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Context.--Chronic histiocytic intervillositis (CHI) is a rare condition characterized by maternal immune cell infiltration into the human placenta. CHI is strongly associated with fetal growth restriction, miscarriage, and stillbirth, and knowledge of its etiology, and consequently effective treatment, is limited. Currently, diagnosis is largely subjective and varies between centers, making comparison between studies challenging. Objective.--To objectively quantify and interrelate inflammatory cells and fibrin in placentas with CHI compared with controls and determine how pathology may be altered in subsequent pregnancies following diagnosis. Macrophage phenotype was also investigated in untreated cases of CHI. Design.--Computerized analysis was applied to immunohistochemically stained untreated (index) cases of CHI, subsequent pregnancies, and controls. Index placentas were additionally stained by immunofluorescence for M1 (CD80 and CD86) and M2 macrophage markers (CD163 and CD206). Results.--Quantification revealed a median 32-fold increase in macrophage infiltration in index cases versus controls, with CHI recurring in 2 of 11 (18.2%) subsequent pregnancies. A total of 4 of 14 placentas (28.6%) with a diagnosis of CHI did not exhibit infiltration above controls. Macrophages in index pregnancies strongly expressed CD163. There was no significant difference in fibrin deposition between index cases and controls, although subsequent pregnancies displayed a 2-fold decrease compared with index pregnancies. [CD3.sup.+] T cells were significantly elevated in index pregnancies; however, they returned to normal levels in subsequent pregnancies. Conclusions.--In CHI, intervillous macrophages expressed CD163, possibly representing an attempt to resolve inflammation. Computerized analysis of inflammation in CHI may be useful in determining how treatment affects recurrence, and alongside pathologist expertise in grading lesion severity. doi: 10.5858/arpa.2022-0494-OA, Chronic histiocytic intervillositis (CHI) is an inflammatory lesion of the human placenta affecting 6 in every 10 000 pregnancies past 12 weeks' gestation, (1) wherein maternal macrophages infiltrate the intervillous [...]

Abstract Chronic histiocytic intervillositis (CHI) is a recurrent placental lesion where maternal macrophages infiltrate the intervillous space. Its cause is unknown, though due to similarities to rejected allografts one hypothesis is that CHI represents maternal–fetal rejection. Here, virtual crossmatching was applied to healthy pregnancies and those with a history of CHI. Anti-HLA antibodies, measured by Luminex, were present in slightly more controls than CHI (8/17 (47.1%) vs 5/14 (35.7%)), but there was no significant difference in levels of sensitisation or fetal specific antibodies. Quantification of immunohistochemical staining for HLA-Class II was increased in syncytiotrophoblast of placentas with CHI (Grade 0.44 [IQR 0.1–0.7]) compared to healthy controls (0.06 [IQR 0–0.2]) and subsequent pregnancies (0.13 [IQR 0–0.3]) (P = 0.0004). HLA-Class II expression was positively related both to the severity of CHI (r = 0.67) and C4d deposition (r = 0.48). There was no difference in overall C4d and HLA-Class I immunostaining. Though increased anti-HLA antibodies were not evident in CHI, increased expression of HLA-Class II at the maternal–fetal interface suggests that they may be relevant in its pathogenesis. Further investigation of antibodies immediately after diagnosis is warranted in a larger cohort of CHI cases to better understand the role of HLA in its pathophysiology.

