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1.  Placental PHLDA2 expression is increased in cases of fetal growth restriction following reduced fetal movements 
BMC Medical Genetics  2016;17:17.
Background
Maternal perception of reduced fetal movements (RFM) is associated with increased risk of fetal growth restriction (FGR) and stillbirth, mediated by placental insufficiency. The maternally expressed imprinted gene PHLDA2 controls fetal growth, placental development and placental lactogen production in a mouse model. A number of studies have also demonstrated abnormally elevated placental PHLDA2 expression in human growth restricted pregnancies. This study examined whether PHLDA2 was aberrantly expressed in placentas of RFM pregnancies resulting in delivery of an FGR infant and explored a possible relationship between PHLDA2 expression and placental lactogen release from the human placenta.
Methods
Villous trophoblast samples were obtained from a cohort of women reporting RFM (N = 109) and PHLDA2 gene expression analysed. hPL levels were assayed in the maternal serum (N = 74).
Results
Placental PHLDA2 expression was significantly 2.3 fold higher in RFM pregnancies resulting in delivery of an infant with FGR (p < 0.01), with highest levels of PHLDA2 expression in the most severe cases. Placental PHLDA2 expression was associated with maternal serum hPL levels (r = −0.30, p = 0.008, n = 74) although this failed to reach statistical significance in multiple linear regression analysis controlling for birth weight (p = 0.07).
Conclusions
These results further highlight a role for placental PHLDA2 in poor perinatal outcomes, specifically FGR associated with RFM. Furthermore, this study suggests a potential relationship between placental PHLDA2 expression and hPL production by the placenta, an association that requires further investigation in a larger cohort.
Electronic supplementary material
The online version of this article (doi:10.1186/s12881-016-0279-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12881-016-0279-1
PMCID: PMC4779203  PMID: 26944942
Reduced fetal movements; Stillbirth; Fetal growth restriction; Placenta; PHLDA2
2.  Quantitative assessment of placental morphology may identify specific causes of stillbirth 
Background
Stillbirth is frequently the result of pathological processes involving the placenta. Understanding the significance of specific lesions is hindered by qualitative subjective evaluation. We hypothesised that quantitative assessment of placental morphology would identify alterations between different causes of stillbirth and that placental phenotype would be independent of post-mortem effects and differ between live births and stillbirths with the same condition.
Methods
Placental tissue was obtained from stillbirths with an established cause of death, those of unknown cause and live births. Image analysis was used to quantify different facets of placental structure including: syncytial nuclear aggregates (SNAs), proliferative cells, blood vessels, leukocytes and trophoblast area. These analyses were then applied to placental tissue from live births and stillbirths associated with fetal growth restriction (FGR), and to placental lobules before and after perfusion of the maternal side of the placental circulation to model post-mortem effects.
Results
Different causes of stillbirth, particularly FGR, cord accident and hypertension had altered placental morphology compared to healthy live births. FGR stillbirths had increased SNAs and trophoblast area and reduced proliferation and villous vascularity; 2 out of 10 stillbirths of unknown cause had similar placental morphology to FGR. Stillbirths with FGR had reduced vascularity, proliferation and trophoblast area compared to FGR live births. Ex vivo perfusion did not reproduce the morphological findings of stillbirth.
Conclusion
These preliminary data suggest that addition of quantitative assessment of placental morphology may distinguish between different causes of stillbirth; these changes do not appear to be due to post-mortem effects. Applying quantitative assessment in addition to qualitative assessment might reduce the proportion of unexplained stillbirths.
Electronic supplementary material
The online version of this article (doi:10.1186/s12907-016-0023-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12907-016-0023-y
PMCID: PMC4748636  PMID: 26865834
Stillbirth; Unexplained Stillbirth; Placental Morphometry; Fetal Growth Restriction; Villous vascularity; Avascular villi
3.  Systematic review to understand and improve care after stillbirth: a review of parents’ and healthcare professionals’ experiences 
Background
2.7 million babies were stillborn in 2015 worldwide; behind these statistics lie the experiences of bereaved parents. The first Lancet series on stillbirth in 2011 described stillbirth as one of the “most shamefully neglected” areas of public health, recommended improving interaction between families and frontline caregivers and made a plea for increased investment in relevant research.
