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Background: The national health care response to coronavirus (COVID-19) has varied between countries. The United Kingdom (UK) and the Netherlands (NL) have comparable maternity and neonatal care systems, and experienced similar numbers of COVID-19 infections, but had different organisational responses to the pandemic. Understanding why and how similarities and differences occurred in these two contexts could inform optimal care in normal circumstances, and during future crises. Aim: To compare the UK and Dutch COVID-19 maternity and neonatal care responses in three key domains: choice of birthplace, companionship, and families in vulnerable situations. Method: A multi-method study, including documentary analysis of national organisation policy and guidance on COVID-19, and interviews with national and regional stakeholders. Findings: Both countries had an infection control focus, with less emphasis on the impact of restrictions. Differences included care providers’ fear of contracting COVID-19; the extent to which personalised care was embedded in the care system before the pandemic; and how far multidisciplinary collaboration and service-user involvement were prioritised. Conclusion: We recommend that countries should 1) make a systematic plan for crisis decision-making before a serious event occurs, and that this must include authentic service-user involvement, multidisciplinary collaboration, and protection of staff wellbeing 2) integrate women’s and families’ values into the maternity and neonatal care system, ensuring equitable inclusion of the most vulnerable and 3) strengthen community provision to ensure system wide resilience to future shocks from pandemics, or other unexpected large-scale events.

A 31-year-old woman with a history of stillbirth due to placental abruption at 29 weeks’ gestation and one first trimester miscarriage documented a continuous record of her perceived fetal movements from 28 to 38 weeks’ gestation. Repeated ultrasound examinations confirmed a viable pregnancy, with normal growth, liquor volume and Doppler profile. She delivered a healthy male infant at 38 weeks and 3 days’ gestation. The data collected give a detailed record of fetal activity in a healthy pregnancy. Perceived fetal activity increased as pregnancy progressed and was greatest in the evenings. We also found that clusters of movements, which have previously been reported as protective against stillbirth, were felt earlier on in pregnancy.

The need for respectful bereavement care following a stillbirth has been poorly recognised within global public health initiatives. To date, there has been no comprehensive cataloguing of providers that support parents after stillbirth, nor any review of the challenges they face. We aimed to identify providers (organisations and point persons) that support bereaved parents worldwide and to investigate the challenges they face. A systematic global online search was conducted to identify providers of support after stillbirth. Subsets of providers were surveyed and interviewed. These were purposively sampled to achieve diversity in geography, organisation size and point person role. Challenges in providing support in six key areas – stigma, funding, reach, policy, workforce, and advocacy – were analysed thematically. Overall, 621 providers from 75 countries were identified. No support providers were identified in 123 countries, and in the 6 countries that carry almost half of the global burden of stillbirths, only 8 support providers were found. Support providers faced challenges in accessing funding, reaching key populations, and training and retaining staff, while complex policies hampered bereavement care. Support providers were challenged by silence and stigma around stillbirth. Overcoming these challenges requires collaboration, effort, and political will at local and international scales.

Objectives To investigate the risk of stillbirth in relation to; 1) a previous CD compared to those following a vaginal birth (VB); and 2) vaginal birth after caesarean (VBAC) compared to a repeat CD. Design Population-based cohort study. Setting The Swedish Medical Birth registry Population Women with their first and second singletons between 1982 and 2012. Methods Multivariable logistic regression models were performed to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) of the association between CD in the first pregnancy and stillbirth in the second pregnancy and the association between VBAC and stillbirth. Sub-group analyses were performed by types of CD and timing of stillbirth (antepartum and intrapartum). Main outcome measures Stillbirth (antepartum and intrapartum fetal death). Results Of the 1,771,700 singleton births from 885,850 women,117,114 (13.2%) women had a CD in the first pregnancy, and 51,755 had VBAC in the second pregnancy. We found a 37% increased odds of stillbirth (aOR:1.37 [95% CI, 1.23–1.52]) in women with a previous CD compared to VB. The odds of intrapartum stillbirth was higher in previous pre-labour CD group (aOR:2.72 [95% CI, 1.51–4.91]) than the previous in-labour CD group (aOR:1.35 [95% CI, 0.76–2.40,]), although not statistically significant in the latter case. No increased odds was found for intrapartum stillbirth in women who had VBAC (aOR:0.99 [95% CI, 0.48–2.06]) compared to women who had a repeat CD, whereas women with antepartum stillbirth were more likely to have a VBAC (aOR:4.49 [95% CI, 3.55–5.67]). Conclusions This study confirms that a CD is associated with an increased risk of subsequent stillbirth, with a greater risk among pre-labour CD. This association is not solely mediated by increases in intrapartum asphyxia, uterine rupture or attempted VBAC. Further research is needed to understand this association, but these findings might help health care providers to reach optimal decisions regarding mode of birth, particularly when CD is unnecessary.

Background Open Disclosure (OD) is open and timely communication about harmful events arising from health care with those affected. It is an entitlement of service-users and an aspect of their recovery, as well as an important dimension of service safety improvement. Recently, OD in maternity care in the English National Health Service has become a pressing public issue, with policymakers promoting multiple interventions to manage the financial and reputational costs of communication failures. There is limited research to understand how OD works and its effects in different contexts. Methods Realist literature screening, data extraction, and retroductive theorisation involving two advisory stakeholder groups. Data relevant to families, clinicians, and services were mapped to theorise the relationships between contexts, mechanisms, and outcomes. From these maps, key aspects for successful OD were identified. Results After realist quality appraisal, 38 documents were included in the synthesis (22 academic, 2 training guidance, and 14 policy report). 135 explanatory accounts were identified from the included documents (with n = 41 relevant to families; n = 37 relevant to staff; and n = 37 relevant to services). These were theorised as five key mechanism sets: (a) meaningful acknowledgement of harm, (b) opportunity for family involvement in reviews and investigations, (c) possibilities for families and staff to make sense of what happened, (d) specialist skills and psychological safety of clinicians, and (e) families and staff knowing that improvements are happening. Three key contextual factors were identified: (a) the configuration of the incident (how and when identified and classified as more or less severe); (b) national or state drivers, such as polices, regulations, and schemes, designed to promote OD; and (c) the organisational context within which these these drivers are recieived and negotiated. Conclusions This is the first review to theorise how OD works, for whom, in what circumstances, and why. We identify and examine from the secondary data the five key mechanisms for successful OD and the three contextual factors that influence this. The next study stage will use interview and ethnographic data to test, deepen, or overturn our five hypothesised programme theories to explain what is required to strengthen OD in maternity services.