Sex differences are widespread during neurodevelopment and play a role in neuropsychiatric conditions such as autism, which is more prevalent in males than females. In humans, males have been shown to have larger brain volumes than females with development of the hippocampus and amygdala showing prominent sex differences. Mechanistically, sex steroids and sex chromosomes drive these differences in brain development, which seem to peak during prenatal and pubertal stages. Animal models have played a crucial role in understanding sex differences, but the study of human sex differences requires an experimental model that can recapitulate complex genetic traits. To fill this gap, human induced pluripotent stem cell–derived brain organoids are now being used to study how complex genetic traits influence prenatal brain development. For example, brain organoids from individuals with autism and individuals with X chromosome–linked Rett syndrome and fragile X syndrome have revealed prenatal differences in cell proliferation, a measure of brain volume differences, and excitatory-inhibitory imbalances. Brain organoids have also revealed increased neurogenesis of excitatory neurons due to androgens. However, despite growing interest in using brain organoids, several key challenges remain that affect its validity as a model system. In this review, we discuss how sex steroids and the sex chromosomes each contribute to sex differences in brain development. Then, we examine the role of X chromosome inactivation as a factor that drives sex differences. Finally, we discuss the combined challenges of modeling X chromosome inactivation and limitations of brain organoids that need to be taken into consideration when studying sex differences.

Abstract Background Women experiencing pregnancy after stillbirth experience high levels of anxiety, fear and depression. Standard antenatal care may be emotionally unsuitable for many women at this time, and there is a lack of evidence on what interventions or approaches to care might benefit these women. Therapeutic massage may assist women after stillbirth by decreasing anxiety, worry and stress. Objective This paper outlines the objectives, methodology, outcome and assessment measures for the Helping suppOrt individuals Pregnant after Experiencing a Stillbirth (HOPES) feasibility trial which evaluates massage as an adjunct approach to care for pregnant women who have experienced a prior stillbirth. It also outlines data collection timing and considerations for analysing the data. Methods HOPES will use a convergent parallel mixed-methods, single-arm repeated measures trial design in trained massage therapists’ private clinics across Australia. HOPES aims to recruit 75 individuals pregnant after a previous stillbirth. The intervention is massage therapy treatments, and participants will receive up to five massages within a 4-month period at intervals of their choosing. Primary quantitative outcomes are the feasibility and acceptability of the massage intervention. Secondary outcomes include determining the optimal timing of massage therapy delivery and the collection of measures for anxiety, worry, stress and self-management. A thematic analysis of women’s experiences undertaking the intervention will also be conducted. A narrative and joint display approach to integrate mixed-methods data is planned. Discussion The HOPES study will determine the feasibility and preliminary evidence for massage therapy as an intervention to support women who are pregnant after a stillbirth. Trial registration. ClinicalTrials.gov NCT05636553. Registered on December 3, 2022, and the trial is ongoing.

Background There is a policy drive in NHS maternity services to improve open disclosure with harmed families and limited information on how better practice can be achieved. Objectives To identify critical factors for improving open disclosure from the perspectives of families, doctors, midwives and services and to produce actionable evidence for service improvement. Design A three-phased, qualitative study using realist methodology. Phase 1: two literature reviews: scoping review of post-2013 NHS policy and realist synthesis of initial programme theories for improvement; an interview study with national stakeholders in NHS maternity safety and families. Phase 2: in-depth ethnographic case studies within three NHS maternity services in England. Phase 3: interpretive forums with study participants. A patient and public involvement strategy underpinned all study phases. Setting National recruitment (study phases 1 and 3); three English maternity services (study phase 2). Participants We completed n = 142 interviews, including 27 with families; 93 hours of ethnographic observations, including 52 service and family meetings over 9 months; and interpretive forums with approximately 69 people, including 11 families. Results The policy review identified a shift from viewing injured families as passive recipients to active contributors of post-incident learning, but a lack of actionable guidance for improving family involvement. The realist synthesis found weak evidence of the effectiveness of open disclosure interventions in the international maternity literature, but some improvements with organisation-wide interventions. Recent evidence was predominantly from the United Kingdom. The research identified and explored five key mechanisms for open disclosure: meaningful acknowledgement of harm; involvement of those affected in reviews/investigations; support for families’ own sense-making; psychological safely of skilled clinicians (doctors and midwives); and knowing that improvements to care have happened. The need for each family to make sense of the incident in their own terms is