Methods
A systematic review of qualitative, quantitative and mixed-method studies researching parents and healthcare professionals experiences of care after stillbirth in high-income westernised countries (Europe, North America, Australia and South Africa) was conducted. The review was designed to inform research, training and improve care for parents who experience stillbirth.
Results
Four thousand four hundred eighty eight abstracts were identified; 52 studies were eligible for inclusion. Synthesis and quantitative aggregation (meta-summary) was used to extract findings and calculate frequency effect sizes (FES%) for each theme (shown in italics), a measure of the prevalence of that finding in the included studies.
Researchers’ areas of interest may influence reporting of findings in the literature and result in higher FES sizes, such as; support memory making (53 %) and fathers have different needs (18 %). Other parental findings were more unexpected; Parents want increased public awareness (20 %) and for stillbirth care to be prioritised (5 %).
Parental findings highlighted lessons for staff; prepare parents for vaginal birth (23 %), discuss concerns (13 %), give options & time (20 %), privacy not abandonment (30 %), tailored post-mortem discussions (20 %) and post-natal information (30 %).
Parental and staff findings were often related; behaviours and actions of staff have a memorable impact on parents (53 %) whilst staff described emotional, knowledge and system-based barriers to providing effective care (100 %). Parents reported distress being caused by midwives hiding behind ‘doing’ and ritualising guidelines whilst staff described distancing themselves from parents and focusing on tasks as coping strategies.
Parents and staff both identified the need for improved training (parents 25 % & staff 57 %); continuity of care (parents 15 % & staff 36 %); supportive systems & structures (parents 50 %); and clear care pathways (parents 5 %).
Conclusions
Parents’ and healthcare workers’ experiences of stillbirth can inform training, improve the provision of care and highlight areas for future research.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-016-0806-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12884-016-0806-2
PMCID: PMC4727309  PMID: 26810220
Stillbirth; Bereavement; Care
4.  From grief, guilt pain and stigma to hope and pride – a systematic review and meta-analysis of mixed-method research of the psychosocial impact of stillbirth 
Background
Despite improvements in maternity healthcare services over the last few decades, more than 2.7 million babies worldwide are stillborn each year. The global health agenda is silent about stillbirth, perhaps, in part, because its wider impact has not been systematically analysed or understood before now across the world. Our study aimed to systematically review, evaluate and summarise the current evidence regarding the psychosocial impact of stillbirth to parents and their families, with the aim of improving guidance in bereavement care worldwide.
Methods
Systematic review and meta-summary (quantitative aggregation of qualitative findings) of quantitative, qualitative, and mixed-methods studies. All languages and countries were included.
Results
Two thousand, six hundred and nineteen abstracts were identified; 144 studies were included. Frequency effect sizes (FES %) were calculated for each theme, as a measure of their prevalence in the literature.
Themes ranged from negative psychological symptoms post bereavement (77 · 1) and in subsequent pregnancies (27 · 1), to disenfranchised grief (31 · 2), and incongruent grief (28 · 5), There was also impact on siblings (23 · 6) and on the wider family (2 · 8).
They included mixed-feelings about decisions made when the baby died (12 · 5), avoidance of memories (13 · 2), anxiety over other children (7 · 6), chronic pain and fatigue (6 · 9), and a different approach to the use of healthcare services (6 · 9).
Some themes were particularly prominent in studies of fathers; grief suppression (avoidance)(18 · 1), employment difficulties, financial debt (5 · 6), and increased substance use (4 · 2). Others found in studies specific to mothers included altered body image (3 · 5) and impact on quality of life (2 · 1). Counter-intuitively, Some themes had mixed connotations. These included parental pride in the baby (5 · 6), motivation for engagement in healthcare improvement (4 · 2) and changed approaches to life and death, self-esteem, and own identity (25 · 7).