Background: Despite progress, stillbirth rates in many high- and upper-middle income countries remain high, and the majority of these deaths are preventable. We introduce the Ending Preventable Stillbirths (EPS) Scorecard for High- and Upper Middle-Income Countries, a tool to track progress against the Lancet’s 2016 EPS Series Call to Action, fostering transparency, consistency and accountability. Methods: The Scorecard for EPS in High- and Upper-Middle Income Countries was adapted from the Scorecard for EPS in Low-Income Countries which includes 20 indicators to track progress against the eight Call to Action targets. The Scorecard for High- and Upper-Middle Income Countries includes 23 indicators tracking progress against these same Call to Action targets. For this inaugural version of the Scorecard, 13 high- and upper-middle income countries supplied data. Data were collated and compared between and within countries. Results: Data were complete for 15 of 23 indicators (65%). Five key issues were identified: (1) there is wide variation in stillbirth rates and related perinatal outcomes, (2) definitions of stillbirth and related perinatal outcomes vary widely across countries, (3) data on key risk factors for stillbirth are often missing and equity is not consistently tracked, (4) most countries lack guidelines and targets for critical areas for stillbirth prevention and care after stillbirth and have not set a national stillbirth rate target, and (5) most countries do not have mechanisms in place for reduction of stigma or guidelines around bereavement care. Conclusions: This inaugural version of the Scorecard for High- and Upper-Middle Income Countries highlights important gaps in performance indicators for stillbirth both between and within countries. The Scorecard provides a basis for future assessment of progress and can be used to help holding individual countries accountable, especially for reducing stillbirth inequities for disadvantaged groups.

Fetal growth restriction (FGR) describes a fetus which has not achieved its genetic growth potential; it is closely linked to placental dysfunction and uteroplacental hypoxia. Estrogen-related receptor gamma (ESRRG) is regulated by hypoxia and is highly expressed in the placenta. We hypothesized ESRRG is a regulator of hypoxia-mediated placental dysfunction in FGR pregnancies. Placentas were collected from women delivering appropriate for gestational age (AGA; n = 14) or FGR (n = 14) infants. Placental explants (n = 15) from uncomplicated pregnancies were cultured for up to 4 days in 21% or 1% O2, or with 200 μM cobalt chloride (CoCl2), or treated with the ESRRG agonists DY131 under different oxygen concentrations. RT-PCR, Western blotting, and immunochemistry were used to assess mRNA and protein levels of ESRRG and its localization in placental tissue from FGR or AGA pregnancies, and in cultured placental explants. ESRRG mRNA and protein expression were significantly reduced in FGR placentas, as was mRNA expression of the downstream targets of ESRRG, hydroxysteroid 11-beta dehydrogenase 2 (HSD11B2), and cytochrome P-450 (CYP19A1.1). Hypoxia-inducible factor 1-alpha protein localized to the nuclei of the cytotrophoblasts and stromal cells in the explants exposed to CoCl2 or 1% O2. Both hypoxia and CoCl2 treatment decreased ESRRG and its downstream genes’ mRNA expression, but not ESRRG protein expression. DY131 increased the expression of ESRRG signaling pathways and prevented abnormal cell turnover induced by hypoxia. These data show that placental ESRRG is hypoxia-sensitive and altered ESRRG-mediated signaling may contribute to hypoxia-induced placental dysfunction in FGR. Furthermore, DY131 could be used as a novel therapeutic approach for the treatment of placental dysfunction.

Background/Aims Globally, 2 million stillbirths occur annually, 98% of which occur in low-income settings. In low-income settings, stillbirth may be associated with maternal perception of reduced fetal movements. However, little is known about maternal experiences of reduced fetal movements and subsequent engagement with health services in low-income settings. This narrative literature review initially aimed to improve understanding of views and experiences of reduced fetal movements in pregnant women in low-income settings using information synthesised from international studies. However, only a small number of articles from low-resource settings were found. Methods The literature reviewed qualitative, quantitative and mixed-method studies guided by a systematic approach. The findings were discussed narratively. Results A total of 40 studies were identified, only four of which were from low-income settings. The four main themes identified were: maternal perception of fetal movements, facilitators and barriers to seeking healthcare, reduced fetal movements as a predictor of fetal outcomes and knowledge of fetal movements and management strategies. Conclusions A variety of factors may influence maternal perception of reduced fetal movements and experience of care. As most studies were conducted in high-income settings, it is imperative to describe women's experiences of reduced fetal movements in low-income settings.

Additional file 1: Appendix 1. Two-stage search strategy for realist synthesis.

Additional file 2: Appendix 2. Document appraisal for realist synthesis.

Supplementary Material 1

This is the study protocol for an international, online survey to determine women's experiences of maternity care and practices during the COVID pandemic. It was developed from questions used for the STARS study (https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-015-0602-4).