noted. The selective initiatives of some clinicians to be more open with some families is identified. The challenges of an adversarial medicolegal landscape and limited support for meeting incentivised targets is evidenced. Limitations Research was conducted after the pandemic, with exceptional pressure on services. Case-study ethnography was of three higher performing services: generalisation from case-study findings is limited. No observations of Health Safety Investigation Branch investigations were possible without researcher access. Family recruitment did not reflect population diversity with limited representation of non-white families, families with disabilities and other socially marginalised groups and disadvantaged groups. Conclusions We identify the need for service-wide systems to ensure that injured families are positioned at the centre of post-incident events, ensure appropriate training and post-incident care of clinicians, and foster ongoing engagement with families beyond the individual efforts made by some clinicians for some families. The need for legislative revisions to promote openness with families across NHS organisations, and wider changes in organisational family engagement practices, is indicated. Examination of how far the study’s findings apply to different English maternity services, and a wider rethinking of how family diversity can be encouraged in maternity services research. Study registration This study is registered as PROSPERO CRD42020164061. The study has been assessed following RAMESES realist guidelines. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research Programme (NIHR award ref: 17/99/85) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 22. See the NIHR Funding and Awards website for further award information. Plain language summary This study describes the experiences of families and healthcare professionals involved in incidents in NHS maternity care. The incidents caused harm-like injury or death to the baby or woman. We wanted to know whether services involved families in investigations and reviews and how this was done, what worked well, what did not work well and why. To do this, we first looked at what had already been written about ‘open disclosure’ or OD. Open disclosure is when the NHS admits to families that the care they provided has directly caused harm. After open disclosure occurs, families should be involved in making sure that the NHS learns so it can deliver better care for families in the future. In our reading, we found that families want a meaningful apology, to be involved in reviews or investigations, to know what happened to their loved one, to be cared for by knowledgeable doctors and midwives who are supported in providing open disclosure and to know things have changed because of what happened. Recommendations for involving families in open disclosure have improved, but there is still work to be done to make sure families are involved. Next, we talked to over 100 healthcare professionals involved in government policy for open disclosure in maternity services and 27 families who experienced harm. We spent 9 months observing the work of clinicians at three maternity services to watch open disclosure. We shared early findings with families, doctors, midwives and managers, and included their views. We found that services need to provide dedicated time, education and emotional support for staff who provide open disclosure. Services need to ensure that families have ongoing support and better communication about incidents. Finally, families must be involved in the review process if they want to be with their experiences reflected in reports and kept informed of ongoing improvements. Scientific summary Background A range of interventions have been introduced in the UK NHS to improve post-incident communication and support of injured families. However, there is limited evidence on the progress of this work and how improvements in open disclosure (OD) are to be embedded. Study aims and objectives The aim was to identify the critical, underlying factors for improving the incidence and quality of post-incident communication with families in NHS maternity services. This required examination of what is necessary and required in different contexts for OD processes and practices to be strengthened for families, doctors and midwives (henceforth clinicians) and service managers. Following a realist evaluation approach, the study objectives were to: establish initial hypotheses to focus investigation of OD improvements in NHS maternity services in England examine the scope of OD in NHS maternity services from the perspectives of regional and national stakeholders refine our initial hypotheses in relation to the analysis of regional and national stakeholder perspectives conduct an in-depth study of OD improvement within services verify data interpretation and study output development with different stakeholders (families, clinicians, service managers and national policy-makers). Overview of methods A qualitative study using realist evaluation methodology to evaluate the progress of OD in English NHS maternity services was conducted (May 2019–March 2022) in three sequential study phases (SPs). Realist approaches are theory-driven and designed for investigation of complex social interventions. They consider if and how an intervention works in different circumstances from the perspectives of different people. Initial hypotheses, developed from the use of a realist evaluation conceptual tool [context–mechanism–outcome (C–M–O) configurations], are developed from literature synthesis and ‘tested’ by primary research to identify potential causal relationships that explain how an intervention works. A Project Advisory Group (PAG), including families, participated in study decisions, from initial theory development, case-study sampling, data collection and interpretation of study findings against a background of rapid policy change. Primary data collection was from November 2019 to January 2022. A patient involvement and public engagement strategy sought to maximise family involvement in all stages of the study cycle. Study phase1a: literature review A scoping review examined recent (2014–22) policy recommendations for family engagement improvements in NHS maternity services. Documents were identified through database searching and included if they were related to safety, incidents, harm, reviews and investigations in maternity care. Academic papers; essays; conference abstractions, papers and presentations; and research studies were excluded. The realist synthesis of primary evidence of the progress of interventions for strengthening OD in international maternity settings included 38 documents appraised for relevance and rigour. Documents were from key database searches, included all English language sources (post 2000), without predetermined exclusion criteria for research methods. Only primary research evidence or evidence synthesis was included. Programme theories were developed with our PAG for testing during later SPs. Study phase 1b: national and regional stakeholder interview study National and regional stakeholders (n = 44), and families (n = 23), were interviewed following a topic guide developed from our literature synthesis. Families included in the study have histories of significant injury, including the stillbirth, death or serious injury of their baby and/or themselves (dating from 2007 to 2021). Study phase 2: ethnographic case studies Three maternity services in two Trusts were identified for in-depth ethnographic research by purposive sampling, based on their capacity to accommodate research immediately following the coronavirus disease 2019 (COVID-19) pandemic, and evidence of their positive deviance in improvement work on openness identified from public data sets. Across these services, we conducted: staff interviews (n = 75) and three return staff interviews, family interviews (n = 4), observations of staff and family meetings (n = 52) and observations of informal unit and office activities (all observations totalled 93 hours, with 30 hours of in-person observations). Families recruited from the case-study services had histories of significant injury dating from 2018 to 2020. We also collected and analysed locally available documentation relating to candour and being open. Study phase 3: interpretation We conducted five interpretive forums to inform the interpretation of findings. These were a forum with project advisors (n = 14), including families (n = 6), a family forum with several SP1b study participants (n = 5) and three service case-study forums, comprised of clinical and service managers and clinicians. Total forum participation was approximately n = 65. All data were managed using NVivo 20 (QSR International, Warrington, UK) and analysed concurrently by two researchers using a retroductive approach. This technique involved the ongoing examination and theorisation of findings to identify causal explanations for how, for whom, and in what ways OD might be improved. We used the five programme theories identified from the realist review to organise the analysis and reporting of our stakeholder interview and ethnographic case-study findings. Findings from our forums are included in the synthesis and discussion of findings. Results Literature reviews Our scoping review of policy documents (n = 39) identified a shift from a paternalistic view of injured families as passive recipients of care to active contributors in reviews, investigations, learning and quality improvement. Two overlapping policy trajectories were identified: one related to the Duty of Candour (DoC) and one related to maternity safety more widely. Seven themes were identified: building trust in organisations; improving systems of care and ensuring accountability; improving the safety of maternity care and saying sorry; shifting to individualised, relational care; enhancing communication; conceptualising families as active partners rather than passive recipients; and enabling families to guide the process. Although the progression of how family involvement is discussed and considered in policy is moving in a positive direction, we note the opportunity for future, specific, actionable recommendations to ensure these ideals translate into practice. In the realist synthesis, documents (n = 39) were appraised for ‘fitness-for-purpose’, that together documented primary evidence of 21 OD improvement interventions from which we identified 5 initial programme theories. Interventions documented were predominantly from USA, Australasia, and, more recently, UK sources. We identified limited evidence of the effectiveness of interventions documented. We found a difference between interventions that were adjuncts to more general safety improvement projects, and organisation-wide interventions focused on post-incident communication and care of injured families. Identified programme theories were: receiving a meaningful acknowledgement of the harm that has happened, being involved during the review/investigation process, making sense of what happened, receiving care from clinicians who are skilled and feel psychologically safe during post-incident communication and knowing that things have changed because of what has happened. Findings by programme theory Receiving a meaningful acknowledgement of the harm that has happened National stakeholders described factors that prevented or slowed improvements in initial post-incident