In studies from low/middle income countries, stigmatisation (13 · 2) and pressure to prioritise or delay conception (9) were especially prevalent.
Conclusion
Experiencing the birth of a stillborn child is a life-changing event. The focus of the consequences may vary with parent gender and country. Stillbirth can have devastating psychological, physical and social costs, with ongoing effects on interpersonal relationships and subsequently born children. However, parents who experience the tragedy of stillbirth can develop resilience and new life-skills and capacities. Future research should focus on developing interventions that may reduce the psychosocial cost of stillbirth.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-016-0800-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12884-016-0800-8
PMCID: PMC4719709  PMID: 26785915
Stillbirth; Bereavement; Psychosocial impact; Parents’ experiences
5.  Exploring the intangible economic costs of stillbirth 
Background
Compared to other pregnancy-related events, the full cost of stillbirth remains poorly described. In the UK one in every 200 births ends in stillbirth. As a follow-up to a recent study which explored the direct costs of stillbirth, this study aimed to explore the intangible costs of stillbirth in terms of their duration and economic implication.
Methods
Systematic searches identified relevant papers on the psychological consequences of stillbirth. A narrative review of the quantitative studies was undertaken. This was followed by a qualitative synthesis using meta-ethnography to identify over-arching themes common to the papers. Finally, the themes were used to generate questions proposed for use in a questionnaire to capture the intangible costs of stillbirth.
Results
The narrative review revealed a higher level of anxiety and depression in couples with stillbirth compared to those without stillbirth. The qualitative synthesis identified a range of psychological effects common to families that have experienced stillbirth. Both methods revealed the persistent nature of these effects and the subsequent economic burden.
Conclusions
The psychological effects of stillbirth adversely impacts on the daily functioning, relationships and employment of those affected with far-reaching economic implications. Knowledge of the intangible costs of stillbirth is therefore important to accurately estimate the size of the impact on families and health services and to inform policy and decision making.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-015-0617-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12884-015-0617-x
PMCID: PMC4556317  PMID: 26323522
6.  An international internet survey of the experiences of 1,714 mothers with a late stillbirth: the STARS cohort study 
Background
Stillbirth occurring after 28 weeks gestation affects between 1.5–4.5 per 1,000 births in high-income countries. The majority of stillbirths in this setting occur in women without risk factors. In addition, many established risk factors such as nulliparity and maternal age are not amenable to modification during pregnancy. Identification of other risk factors which could be amenable to change in pregnancy should be a priority in stillbirth prevention research. Therefore, this study aimed to utilise an online survey asking women who had a stillbirth about their pregnancy in order to identify any common symptoms and experiences.
Methods
A web-based survey.
Results
A total of 1,714 women who had experienced a stillbirth >3 weeks prior to enrolment completed the survey. Common experiences identified were: perception of changes in fetal movement (63 % of respondents), reports of a “gut instinct” that something was wrong (68 %), and perceived time of death occurring overnight (56 %). A quarter of participants believed that their baby’s death was due to a cord issue and another 18 % indicated that they did not know the reason why their baby died. In many cases (55 %) the mother believed the cause of death was different to that told by clinicians.
Conclusions
This study confirms the association between altered fetal movements and stillbirth and highlights novel associations that merit closer scrutiny including a maternal gut instinct that something was wrong. The potential importance of maternal sleep is highlighted by the finding of more than half the mothers believing their baby died during the night. This study supports the importance of listening to mothers’ concerns and symptoms during pregnancy and highlights the need for thorough investigation of stillbirth and appropriate explanation being given to parents.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-015-0602-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12884-015-0602-4
PMCID: PMC4537542  PMID: 26276347
7.  Placental Features of Late-Onset Adverse Pregnancy Outcome 
PLoS ONE  2015;10(6):e0129117.
Objective
Currently, no investigations reliably identify placental dysfunction in late pregnancy. To facilitate the development of such investigations we aimed to identify placental features that differ between normal and adverse outcome in late pregnancy in a group of pregnancies with reduced fetal movement.