This document is the conference abstract booklet from the National Rainbow Clinic Learning and Sharing Event on 17th April 2023. It includes abstracts from the keynote speakers (Dr Kate Obst and Dr Debbie Smith) and the other presenters. This has been shared to allow the information to be more widely accessed and to allow relevant data to be shared.

usc Background: Presentations for decreased fetal movements comprise a significant proportion of acute antenatal assessments. Decreased fetal movements are associated with increased likelihood of adverse pregnancy outcomes including stillbirth. Consensus-based guidelines recommend pregnant women routinely receive information about fetal movements, but practice is inconsistent, and the information shared is frequently not evidence-based. There are also knowledge gaps about the assessment and management of fetal movement concerns. Women have indicated that they would like more accurate information about what to expect regarding fetal movements. Discussion: Historically, fetal movement information has focussed on movement counts. This is problematic, as the number of fetal movements perceived varies widely between pregnant women, and no set number of movements has been established as a reliable indicator of fetal wellbeing. Of late, maternity care providers have also advised women to observe their baby’s movement pattern, and promptly present if they notice a change. However, normal fetal movement patterns are rarely defined. Recently, a body of research has emerged relating to maternal perception of fetal movement features such as strength, presence of hiccups, and diurnal pattern as indicators of fetal wellbeing in addition to frequency. Conclusion: Sharing comprehensive and gestation-appropriate information about fetal movements may be more satisfying for women, empowering women to identify for themselves when their baby is doing well, and importantly when additional assessment is needed. We propose a conversational approach to fetal movement information sharing, focusing on fetal movement strength, frequency, circadian pattern, and changes with normal fetal development, tailored to the individual. Refereed/Peer-reviewed

Combined with perinatal mortality review, neonatal near-miss (NNM) audit has the potential to inform strategies to better prevent adverse perinatal outcomes. Nonetheless, there is lack of standardised definitions of NNM and limited evidence of implementation of NNM audits.To describe definitions of NNM and assess current approaches and attitudes toward perinatal mortality and morbidity audit.Online survey from December 2021 to February 2022, with a mix of Likert scales, polar, pool, multi-choice, and open-ended questions, disseminated through national and international organisations to perinatal healthcare workers from high-income countries.One hundred and twenty participants came from Australia (n = 86), New Zealand (n = 18), Canada (n = 7), USA (n = 4), Netherlands (n = 2), other countries (n = 3). Neonatologists (35%), midwives (21.7%), obstetricians (12.5%), neonatal nurse practitioners (11.7%) and others (23.3%) responded. Most respondents thought the main characteristics to define NNM were birth asphyxia needing therapeutic hypothermia (68.3%), unexpected resuscitation at birth (67.5%), need for intubation/chest compression/adrenaline (65.0%) and metabolic acidosis at birth (60.0%). There were 97.5% of participants who considered NNM important for identifying cases for perinatal morbidity audits. However, only 10.0% of their institutions used a NNM definition. Overall, 98.4% of participants considered perinatal mortality and morbidity audits important to prevent adverse outcomes.Neonatal near-miss audit is viewed as a valuable tool to reduce adverse neonatal outcomes. There was reasonable consensus that NNM encompassed evidence of birth asphyxia and/or advanced neonatal resuscitation. Data from this international survey identifies a starting point for a consensus definition of NNM, which can be used for perinatal audits to identify opportunities for improvement.

Stillbirth, the death of a baby at or before the time of birth, affects at least 2 million families around the world each year. The global burden of stillbirth is borne unequally, with families in Sub-Saharan Africa, South East Asia, and South America most affected. Although similar to the numbers of newborn deaths, stillbirth is only recently being addressed as a global public health issue. Utilizing a systems-thinking approach to stillbirth is necessary to address the inherent complexities in reducing its burden. This chapter discusses addressing the complexities of stillbirth using the WHO Health Systems Framework and provides salient examples from global partners who are all working to reduce the ongoing deaths from stillbirth.

Background: The COVID-19 pandemic has resulted in profound and far-reaching impacts on maternal and newborn care and outcomes. As part of the ASPIRE COVID-19 project, we describe processes and outcome measures relating to safe and personalised maternity care in England which we map against a pre-developed ASPIRE framework to establish the potential impact of the COVID-19 pandemic for two UK trusts. Methods: We undertook a mixed-methods system-wide case study using quantitative routinely collected data and qualitative data from two Trusts and their service users from 2019 to 2021 (start and completion dates varied by available data). We mapped findings to our prior ASPIRE conceptual framework that explains pathways for the impact of COVID-19 on safe and personalised care. Results: The ASPIRE framework enabled us to develop a comprehensive, systems-level understanding of the impact of the pandemic on service delivery, user experience and staff wellbeing, and place it within the context of pre-existing challenges. Maternity services experienced some impacts on core service coverage, though not on Trust level clinical health outcomes (with the possible exception of readmissions in one Trust). Both users and staff found some pandemic-driven changes challenging such as remote or reduced antenatal and community postnatal contacts, and restrictions on companionship. Other key changes included an increased need for mental health support, changes in the availability and uptake of home birth services and changes in induction procedures. Many emergency adaptations persisted at the end of data collection. Differences between the trusts indicate complex change pathways. Staff reported some removal of bureaucracy, which allowed greater flexibility. During the first wave of COVID-19 staffing numbers increased, resolving some pre-pandemic shortages: however, by October 2021 they declined markedly. Trying to maintain the quality and availability of services had marked negative consequences for personnel. Timely routine clinical and staffing data were not always available and personalised care and user and staff experiences were poorly captured. Conclusions: The COVID-19 crisis magnified pre-pandemic problems and in particular, poor staffing levels. Maintaining services took a significant toll on staff wellbeing. There is some evidence that these pressures are continuing. There was marked variation in Trust responses. Lack of accessible and timely data at Trust and national levels hampered rapid insights. The ASPIRE COVID-19 framework could be useful for modelling the impact of future crises on routine care.