communication and ongoing care of injured families. These were: the risks of litigation and reputational damage which may be associated with an apology and the obligation to be candid. This was particularly challenging when the extent or circumstances of injury were uncertain. Variation in the confidence and willingness of clinicians to undertake initial and ongoing disclosure with families was noted across the case studies. Alongside general medicolegal and ethical challenges to disclosure improvements, wider erosion of compassionate disclosure with families in relation to the escalation of organisational compliance in maternity safety initiatives was noted by stakeholders. Interviews with families on their post-incident experiences (2007–11) highlighted an ongoing lack of compassionate care and of prompt disclosure in many services. Many families distrusted post-incident communication, suspecting that information was being withheld. In the case-study services, the main concern for OD leads was the recovery of family trust in the service. Here, the tension between disclosure as a mandated directive and as ongoing communication was notable, with lack of investment and organisational support for the latter. A significant context of OD work was the churn of work schedules and the speed of family transfers. This complicated efforts to develop consistency of communication and care across initial, mandated and ongoing post-incident meetings, particularly where the uniqueness and flux in the needs of harmed families were paramount and families were already distrustful. These conditions led to a situation where OD was sustained as an individual and selective initiative conducted by some clinicians with some families. Being involved during the review/investigation process We examined experiences of the implementation of family engagement through the Perinatal Mortality Review Tool (PMRT) and independent Health Safety Investigation Branch (HSIB) reviews/investigations from national, in-depth, case-study perspectives. We found PMRT implementation sometimes lacked relational care for families. Additionally, families were sometimes suspicious of the independence of external incident reviews. The case-study services reported inadequacies in family inclusion, with limited proactive approaches to family involvement. A range of family involvement approaches and rationales for involvement were found across and within the case-study services, with an emphasis on families as contributing value to organisational learning for safety improvement. The tension felt by clinicians between sharing uncertain knowledge of an incident with a family and sustaining OD is identified, as is the tension between the different goals of families and services, with the former desiring answers about their case and the latter seeking system-based learning for ongoing safety improvement. Making sense of what happened We explore the practices of knowledge construction in incidents and the management of this knowledge from the perspectives of national stakeholders, staff and families. The impact of widespread organisational defensiveness over documentation sent to families, along with confusion over the purpose of reports, generated distrust. Nationally, the poor quality or inaccuracies in clinical records exacerbated differences between service and family perspectives. In the crafting of reports, during ongoing family debriefings on report findings and through informal avenues and networks, the support for families to make sense of what happened could sometimes be recovered. However, we identify the privilege and capacity required for families to gather information and garner personal networks and expertise independently of services for this to take place. Receiving care from clinicians who are skilled and feel psychologically safe during post-incident communication We identified a national underinvestment in the training of clinicians in the care of injured families and in specialist OD skills. Interviews with junior clinicians, including Band 5/6 midwives; obstetric trainees and clinical fellows, highlighted the importance of early, non-judgemental, post-incident support for junior staff. The ongoing impact of avoidable harm on clinicians is examined, along with the impact of the limited involvement of staff in Trust-level investigation and review processes. We mapped the organisation and reported use of post-incident staff support for the three case-study services and found that debriefs, organised within a few weeks of the incident, and opportunities for meeting with families were most valued by staff. Services designed or commissioned by organisations without consultation with front-line staff themselves were underused and there was also a tendency for expert clinicians to see OD work as a personal rather than a professional or service imperative. Knowing that things have changed because of what has happened The importance for injured families and staff involved in an incident to see learning and service change following an incident was clear in national and case-study findings. Demonstrating that changes were in progress was key to a service demonstrating trustworthiness to the injured family. Some injured families felt a personal responsibility to ensure that change was secured. However, in most cases, services did not maintain contact with families after their review or investigation debriefs. For some clinical leads, there was a tension between ‘quick wins’ and protracted, significant, service investment. For wider staff groups, there was a lack of effective service-level communication strategies for updating on learning and change from incidents. Embedded, ongoing multidisciplinary team meetings, where