Methods
Following third trimester presentation with reduced fetal movement (N = 100), placental structure ex vivo was measured. Placental function was then assessed in terms of (i) chorionic plate artery agonist responses and length-tension characteristics using wire myography and (ii) production and release of placentally derived hormones (by quantitative polymerase chain reaction and enzyme linked immunosorbant assay of villous tissue and explant conditioned culture medium).
Results
Placentas from pregnancies ending in adverse outcome (N = 23) were ~25% smaller in weight, volume, length, width and disc area (all p<0.0001) compared with those from normal outcome pregnancies. Villous and trophoblast areas were unchanged, but villous vascularity was reduced (median (interquartile range): adverse outcome 10 (10–12) vessels/mm2 vs. normal outcome 13 (12–15), p = 0.002). Adverse outcome pregnancy placental arteries were relatively insensitive to nitric oxide donated by sodium nitroprusside compared to normal outcome pregnancy placental arteries (50% Effective Concentration 30 (19–50) nM vs. 12 (6–24), p = 0.02). Adverse outcome pregnancy placental tissue contained less human chorionic gonadotrophin (20 (11–50) vs. 55 (24–102) mIU/mg, p = 0.007) and human placental lactogen (11 (6–14) vs. 27 (9–50) mg/mg, p = 0.006) and released more soluble fms-like tyrosine kinase-1 (21 (13–29) vs. 5 (2–15) ng/mg, p = 0.01) compared with normal outcome pregnancy placental tissue.
Conclusion
These data provide a description of the placental phenotype of adverse outcome in late pregnancy. Antenatal tests that accurately reflect elements of this phenotype may improve its prediction.
doi:10.1371/journal.pone.0129117
PMCID: PMC4488264  PMID: 26120838
10.  Circulating Cytokines and Alarmins Associated with Placental Inflammation in High-Risk Pregnancies 
Problem
Inflammation during pregnancy has devastating consequences for the placenta and fetus. These events are incompletely understood, thereby hampering screening and treatment.
Method of study
The inflammatory profile of villous tissue was studied in pregnancies at high-risk of placental dysfunction and compared to uncomplicated pregnancies. The systemic inflammatory profile was assessed in matched maternal serum samples in cases of reduced fetal movements (RFM).
Results
Placentas from RFM pregnancies had a unique inflammatory profile characterized by increased interleukin (IL)-1 receptor antagonist and decreased IL-10 expression, concomitant with increased numbers of placental macrophages. This aberrant cytokine profile was evident in maternal serum in RFM, as were increased levels of alarmins (uric acid, HMGB1, cell-free fetal DNA).
Conclusion
This distinct inflammatory profile at the maternal-fetal interface, mirrored in maternal serum, could represent biomarkers of placental inflammation and could offer novel therapeutic options to protect the placenta and fetus from an adverse maternal environment.
doi:10.1111/aji.12274
PMCID: PMC4369138  PMID: 24867252
High-risk pregnancy; inflammation; placental dysfunction; stillbirth
11.  Evaluation of the quality of guidelines for the management of reduced fetal movements in UK maternity units 
Background
The development of evidence-based guidelines is a key step in ensuring that maternity care is of a universally high standard. To influence patient care national and international guidelines need to be interpreted and implemented locally. In 2011, the Royal College of Obstetricians and Gynaecologists published guidelines for the management of reduced fetal movements (RFM), which can be an important symptom of fetal compromise. Following dissemination it was anticipated that this guidance would be implemented in UK maternity units. This study aimed to assess the quality of local guidelines for the management of RFM in comparison to published national standards.
Methods
Cross-sectional survey of maternity unit guidelines for RFM. The guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Tool and scored by two independent investigators. Two national guidelines were used as standards to evaluate unit guidelines.
Results
Responses were received from 98 units (42%); 12 units had no guideline. National guidelines scored highly using the AGREE II tool but there was wide variation in the quality of individual maternity unit guidelines, which were frequently of low quality. No guidelines incorporated all the recommendations from the national guideline. Maternity unit guidelines performed well for clarity and presentation but had low scores for stakeholder involvement, rigour of development and applicability.