INTRODUCTION: Stillbirth is associated with significant physical, psychosocial and economic consequences for parents, families, wider society and the healthcare system. There is emerging momentum to design and evaluate interventions for care after stillbirth and in subsequent pregnancies. However, there is insufficient evidence to inform clinical practice compounded by inconsistent outcome reporting in research studies. To address this paucity of evidence, we plan to develop a core outcome set for stillbirth care research, through an international consensus process with key stakeholders including parents, healthcare professionals and researchers. METHODS AND ANALYSIS: The development of this core outcome set will be divided into five distinct phases: (1) Identifying potential outcomes from a mixed-methods systematic review and analysis of interviews with parents who have experienced stillbirth; (2) Creating a comprehensive outcome long-list and piloting of a Delphi questionnaire using think-aloud interviews; (3) Choosing the most important outcomes by conducting an international two-round Delphi survey including high-income, middle-income and low-income countries; (4) Deciding the core outcome set by consensus meetings with key stakeholders and (5) Dissemination and promotion of the core outcome set. A parent and public involvement panel and international steering committee has been convened to coproduce every stage of the development of this core outcome set. ETHICS AND DISSEMINATION: Ethical approval for the qualitative interviews has been approved by Berkshire Ethics Committee REC Reference 12/SC/0495. Ethical approval for the think-aloud interviews, Delphi survey and consensus meetings has been awarded from the University of Bristol Faculty of Health Sciences Research Ethics Committee (Reference number: 116535). The dissemination strategy is being developed with the parent and public involvement panel and steering committee. Results will be published in peer-reviewed specialty journals, shared at national and international conferences and promoted through parent organisations and charities. PROSPERO REGISTRATION NUMBER: CRD42018087748., National Institute of Health Research

OBJECTIVE Globally, preeclampsia is a significant contributor to adverse maternal outcomes. Once women develop eclampsia, they face considerable risks especially in countries with limited resources to deal with such a life-threatening complication. This study was carried out to investigate determinants of eclampsia in pregnant mothers with severe preeclampsia. STUDY DESIGN This institutional based study was completed at Mpilo Central Hospital, a quaternary referral unit from 1st January 2016 - 31st December 2018. In this study, pregnant women with severe preeclampsia/eclampsia were the study participants. The independent variables included socio-demographic and clinical characteristics, and maternal outcomes. Multivariable logistic regression analyses were used to determine independent association with p

Pregnancy is an opportune time for women to make healthy changes to their lifestyle, however, many women struggle to do so. Multiple reasons have been posited as to why this may be. This review aimed to synthesise this literature by identifying factors that influence women's health behaviour during pregnancy, specifically in relation to dietary behaviour, physical activity, smoking, and alcohol use. Bibliographic databases (MEDLINE, PsycINFO, CINAHL-P, MIDIRS) were systematically searched to retrieve studies reporting qualitative data regarding women's experiences or perceptions of pregnancy-related behaviour change relating to the four key behaviours. Based on the eligibility criteria, 30,852 records were identified and 92 studies were included. Study quality was assessed using the CASP tool and data were thematically synthesised. Three overarching themes were generated from the data. These were (1) A time to think about 'me', (2) Adopting the 'good mother' role, and (3) Beyond mother and baby. These findings provide an improved understanding of the various internal and external factors influencing women's health behaviour during the antenatal period. This knowledge provides the foundations from which future pregnancy-specific theories of behaviour change can be developed and highlights the importance of taking a holistic approach to maternal behaviour change in clinical practice.

Background Stillbirth, the death of a baby before birth, is associated with significant psychological and social consequences that can be mitigated by respectful and supportive bereavement care. The absence of high-level evidence to support the broad scope of perinatal bereavement practices means that offering a range of options identified as valued by parents has become an important indicator of care quality. This study aimed to describe bereavement care practices offered to parents across different high-income and middle-income countries. Methods An online survey of parents of stillborn babies was conducted between December 2014 and February 2015. Frequencies of nine practices were compared between high-income and middle-income countries. Differences in proportions of reported practices and their associated odds ratios were calculated to compare high-income and middle-income countries. Results Over three thousand parents (3041) with a self-reported stillbirth in the preceding five years from 40 countries responded. Fifteen countries had atleast 40 responses. Significant differences in the prevalence of offering nine bereavement care practices were reported by women in high-income countries (HICs) compared with women in middle-income countries (MICs). All nine practices were reported to occur significantly more frequently by women in HICs, including opportunity to see and hold their baby (OR = 4.8, 95% CI 4.0-5.9). The widespread occurrence of all nine practices was reported only for The Netherlands. Conclusions Bereavement care after stillbirth varies between countries. Future research should look at why these differences occur, their impact on parents, and whether differences should be addressed, particularly how to support effective communication, decision-making, and follow-up care.

Normal placental development and function is of key importance to fetal growth. Conversely aberrations of placental structure and function are evident in pregnancy complications including fetal growth restriction (FGR) and preeclampsia. Although trophoblast turnover and function is altered in these conditions, their underlying aetiologies and pathophysiology remains unclear, which hampers development of therapeutic interventions. Here we review evidence that supports a role for estrogen related receptor-gamma (ESRRG) in the development of placental dysfunction in FGR and preeclampsia. This relationship deserves particular consideration because ESRRG is highly expressed in normal placenta, is reduced in FGR and preeclampsia and its expression is altered by hypoxia, which is thought to result from deficient placentation seen in FGR and preeclampsia. Several studies have also found microRNA (miRNA) or other potential upstream regulators of ESRRG negatively influence trophoblast function which could contribute to placental dysfunction seen in FGR and preeclampsia. Interestingly, miRNAs regulate ESRRG expression in human trophoblast. Thus, if ESRRG is pivotally associated with the abnormal trophoblast turnover and function it may be targeted by microRNAs or other possible upstream regulators in the placenta. This review explores altered expression of ESRRG and upstream regulation of ESRRG-mediated pathways resulting in the trophoblast turnover, placental vascularisation, and placental metabolism underlying placental dysfunctions. This demonstrates that the ESRRG pathway merits further investigation as a potential therapeutic target in FGR and preeclampsia.