non-judgemental discussion of incidents and their effects could take place, were identified as important for establishing a wider culture of openness. The extent and tone of clinical governance (CG) outreach to front-line staff were also significant in shaping staff attitudes and behaviours towards incidents and harmed families. Discussion Realist analysis identified the significant factors and contexts that impacted efforts to strengthen OD in maternity care. We explored several layers of context influencing the progress of this work. Nationally, we identified an ongoing tension between policy prompting OD and a medicolegal context where this openness continued to place clinicians and services at reputational or legal risk. Trust-level clinical leadership and the maturation of related service approaches (notably, family and patient involvement expertise and access to post-pregnancy support pathways) played a significant role in supporting OD. For families, variations in post-incident communication and care depended on two main factors: first, the assignment of an incident to one or more national maternity safety improvement programmes that entailed particular expectations of, and processes for, family involvement, and second, the capacity of a family to proactively seek out explanations and to foster relationships for personalised support from some clinicians. In the case-study services, where some harmed families were proactive in demanding a hearing and ongoing care, and where individual clinicians reached personal judgements on a family’s entitlement to this, examples of improved OD were observed. Overall, variations in post-incident communication and support for families were explained by a lack of service investment and by individual differences in attitudes to risk and family entitlement from clinicians. Conclusions This study is the first to establish a national overview and in-depth analysis of the progress of interventions intended to support OD with families. It provides an evidence base of experiences of harmed families (incidents ranging from 2007 to 2021) and of clinicians and managers working in this field (2020–1). There are growing calls for service-level improvements in responsiveness to the experiences and needs of families post incident as well as to their calls for greater openness. However, we find that without dedicated investment in and focus on the post-incident care of families and the emotional and organisational demands of this work on clinicians; without an understanding of these needs by external agencies incentivising improvement; and without national revision in the medicolegal landscape where this work happens, candour about harm in health care will continue to divide the interests of families, staff and services. Research gaps and recommendations Research was conducted immediately after the COVID-19 pandemic, with services under considerable strain. Three high-performing services were recruited for the observational research; therefore, generalisation from findings is limited. Access to observe external (HSIB) investigations was not possible. Despite ongoing revisions to the patient and public involvement (PPI) strategy, families often marginalised by maternity services remain under-represented in this study. A multi-methods study across English maternity services to establish the validity of findings and family recruitment strategies ensuring diversity are recommended for the future. Study registration This study is registered as PROSPERO CRD42020164061. The study has been assessed following RAMESES realist guidelines. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research Programme (NIHR award ref: 17/99/85) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 22. See the NIHR Funding and Awards website for further award information.

Abstract In the United Kingdom, roughly 1 in 250 babies are stillborn each year. Most women who experience stillbirth become pregnant again – 80% within a year of loss. Presently, obstetric-led care is recommended; though there is a growing body of evidence to support provision of specialist services. The Rainbow Clinic is a specialist antenatal service providing care for pregnancies after loss incorporating clinical and psychological care. This study aimed to assess patient experience at the Rainbow Clinic and identify areas for clinical improvement. A 13-item questionnaire was distributed to pregnant women who attended the Rainbow Clinics at the Oxford Road and Wythenshawe sites of Saint Mary’s Hospital, Manchester, UK between July 2016 and June 2021. Descriptive statistics and unpaired t-test were used for quantitative data and summative content analysis for qualitative data. Four-hundred and fifty-six women completed the questionnaire. The mean patient experience score per quarter was stable with an average of 21.1 (± 3.0) for the five years, with a maximum attainable score of 25. The COVID-19 pandemic had no effect on patient experience at the Rainbow Clinic (pre-pandemic vs. during-pandemic: mean 21.2 v 21.3; p = 0.75). Free-text responses demonstrated women felt positively about the antenatal care received. Identified areas for improvement included “more awareness of the [Rainbow] sticker” to ensure women with previous loss are identified; increased publicity of the Rainbow Clinic services; developing more clinics at different locations to improve accessibility; and continuing specialist input into intrapartum care. Specialist antenatal care provided by the Rainbow Clinic was rated as of a high standard. Potential future improvements include sticker alterations (or other mechanisms to identify women who have experienced a previous loss) and develop increased awareness of the clinic in other institutions.