Conclusions
In contrast to national evidence based guidance the quality of maternity unit guidelines for RFM is variable and frequently of low quality. To increase quality, guidelines need to include up to date evidence and audit standards which could be taken directly from national evidence-based guidance. Barriers to local implementation and resource implications need to be taken into consideration. Training may also improve the implementation of the guideline. Research is needed to inform strategies to realize the benefits of clinical guidance in practice.
doi:10.1186/s12884-015-0484-5
PMCID: PMC4352260  PMID: 25884544
Reduced fetal movements; Management; Stillbirth; Stillbirth prevention; Risk management
12.  A stochastic model for early placental development† 
In the human, placental structure is closely related to placental function and consequent pregnancy outcome. Studies have noted abnormal placental shape in small-for-gestational-age infants which extends to increased lifetime risk of cardiovascular disease. The origins and determinants of placental shape are incompletely understood and are difficult to study in vivo. In this paper, we model the early development of the human placenta, based on the hypothesis that this is driven by a chemoattractant effect emanating from proximal spiral arteries in the decidua. We derive and explore a two-dimensional stochastic model, and investigate the effects of loss of spiral arteries in regions near to the cord insertion on the shape of the placenta. This model demonstrates that disruption of spiral arteries can exert profound effects on placental shape, particularly if this is close to the cord insertion. Thus, placental shape reflects the underlying maternal vascular bed. Abnormal placental shape may reflect an abnormal uterine environment, predisposing to pregnancy complications. Through statistical analysis of model placentas, we are able to characterize the probability that a given placenta grew in a disrupted environment, and even able to distinguish between different disruptions.
doi:10.1098/rsif.2014.0149
PMCID: PMC4208356  PMID: 24850904
mathematical modelling; placental development; placental shape; spiral artery; stochastic dynamics
13.  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
doi:10.1186/1471-2393-14-171
PMCID: PMC4032501  PMID: 24885461
Stillbirth; Perinatal mortality; Perinatal death; Risk factors; Sleep position; Reduced fetal movements; Fetal growth restriction
14.  Preeclampsia Is Associated with Alterations in the p53-Pathway in Villous Trophoblast 
PLoS ONE  2014;9(1):e87621.
Background
Preeclampsia (PE) is characterized by exaggerated apoptosis of the villous trophoblast of placental villi. Since p53 is a critical regulator of apoptosis we hypothesized that excessive apoptosis in PE is mediated by abnormal expression of proteins participating in the p53 pathway and that modulation of the p53 pathway alters trophoblast apoptosis in vitro.
Methods
Fresh placental villous tissue was collected from normal pregnancies and pregnancies complicated by PE; Western blotting and real-time PCR were performed on tissue lysate for protein and mRNA expression of p53 and downstream effector proteins, p21, Bax and caspases 3 and 8. To further assess the ability of p53 to modulate apoptosis within trophoblast, BeWo cells and placental villous tissue were exposed to the p53-activator, Nutlin-3, alone or in combination with the p53-inhibitor, Pifithrin-α (PFT- α). Equally, Mdm2 was knocked-down with siRNA.
Results
Protein expression of p53, p21 and Bax was significantly increased in pregnancies complicated by PE. Conversely, Mdm2 protein levels were significantly depleted in PE; immunohistochemistry showed these changes to be confined to trophoblast. Reduction in the negative feedback of p53 by Mdm2, using siRNA and Nutlin-3, caused an imbalance between p53 and Mdm2 that triggered apoptosis in term villous explants. In the case of Nutlin, this was attenuated by Pifithrin-α.
Conclusions
These data illustrate the potential for an imbalance in p53 and Mdm2 expression to promote excessive apoptosis in villous trophoblast. The upstream regulation of p53 and Mdm2, with regard to exaggerated apoptosis and autophagy in PE, merits further investigation.
doi:10.1371/journal.pone.0087621
PMCID: PMC3907567  PMID: 24498154
15.  A structured review and exploration of the healthcare costs associated with stillbirth and a subsequent pregnancy in England and Wales 
Background
In contrast to other pregnancy complications the economic impact of stillbirth is poorly understood. We aimed to carry out a preliminary exploration of the healthcare costs of stillbirth from the time of pregnancy loss and the period afterwards; also to explore and include the impact of a previous stillbirth on the healthcare costs of the next pregnancy.