Hypertensive disorders of pregnancy are major causes of global maternal and neonatal morbidity and mortality. This study aimed to develop and validate models to predict composite adverse maternal and neonatal outcome in severe preeclampsia in low-resource settings.A retrospective cross-sectional study of women with severe preeclampsia giving birth in a tertiary referral centre in Zimbabwe between 01/01/2014-31/12/2018. Candidate variables identified from univariable logistic regression (p 0.2) were entered into stepwise backward elimination logistic regression models to predict composite adverse maternal and neonatal outcomes. Models' performance was assessed by the area under the curve of the receiver operator characteristic (AUC ROC). The models were validated internally using bootstrap-based methods and externally using the Preeclampsia Integrated Estimate of RiSk dataset.The co-primary outcomes were composite adverse maternal outcome and composite adverse neonatal outcome.549 women had severe preeclampsia from whom 567 neonates were born. The predictive model for composite adverse maternal outcome included maternal age, gestational age on admission, epigastric pain, vaginal bleeding with abdominal pain, haemoglobin concentration and platelets; the AUC ROC was 0.796 (95% CI 0.758-0.833). External validation showed poor discrimination (AUC ROC 0.494, 95% CI 0.458-0.552). The model for composite adverse neonatal outcome included: gestational age, platelets, alanine transaminase and birth weight; the AUC ROC was 0.902 (95% CI 0.876-0.927).While the models accurately predicted composite adverse maternal and neonatal outcomes in the study population, they did not in another cohort. Understanding factors which affect model performance will help optimize prediction of adverse outcomes in severe preeclampsia.

Objectives Despite the use of post-mortem investigations, approximately 20% of stillbirths remain unexplained. Cardiac ion channelopathies have been identified as a cause of death in Sudden Infant Death Syndrome (SIDS) and could be associated with unexplained stillbirths. This study aimed to understand if the expression or localisation of cardiac ion channels associated with channelopathies were altered in cases of unexplained stillbirths. Methods A case control study was conducted using formalin-fixed cardiac tissue from 20 cases of unexplained stillbirth and a control group of 20 cases of stillbirths from intrapartum hypoxia. 4 µm tissue sections were stained using haematoxylin and eosin, Masson’s trichrome (MT) and Elastic van Gieson (EVG). Immunohistochemistry (IHC) was performed using antibodies against CACNA1G, KCNJ2, KCNQ1, KCNH2 and KCNE1. The cardiac conduction system in samples stained with MT and EVG could not be identified. Therefore, the levels of immunoperoxidase staining were quantified using QuPath software. Results The nuclear-cytoplasmic ratio of sections stained with haematoxylin and eosin was higher for the hypoxia group (hypoxia median 0.13 vs. 0.04 unexplained, p Conclusions Two ion channels associated with channelopathies demonstrated lower levels of expression in cases of unexplained stillbirth. Further genetic studies using human tissue should be performed to understand the association between channelopathies and otherwise unexplained stillbirths.

Objective The consumption of caffeinated drinks and soft drinks is widespread in society, including by pregnant women. Data regarding the association of caffeine intake and stillbirth are varied. We aimed to investigate the degree of consumption of caffeinated drinks or soft drinks in the last four weeks of pregnancy in women who experienced a late stillbirth compared to women with ongoing live pregnancies at similar gestation. Influences on maternal caffeine intake and soft drink consumption during pregnancy were also investigated. Study Design A case-control study undertaken in 41 maternity units in the United Kingdom. Cases were women who had a singleton non-anomalous stillbirth ≥28 weeks’ gestation (n = 290) and controls were women with an ongoing pregnancy at the time of interview (n = 729). Data were collected using an interviewer-administered questionnaire which included questions regarding consumption of a variety of caffeinated drinks and soft drinks in the last four weeks of pregnancy as well as other behaviours (e.g. cigarette smoking). Results Multivariable analysis adjusting for co-existing demographic and behavioural factors found the consumption of instant coffee, energy drinks and cola were associated with increased risk of stillbirth. There was an independent association between caffeine intake and late stillbirth (adjusted Odds Ratio 1.27, 95 % Confidence Interval (95 %CI) 1.14, 1.43 for each 100 mg increment/day). 15 % of cases and 8% of controls consumed more than the World Health Organisation (WHO) recommendation (>300 mg of caffeine/day; aOR 2.30, 95 % CI 1.40, 4.24). The population attributable risk for stillbirth associated with >300 mg of caffeine/day was 7.4 %. The majority of respondents reduced caffeine consumption in pregnancy. Midwives and internet resources were the most frequently used sources of information which influenced maternal behaviour with regard to soft drinks and caffeine, and this did not differ between cases and controls. Conclusions Women should be informed that consumption of caffeine during pregnancy is associated with increased risk of stillbirth, particularly at levels greater than recommended by the WHO (>300 mg/day). Recommendations from midwives and internet-based resources are likely to be the most effective means to influence maternal behaviour.

OBJECTIVE To investigate behavioural and social characteristics of women who experienced a late stillbirth compared with women with ongoing live pregnancies at similar gestation. DESIGN Case-control study. SETTING 41 maternity units in the UK. POPULATION Women who had a stillbirth ≥28 weeks' gestation (n = 287) and women with an ongoing pregnancy at the time of interview (n = 714). METHODS Data were collected using an interviewer-administered questionnaire which included questions regarding women's behaviours (e.g. alcohol intake and household smoke exposure) and social characteristics (e.g. ethnicity, employment, housing). Stress was measured by the 10-item Perceived Stress Scale. MAIN OUTCOME MEASURE Late stillbirth. RESULTS Multivariable analysis adjusting for co-existing social and behavioural factors showed women living in the most deprived quintile had an increased risk of stillbirth compared with the least deprived quintile (adjusted odds ratio [aOR] 3.16; 95% CI 1.47-6.77). There was an increased risk of late stillbirth associated with unemployment (aOR 2.32; 95% CI 1.00-5.38) and women who declined to answer the question about domestic abuse (aOR 4.12; 95% CI 2.49-6.81). A greater number of antenatal visits than recommended was associated with a reduction in stillbirth (aOR 0.26; 95% CI 0.16-0.42). CONCLUSIONS This study demonstrates associations between late stillbirth and socio-economic deprivation, perceived stress and domestic abuse, highlighting the need for strategies to prevent stillbirth to extend beyond maternity care. Enhanced antenatal care may be able to mitigate some of the increased risk of stillbirth. TWEETABLE ABSTRACT Deprivation, unemployment, social stress & declining to answer about domestic abuse increase risk of #stillbirth after 28 weeks' gestation.

