Alexander Heazell

Placental Apoptosis in Health and Disease

Citation Sharp AN, Heazell AEP, Crocker IP, Mor G. Placental apoptosis in health and disease. Am J Reprod Immunol 2010; 64: 159–169

Stillbirths: recall to action in high-income countries

Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19,439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20-30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.

Methods of fetal movement counting and the detection of fetal compromise.

Summary Maternal perception of fetal movements is widely used as a marker of fetal viability and well-being. A reduction in fetal movements is associated with fetal hypoxia, increased incidence of stillbirth and fetal growth restriction (FGR). Therefore, a reduction in fetal movements has been proposed as a screening tool for FGR or fetal compromise. The problem of this approach is that there is no widely accepted definition of reduced fetal activity or ‘alarm limits’, and pregnant women are currently given a wide range of non-evidence-based advice. We have reviewed the background of published definitions and their potential usefulness in screening. A formal meta-analysis of these studies is not possible due to variation in methodology and definitions of reduced fetal movements. Assessment of fetal movements using formal fetal movement counting has shown equivocal results. Importantly, in all studies, there was a decrease in perinatal mortality suggesting a beneficial role for raising maternal awareness of fetal movements. Most studies implemented limits to define reduced fetal movements based on small groups of high risk pregnancies and obsolete counting methodology. A single case-control study developed ‘normal limits’ in a low risk population, and successfully implemented it prospectively for screening. At present, there is no evidence that any absolute definition of reduced fetal movements is of greater value than maternal subjective perception of reduced fetal movements in the detection of intrauterine fetal death or fetal compromise. Further investigation is required to determine an effective method of identifying patients with reduced fetal movements and to determine the best subsequent management.

Stillbirths: economic and psychosocial consequences.

Despite the frequency of stillbirths, the subsequent implications are overlooked and underappreciated. We present findings from comprehensive, systematic literature reviews, and new analyses of published and unpublished data, to establish the effect of stillbirth on parents, families, health-care providers, and societies worldwide. Data for direct costs of this event are sparse but suggest that a stillbirth needs more resources than a livebirth, both in the perinatal period and in additional surveillance during subsequent pregnancies. Indirect and intangible costs of stillbirth are extensive and are usually met by families alone. This issue is particularly onerous for those with few resources. Negative effects, particularly on parental mental health, might be moderated by empathic attitudes of care providers and tailored interventions. The value of the baby, as well as the associated costs for parents, families, care providers, communities, and society, should be considered to prevent stillbirths and reduce associated morbidity.

Live and Let Die – Regulation of Villous Trophoblast Apoptosis in Normal and Abnormal Pregnancies

Since 1995 the number of publications investigating apoptosis in villous trophoblast has increased exponentially. This scientific interest is in part due to observations that this specialised form of cell death is increased in pregnancy complications such as pre-eclampsia and intra-uterine growth restriction. In addition, apoptosis is described in normal villous trophoblast and elements of the apoptotic machinery are involved in the fusion between cytotrophoblast and the overlying multinucleate syncytiotrophoblast. The increase in descriptions of apoptotic cell death in villous trophoblast has been accompanied by investigations of regulators of apoptosis. It is anticipated that understanding the regulation of apoptosis in villous trophoblast may provide new insights into placental pathologies. This review describes current knowledge regarding the expression and function of these regulators in villous trophoblast, both in normal and complicated pregnancies.

Predicting poor perinatal outcome in women who present with decreased fetal movements

Summary Maternal perception of decreased fetal movements (DFM) is associated with increased incidence of stillbirth and intrauterine growth restriction. We hypothesised that clinical assessment of women perceiving DFM may identify patients at highest risk of poor perinatal outcome. This was a retrospective study of 203 patients presenting to the obstetric triage service with DFM. Information on obstetric and past medical history, the current presentation with DFM and the outcome of pregnancy was collected. Using multivariate analysis, odds ratios (OR) and 95% confidence intervals (CI) were calculated for poor pregnancy outcome defined as stillbirth, small for gestational age or pre-term delivery. The rate of stillbirth was increased in women with DFM (OR 2.9). Some 26.6% of women perceiving DFM had a poor perinatal outcome. Women with relevant past obstetric history (OR 2.11), two or more presentations of DFM (OR 1.92), or who measured small-for-dates (OR 19.53) were at increased risk of poor pregnancy outcome. These preliminary data suggest that some features of clinical assessment can identify patients at increased risk of poor perinatal outcome after presentation with DFM. Such patients may be prioritised for detailed assessment of fetal growth and wellbeing.

Changes in the Metabolic Footprint of Placental Explant-Conditioned Culture Medium Identifies Metabolic Disturbances Related to Hypoxia and Pre-Eclampsia

Pre-eclampsia (PE) is a multi-system disorder thought to be mediated by circulating factors released from damaged placental villous trophoblast. There is extensive evidence of changes in the villous tissue in PE, some of which may be replicated by culturing villous tissue in hypoxic conditions. Metabolic footprinting offers a hypothesis-generating strategy to investigate factors released from this tissue in vitro. This study investigated differences in the factors released from villous trophoblast from uncomplicated pregnancies (n=6) and those with PE (n=6). In both cases, explanted placental villous fragments were cultured for 96 h in 1% O(2) (hypoxia) or 6% O(2) (placental normoxia). Metabolites consumed from and released into serum-conditioned culture medium were analysed by Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). The relative concentration of 154 features of the metabolic footprint were observed to change in culture medium from uncomplicated pregnancies cultured in normoxic and hypoxic conditions (p<0.00005). 21 and 80 features were also different in culture medium from PE versus uncomplicated pregnancies cultured in hypoxic and normoxic conditions, respectively (p<0.00005). When comparing all 4 groups, 47 metabolic features showed a similar relative concentration in PE-derived media cultured in normoxic conditions to conditioned media from normal villous tissue cultured in hypoxic conditions. These data suggest that hypoxia may have a role in the placental pathogenesis of PE. Three areas of metabolism were highlighted for systems biology investigation; glutamate and glutamine, tryptophan metabolism and leukotriene or prostaglandin metabolism.

Maternal Perception of Reduced Fetal Movements Is Associated with Altered Placental Structure and Function

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.

Predictors of Poor Perinatal Outcome following Maternal Perception of Reduced Fetal Movements – A Prospective Cohort Study

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.

Bereaved parents' experience of stillbirth in UK hospitals: a qualitative interview study.

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.