Methods
A structured review of the literature including cost studies and description of costs to health-care providers for care provided at the time of stillbirth and in a subsequent pregnancy. Costs in a subsequent pregnancy were compared in three alternative models of care for multiparous women developed from national guidelines and expert opinion: i) “low risk” women who had a live birth, ii) “high risk” women who had a live birth and iii) women with a previous stillbirth.
Results
The costs to the National Health Service (NHS) for investigation immediately following stillbirth ranged from £1,242 (core recommended investigations) to £1,804 (comprehensive investigation). The costs in the next pregnancy following a stillbirth ranged from £2,147 (low-risk woman with a previous healthy child) to £3,751 (Woman with a previous stillbirth of unknown cause). The cost in the next pregnancy following a stillbirth due to a known recurrent or an unknown cause is almost £500 greater than the pregnancy following a stillbirth due to a known non-recurrent cause.
Conclusions
The study has highlighted the paucity of evidence regarding economic issues surrounding stillbirth. Women who have experienced a previous stillbirth are likely to utilise more health care services in their next pregnancy particularly where no cause is found. Every effort should be made to determine the cause of stillbirth to reduce the overall cost to the NHS. The cost associated with identifying the cause of stillbirth could offset the costs of care in the next pregnancy. Future research should concentrate on robust studies looking into the wider economic impact of stillbirth.
doi:10.1186/1471-2393-13-236
PMCID: PMC3878511  PMID: 24341329
Costs and cost analysis; Stillbirth; Multiparous women; NHS
16.  A randomised controlled trial comparing standard or intensive management of reduced fetal movements after 36 weeks gestation-a feasibility study 
Background
Women presenting with reduced fetal movements (RFM) in the third trimester are at increased risk of stillbirth or fetal growth restriction. These outcomes after RFM are related to smaller fetal size on ultrasound scan, oligohydramnios and lower human placental lactogen (hPL) in maternal serum. We performed this study to address whether a randomised controlled trial (RCT) of the management of RFM was feasible with regard to: i) maternal recruitment and retention ii) patient acceptability, iii) adherence to protocol. Additionally, we aimed to confirm the prevalence of poor perinatal outcomes defined as: stillbirth, birthweight <10th centile, umbilical arterial pH <7.1 or unexpected admission to the neonatal intensive care unit.
Methods
Women with RFM ≥36 weeks gestation were invited to participate in a RCT comparing standard management (ultrasound scan if indicated, induction of labour (IOL) based on consultant decision) with intensive management (ultrasound scan, maternal serum hPL, IOL if either result was abnormal). Anxiety was assessed by state-trait anxiety index (STAI) before and after investigations for RFM. Rates of protocol compliance and IOL for RFM were calculated. Participant views were assessed by questionnaires.
Results
137 women were approached, 120 (88%) participated, 60 in each group, 2 women in the standard group did not complete the study. 20% of participants had a poor perinatal outcome. All women in the intensive group had ultrasound assessment of fetal size and liquor volume vs. 97% in the standard group. 50% of the intensive group had IOL for abnormal scan or low hPL after RFM vs. 26% of controls (p < 0.01). STAI reduced for all women after investigations, but this reduction was greater in the standard group (p = 0.02). Participants had positive views about their involvement in the study.
Conclusion
An RCT of management of RFM is feasible with a low rate of attrition. Investigations decrease maternal anxiety. Participants in the intensive group were more likely to have IOL for RFM. Further work is required to determine the likely level of intervention in the standard care arm in multiple centres, to develop additional placental biomarkers and to confirm that the composite outcome is valid.