Background Stillbirth accounts for over 2 million deaths a year worldwide and rates remains stubbornly high. Multivariable prediction models may be key to individualised monitoring, intervention or early birth in pregnancy to prevent stillbirth. Objectives To collate and evaluate systematic reviews of factors associated with stillbirth in order to identify variables relevant to prediction model development. Search strategy MEDLINE, Embase, DARE and Cochrane Library databases and reference lists were searched up to November 2019. Selection criteria We included systematic reviews of association of individual variables with stillbirth without language restriction. Data collection and analysis Abstract screening and data extraction were conducted in duplicate. Methodological quality was assessed using AMSTAR and QUIPS criteria. The evidence supporting association with each variable was graded. Results The search identified 1198 citations. Sixty-nine systematic reviews reporting 64 variables were included. The most frequently reported were maternal age (n = 5), body mass index (n = 6) and maternal diabetes (n = 5). Uterine artery Doppler appeared to have the best performance of any single test for stillbirth. The strongest evidence of association was for nulliparity and pre-existing hypertension. Conclusion We have identified variables relevant to the development of prediction models for stillbirth. Age, parity and prior adverse pregnancy outcomes had a more convincing association than the best performing tests, which were PAPP-A, PlGF and UtAD. The evidence was limited by high heterogeneity and lack of data on intervention bias. Tweetable abstract Review shows key predictors for use in developing models predicting stillbirth include age, prior pregnancy outcome and PAPP-A, PLGF and Uterine artery Doppler.

Objective Twin pregnancies have a significantly higher perinatal mortality than singleton pregnancies. Current classification systems for perinatal death lack twin-specific categories, potentially leading to loss of important information regarding cause of death. We introduce and test a classification system designed to assign a cause of death in twin pregnancies (CoDiT). Design Retrospective cross-sectional study. Setting Tertiary maternity unit in England with a perinatal pathology service. Population Twin pregnancies in the West Midlands affected by fetal or neonatal demise of one or both twins between 1 January 2005 and 31 December 2016 in which postmortem examination was undertaken. Methods A multidisciplinary panel designed CoDiT by adapting the most appropriate elements of singleton classification systems. The system was tested by assigning cause of death in 265 fetal and neonatal deaths from 144 twin pregnancies. Cause of death was validated by another obstetrician blinded to the original classification. Main outcome measures Inter-rater, intra-rater, inter-disciplinary agreement and cause of death. Results Cohen's Kappa demonstrated 'strong' (>0.8) inter-rater, intra-rater and inter-disciplinary agreement (95% CI 0.70-0.91). The commonest cause of death irrespective of chorionicity was the placenta; twin-to-twin transfusion syndrome (TTTS) was the commonest placental cause in monochorionic twins and acute chorioamnionitis in dichorionic twins. Conclusions This novel classification system records causes of death in twin pregnancies from postmortem reports with high inter-user agreement. We highlight differences in aetiology of death between monochorionic and dichorionic twins. Tweetable abstract New classification system for #twin cause of death 'CoDiT' shows high rater agreement.

OBJECTIVE This study assessed prevalence of connective tissue disease (CTDs), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPL) in women with previous adverse pregnancy outcome compared with uncomplicated livebirths. DESIGN Retrospective case-control study. SETTING UK Primary Care. POPULATION OR SAMPLE Records of women, 18 years and older, within the Clinical Practice Research Datalink (CPRD) (1 January 2000-31 December 2013). METHODS Clinical Practice Research Datalink was searched for pregnancy terms to identify adverse pregnancy outcome. Each identified case was matched to five livebirths. MAIN OUTCOME MEASURES Diagnosis of SLE, CTD, APS or autoimmune antibodies. Poisson regression was performed to calculate relative risk ratios (RR), comparing adverse pregnancy outcome with livebirth cohorts. RESULTS Clinical Practice Research Datalink identified 20 123 adverse pregnancy outcomes matched to 97 323 livebirths, with a total of 875 590 person-years follow up. Median follow up from study entry was 7.29 years (SD 4.39). Compared with women with an uncomplicated livebirth, women with adverse pregnancy outcome had an increased risk of developing CTD or autoimmune antibodies (RR 3.20, 95% CI 2.90-3.51). Risk was greatest following a stillbirth (RR 5.82, 95% CI 4.97-6.81). For CTD and SLE, the risk was greatest within the first 5 years of adverse pregnancy outcome. Risk for aPL and APS diagnosis was highest ≥5 years from adverse pregnancy outcome. CONCLUSIONS Adverse pregnancy outcome is associated with increased risk of developing maternal CTD, including SLE. Either immunological factors predispose women to adverse pregnancy outcome and subsequent CTD diagnosis or, alternatively, adverse pregnancy outcome initiates autoimmune events which culminate in CTD in later life. TWEETABLE ABSTRACT Stillbirth is associated with increased maternal risk of developing systemic lupus erythematosus (SLE).

