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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  Reduced fetal movements 
BMC Pregnancy and Childbirth  2012;12(Suppl 1):A10.
doi:10.1186/1471-2393-12-S1-A10
PMCID: PMC3428674
8.  Abnormalities of the placenta 
BMC Pregnancy and Childbirth  2012;12(Suppl 1):A2.
doi:10.1186/1471-2393-12-S1-A2
PMCID: PMC3428682
9.  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
10.  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
11.  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
12.  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

Results 1-12 (12)