Trial registration
ISRCTN07944306
doi:10.1186/1471-2393-13-95
PMCID: PMC3640967  PMID: 23590451
Reduced fetal movements; Randomised controlled trial; Human placental lactogen; Feasibility; Maternal anxiety
17.  Bereaved parents’ experience of stillbirth in UK hospitals: a qualitative interview study 
BMJ Open  2013;3(2):e002237.
Objective
To obtain the views of bereaved parents about their interactions with healthcare staff when their baby died just before or during labour.
Design
Qualitative in-depth interview study, following an earlier national survey. All interviews took place during 2011, either face-to-face or on the telephone. Data analysis was informed by the constant comparative technique from grounded theory.
Setting
Every National Health Service (NHS) region in the UK was represented.
Participants
Bereaved parents who had completed an e-questionnaire, via the website of Sands (Stillbirth and Neonatal Death Society). Of the 304 survey respondents who gave provisional consent, 29 families were approached to take part, based on maximum variation sampling and data saturation.
Results
22 families (n=25) participated. Births took place between 2002 and 2010. Specific practices were identified that were particularly helpful to the parents. Respondents talked about their interactions with hospital staff as having profound effects on their capacity to cope, both during labour and in the longer term. The data generated three key themes: ‘enduring and multiple loss’: ‘making irretrievable moments precious’; and the ‘best care possible to the worst imaginable’. The overall synthesis of findings is encapsulated in the meta-theme ‘One chance to get it right.’ This pertains to the parents and family themselves, clinical and support staff who care for them directly, and the NHS organisations that indirectly provide the resources and governance procedures that may (or may not) foster a caring ethos.
Conclusions
Positive memories and outcomes following stillbirth depend as much on genuinely caring staff attitudes and behaviours as on high-quality clinical procedures. All staff who encounter parents in this situation need to see each meeting as their one chance to get it right.
doi:10.1136/bmjopen-2012-002237
PMCID: PMC3586079  PMID: 23418300
Delivery of Care; emotional reaction; Healthcare quality improvement; Qualitative Research; Obstetrics; Patient-centred care
18.  Reduced fetal movements 
BMC Pregnancy and Childbirth  2012;12(Suppl 1):A10.
doi:10.1186/1471-2393-12-S1-A10
PMCID: PMC3428674
19.  Abnormalities of the placenta 
BMC Pregnancy and Childbirth  2012;12(Suppl 1):A2.
doi:10.1186/1471-2393-12-S1-A2
PMCID: PMC3428682
20.  Predictors of Poor Perinatal Outcome following Maternal Perception of Reduced Fetal Movements – A Prospective Cohort Study 
PLoS ONE  2012;7(7):e39784.
Background
Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). RFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency.
Objective
To identify predictors of poor perinatal outcome after maternal perception of reduced fetal movements (RFM).
Design
Prospective cohort study.
Methods
305 women presenting with RFM after 28 weeks of gestation were recruited. Demographic factors and clinical history were recorded and ultrasound performed to assess fetal biometry, liquor volume and umbilical artery Doppler. A maternal serum sample was obtained for measurement of placentally-derived or modified proteins including: alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), human placental lactogen (hPL), ischaemia-modified albumin (IMA), pregnancy associated plasma protein A (PAPP-A) and progesterone. Factors related to poor perinatal outcome were determined by logistic regression.
Results
22.1% of pregnancies ended in a poor perinatal outcome after RFM. The most common complication was small-for-gestational age infants. Pregnancy outcome after maternal perception of RFM was related to amount of fetal activity while being monitored, abnormal fetal heart rate trace, diastolic blood pressure, estimated fetal weight, liquor volume, serum hCG and hPL. Following multiple logistic regression abnormal fetal heart rate trace (Odds ratio 7.08, 95% Confidence Interval 1.31–38.18), (OR) diastolic blood pressure (OR 1.04 (95% CI 1.01–1.09), estimated fetal weight centile (OR 0.95, 95% CI 0.94–0.97) and log maternal serum hPL (OR 0.13, 95% CI 0.02–0.99) were independently related to pregnancy outcome. hPL was related to placental mass.