Background Placental growth factor (PlGF) and soluble-fms-like tyrosine kinase 1 (sFlt-1) are biomarkers of placental function used to aid the diagnosis and prediction of pregnancy complications. This work verified the analytical performance of both biomarkers and provides preliminary diagnostic accuracy data to identify adverse pregnancy outcome in women with reduced fetal movement. Methods Verification of sFlt-1 and PlGF assays included a comparative accuracy assessment of 24 serum samples analysed at six different sites and laboratory-specific precision estimates. The sFlt-1/PlGF ratio was assessed in serum samples obtained prospectively from 295 women with reduced fetal movement ≥36 weeks’ gestation; diagnostic accuracy was evaluated using 2 × 2 tables and area under the receiver operator characteristic (AUROC) curve. Results Regression analysis showed that performance between sites was good with Passing-Bablok slopes ranging from 0.96 to 1.05 (sFlt-1) and 0.93 to 1.08 (PlGF). All sites had a mean bias Conclusions Analytical performance of the sFlt-1 and PlGF assays was comparable across different sites. The sensitivity of sFlt-1/PlGF to identify adverse pregnancy outcome in women with reduced fetal movement was considered acceptable, in the absence of other tests, to progress to a pilot randomized controlled trial.

Context.— Women with diabetes have increased stillbirth risk. Although the underlying pathophysiological processes are poorly understood, stillbirth is frequently related to abnormal placental structure and function. Objective.— To investigate placental morphology and cellular characteristics in the placentas of women with diabetes who had stillbirths and stillbirths of unexplained cause. Design.— Placentas from women with uncomplicated live births, live births in women with diabetes, unexplained stillbirths, and stillbirths related to diabetes (n = 10/group) underwent clinical histopathologic assessment and were also investigated using immunohistochemical staining to quantify syncytial nuclear aggregates, proliferation, trophoblast area, vascularization, T cells, placental macrophages (Hofbauer cells), and the receptor for advanced glycation end products. Results.— Ki67+ cells were decreased in unexplained stillbirths compared with live births in women with diabetes. Both stillbirth groups had increased cytokeratin 7+/nuclear area compared with controls. Blood vessels/villi were decreased in unexplained stillbirth compared with live births from women with diabetes. Compared with uncomplicated controls, CD163+ macrophages were increased in live births in women with diabetes and unexplained stillbirths, and further increased in stillbirths related to diabetes. There was no change in CD3+ T cells or syncytial nuclear aggregates. Receptor for advanced glycation end products–positive cells were decreased in both stillbirth groups compared with diabetes-related live births. Co-localization of receptor for advanced glycation end products in macrophages was increased in both stillbirth groups compared with live birth groups. Conclusions.— Stillbirths related to diabetes exhibit placental phenotypic differences compared with live births. Further investigation of these parameters may provide understanding of the pathologic mechanisms of stillbirth and aid the development of stillbirth prevention strategies.

Because of the critical role that placental structure and function plays during pregnancy, abnormal placental structure and function is closely related to stillbirth: when an infant dies before birth. However, understanding the role of the placental and specific lesions is incomplete, in part because of the variation in definitions of lesions and in classifying causes of stillbirths. Nevertheless, placental abnormalities are seen more frequently in stillbirths than live births, with placental abruption, chorioamnionitis, and maternal vascular malperfusion most commonly reported. Critically, some placental lesions affect the management of subsequent pregnancies. Histopathological examination of the placenta is recommended following stillbirth.

Objectives Stillbirth remains a global public health issue; in low-resource settings stillbirth rates remain high (>12 per 1,000 births target of Every Newborn Action Plan). Preeclampsia is major risk factor for stillbirths. This study aimed to determine the prevalence and risk factors for stillbirth amongst women with severe preeclampsia at Mpilo Central Hospital. Methods A retrospective cross-sectional study was conducted of women with severe preeclampsia from 01/01/2016 to 31/12/2018 at Mpilo Central Hospital, Bulawayo, Zimbabwe. Multivariable logistic regression was used to determine risk factors that were independently associated with stillbirths. Results Of 469 women that met the inclusion criteria, 46 had a stillbirth giving a stillbirth prevalence of 9.8%. The risk factors for stillbirths in women with severe preeclampsia were: unbooked status (adjusted odds ratio (aOR) 3.01, 95% (confidence interval) CI 2.20–9.10), frontal headaches (aOR 2.33, 95% CI 0.14–5.78), vaginal bleeding with abdominal pain (aOR 4.71, 95% CI 1.12–19.94), diastolic blood pressure ≥150 mmHg (aOR 15.04, 95% CI 1.78–126.79), platelet count 0–49 × 109/L (aOR 2.80, 95% CI 1.26–6.21), platelet count 50–99 × 109/L (aOR 2.48, 95% CI 0.99–6.18), antepartum haemorrhage (aOR 12.71, 95% CI 4.15–38.96), haemolysis elevated liver enzymes syndrome (HELLP) (aOR 6.02, 95% CI 2.22–16.33) and fetal sex (aOR 2.75, 95% CI 1.37–5.53). Conclusions Women with severe preeclampsia are at significantly increased risk of stillbirth. This study has identified risk factors for stillbirth in this high-risk population; which we hope could be used by clinicians to reduce the burden of stillbirths in women with severe preeclampsia.

Objectives: Theoretical models have informed the understanding of pregnancy as a ‘teachable moment’ for health behaviour change. However, these models have not been developed specifically for, nor widely tested, in this population. Currently, no pregnancy-specific model of behaviour change exists, which is important given it is a unique yet common health event. This study aimed to assess the extent to which factors influencing antenatal behaviour change are accounted for by the COM-B model and Teachable Moments (TM) model, and to identify which model is best used to understand behaviour change during pregnancy. Design: Theoretical mapping exercise.Methods: A deductive approach was adopted; nine sub-themes identified in a previous thematic synthesis of 92 studies were mapped to the constructs of the TM and COM-B models. The sub-themes reflected factors influencing antenatal health behaviour.Findings: All sub-themes mapped to the COM-B model constructs, whereas the TM model failed to incorporate three sub-themes. Missed factors were non-psychological, including practical and environmental factors, social influences, and physical pregnancy symptoms. In contrast to the COM-B model, the TM model provided an enhanced conceptual understanding of pregnancy as a teachable moment for behaviour change, however neither model accounted for the changeable salience of influencing factors throughout the pregnancy experience.Conclusions: The TM and COM-B models are both limited when applied within the context of pregnancy. Nevertheless, both models offer valuable insight that should be drawn upon when developing a pregnancy-specific model of behaviour change.

