of three immunizations at 14-day intervals in conjunction with rIL-15, epitope-specific T cell responses were observed to eight of the 24 epitopes contained in the DNA construct, one week following the last injection. The systematic application of bioinformatics tools to whole genomes, in combination with in vitro methods for screening and confirming epitopes, may lead to the development of novel vaccines for infectious diseases like TB.