Conclusion
Poor perinatal outcome after maternal perception of RFM is closely related to factors which are connected to placental dysfunction. Novel tests of placental function and associated fetal response may provide improved means to detect fetuses at greatest risk of poor perinatal outcome after RFM.
doi:10.1371/journal.pone.0039784
PMCID: PMC3394759  PMID: 22808059
21.  Maternal Perception of Reduced Fetal Movements Is Associated with Altered Placental Structure and Function 
PLoS ONE  2012;7(4):e34851.
Background
Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). DFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency. To date there have been no studies of placental structure in cases of DFM.
Objective
To determine whether maternal perception of reduced fetal movements (RFM) is associated with abnormalities in placental structure and function.
Design
Placentas were collected from women with RFM after 28 weeks gestation if delivery occurred within 1 week. Women with normal movements served as a control group. Placentas were weighed and photographs taken. Microscopic structure was evaluated by immunohistochemical staining and image analysis. System A amino acid transporter activity was measured as a marker of placental function.
Placentas from all pregnancies with RFM (irrespective of outcome) had greater area with signs of infarction (3.5% vs. 0.6%; p<0.01), a higher density of syncytial knots (p<0.001) and greater proliferation index (p<0.01). Villous vascularity (p<0.001), trophoblast area (p<0.01) and system A activity (p<0.01) were decreased in placentas from RFM compared to controls irrespective of outcome of pregnancy.
Conclusions
This study provides evidence of abnormal placental morphology and function in women with RFM and supports the proposition of a causal association between placental insufficiency and RFM. This suggests that women presenting with RFM require further investigation to identify those with placental insufficiency.
doi:10.1371/journal.pone.0034851
PMCID: PMC3327709  PMID: 22523561
22.  Endometrioid adenocarcinoma presenting in a patient 18 years after hysterectomy: a potential hazard of unopposed oestrogen therapy 
BMJ Case Reports  2009;2009:bcr05.2009.1829.
We present a case of endometrioid adenocarcinoma arising from extragonadal endometriosis 18 years after total abdominal hysterectomy with bilateral salpingo-oophorectomy. After the primary surgery the patient received 11 years of unopposed oestrogen hormone replacement therapy. She presented with symptoms of urinary retention and pelvic mass. Following resection, histopathology identified the mass as an endometrioid adenocarcinoma. The association between persistent endometriosis and the development of endometrial cancer are discussed here together with the risks of unopposed oestrogen in the development of such lesions.
doi:10.1136/bcr.05.2009.1829
PMCID: PMC3027906  PMID: 21841948
23.  Placental Apoptosis in Health and Disease 
Apoptosis, programmed cell death, is an essential feature of normal placental development but is exaggerated in association with placental disease. Placental development relies upon effective implantation and invasion of the maternal decidua by the placental trophoblast. In normal pregnancy, trophoblast apoptosis increases with placental growth and advancing gestation. However, apoptosis is notably exaggerated in the pregnancy complications, hydatidiform mole, pre-eclampsia, and intra-uterine growth restriction (IUGR). Placental apoptosis may be initiated by a variety of stimuli, including hypoxia and oxidative stress. In common with other cell-types, trophoblast apoptosis follows the extrinsic or intrinsic pathways culminating in the activation of caspases. In contrast, the formation of apoptotic bodies is less clearly identified, but postulated by some to involve the clustering of apoptotic nuclei and liberation of this material into the maternal circulation. In addition to promoting a favorable maternal immune response, the release of this placental-derived material is thought to provoke the endothelial dysfunction of pre-eclampsia. Widespread apoptosis of the syncytiotrophoblast may also impair trophoblast function leading to the reduction in nutrient transport seen in IUGR. A clearer understanding of placental apoptosis and its regulation may provide new insights into placental pathologies, potentially suggesting therapeutic targets.
doi:10.1111/j.1600-0897.2010.00837.x
PMCID: PMC3025811  PMID: 20367628
Apoptosis; IUGR; pre-eclampsia; trophoblast

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