Objective Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. Methods MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. Results Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. Conclusions The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. (c) 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Additional file 1

Additional file 1: Figure S1. Psychological outcomes (Women). Figure S2. Psychological outcomes (Partners). Table S1. Summary of utility values derived from the EQ-5D-5L for women and partners at baseline (recruitment), follow up (late pregnancy) and postnatal (4-6 weeks) post birth.

Statistical analysis plan for the Evaluating Antenatal Risk in Twins Pilot Study. Version 1.0

Pregnancy is often conceptualised as a 'teachable moment' for health behaviour change. However, it is likely that different stages of pregnancy, and individual antenatal events, provide multiple distinct teachable moments to prompt behaviour change. Whilst previous quantitative research supports this argument, it is unable to provide a full understanding of the nuanced factors influencing eating behaviour. The aim of this study was to explore influences on women's eating behaviour throughout pregnancy.In-depth interviews were conducted online with 25 women who were less than six-months postpartum. Interviews were audio-recorded and transcribed verbatim. Data were analysed thematically.Five themes were generated from the data that capture influences on women's eating behaviour throughout pregnancy: 'The preconceptual self', 'A desire for good health', 'Retaining control', 'Relaxing into pregnancy', and 'The lived environment'.Mid-pregnancy may provide a more salient opportunity for eating behaviour change than other stages of pregnancy. Individual antenatal events, such as the glucose test, can also prompt change. In clinical practice, it will be important to consider the changing barriers and facilitators operating throughout pregnancy, and to match health advice to stages of pregnancy, where possible. Existing models of teachable moments may be improved by considering the dynamic nature of pregnancy, along with the influence of the lived environment, pregnancy symptoms, and past behaviour. These findings provide an enhanced understanding of the diverse influences on women's eating behaviour throughout pregnancy and provide a direction for how to adapt existing theories to the context of pregnancy.

Matters Arising article, arising from H. Bové et al. Nature Communications https://doi.org/10.1038/s41467-019-11654-3 (2019).

Prolonged pregnancy describes a pregnancy that progresses beyond 42 weeks’ gestation (294 days). In humans, prolonged pregnancy is associated with increasing perinatal mortality, neonatal compromise and birth by Caesarean section. The underpinning reasons behind these increased risks are unknown; one potential explanation is reduced placental function due to ageing processes. This review describes the structural and functional changes seen in prolonged pregnancy in humans and in animal models. Prolonged pregnancies are associated with reduced placental growth, leading to an increase in fetal to placental weight ratio. Microscopic changes include aggregation of syncytiotrophoblast nuclei, reduced villous vascularity with a concomitant impairment of trophoblast transport processes (reduced pinocytosis); this is associated with increased evidence of oxidative stress, with downstream consequences including cellular senescence, autophagy and apoptosis; importantly many of these changes are similar to fetal growth restriction and pre-eclampsia. Thus, we argue that these observations provide evidence of ageing within the placenta, which may initially be adaptive but can become pathological leading to a reduction in placental function. This provides a biological basis for the increased risk of adverse outcomes observed in prolonged pregnancies. Greater insight into the effects and risks of placental ageing may be useful to guide clinicians on the management of prolonged pregnancies.

Histological examination of the placenta significantly contributes to diagnosis in adverse birth outcomes. One challenge in image analysis is variation in staining intensity caused by batch variation. We investigated if dynamic threshold image analysis methods may increase accuracy. Placenta samples were stained for endothelial cells and syncytial nuclear aggregates and analysed in Qupath software. Dynamically setting the threshold resulted in data more similar to manual method data. The method is simple and effective at modelling the dynamic interpretation of variation in staining intensity achieved by manual methods. We anticipate dynamic methods could be used to enhance placental diagnosis.

Bisphenol A (BPA) exposure during pregnancy is associated with low fetal weight, particularly in male fetuses. The expression of estrogen-related receptor gamma (ESRRG), a receptor for BPA in the human placenta, is reduced in fetal growth restriction. This study sought to explore whether ESRRG signaling mediates BPA-induced placental dysfunction and determine whether changes in the ESRRG signaling pathway are sex-specific. Placental villous explants from 18 normal term pregnancies were cultured with a range of BPA concentrations (1 nM–1 μM). Baseline BPA concentrations in the placental tissue used for explant culture ranged from 0.04 to 5.1 nM (average 2.3 ±1.9 nM; n = 6). Expression of ESRRG signaling pathway constituents and cell turnover were quantified. BPA (1 μM) increased ESRRG mRNA expression after 24 h in both sexes. ESRRG mRNA and protein expression was increased in female placentas treated with 1 μM BPA for 24 h but was decreased in male placentas treated with 1 nM or 1 μM for 48 h. Levels of 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) and placenta specific-1 (PLAC1), genes downstream of ESRRG, were also affected. HSD17B1 mRNA expression was increased in female placentas by 1 μM BPA; however, 1 nM BPA reduced HSD17B1 and PLAC1 expression in male placentas at 48 h. BPA treatment did not affect rates of proliferation, apoptosis, or syncytiotrophoblast differentiation in cultured villous explants. This study has demonstrated that BPA affects the ESRRG signaling pathway in a sex-specific manner in human placentas and a possible biological mechanism to explain the differential effects of BPA exposure on male and female fetuses observed in epidemiological studies.