Introduction In the UK, 1600 babies die every year before, during or immediately after birth at 20–28 weeks’ gestation. This bereavement has a similar impact on parental physical and psychological well-being to late stillbirth (>28 weeks’ gestation). Improved understanding of potentially modifiable risk factors for late stillbirth (including supine going-to-sleep position) has influenced international clinical practice. Information is now urgently required to similarly inform clinical practice and aid decision-making by expectant mothers/parents, addressing inequalities in pregnancy loss between 20 and 28 weeks.Methods and analysis This study focuses on what portion of risk of pregnancy loss 20–28 weeks’ gestation is associated with exposures amenable to public health campaigns/antenatal care adaptation. A case–control study of non-anomalous singleton baby loss (via miscarriage, stillbirth or early neonatal death) 20+0 to 27+6 (n=316) and randomly selected control pregnancies (2:1 ratio; n=632) at group-matched gestations will be conducted. Data is collected via participant recall (researcher-administered questionnaire) and extraction from contemporaneous medical records. Unadjusted/confounder-adjusted ORs will be calculated. Exposures associated with early stillbirth at OR≥1.5 will be detectable (p0.80) assuming exposure prevalence of 30%–60%.Ethics and dissemination NHS research ethical approval has been obtained from the London—Seasonal research ethics committee (23/LO/0622). The results will be presented at international conferences and published in peer-reviewed open-access journals. Information from this study will enable development of antenatal care and education for healthcare professionals and pregnant people to reduce risk of early stillbirth.Trial registration number NCT06005272.

Objective: To establish proof‐of‐concept for the dynamic prediction of adverse pregnancy outcome in women with a history of stillbirth or perinatal death, repeatedly throughout the pregnancy. Methods: A retrospective cohort study of women in a subsequent pregnancy following previous perinatal loss, who received antenatal care at a tertiary hospital between January 2014 and December 2017, was used as the basis for exploratory prognostic model development. Models were developed to repeatedly predict a composite adverse outcome (stillbirth or neonatal death, 5‐min Apgar score < 7, umbilical artery pH ≤ 7.05, admission to the neonatal intensive care unit for longer than 24 h, preterm birth (< 37 completed weeks) or birth weight < 10th centile) using the findings of sequential ultrasound scans for fetal biometry and umbilical and uterine artery Doppler. Results: In total, 506 participants were eligible, of whom 504 were included in the analysis. An adverse pregnancy outcome was experienced by 110 (22%) participants. The ability to predict the composite outcome using repeated head circumference and estimated fetal weight measurements improved as the pregnancy progressed (e.g. area under the receiver‐operating‐characteristics curve improved from 0.59 at 24 weeks' gestation to 0.74 at 36 weeks' gestation), supporting proof‐of‐concept. Predictors to include in dynamic prediction models were identified, including ultrasound measurements of fetal biometry, umbilical and uterine artery Doppler and placental size and shape. Conclusion: The present study supports proof‐of‐concept for dynamic prediction of adverse outcome in pregnancy following prior stillbirth or perinatal death, which could be used to identify risks earlier in pregnancy, while highlighting methodological challenges and requirements for subsequent large‐scale model development studies. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Background: Sex differences in human brain anatomy have been well-documented, though remain significantly underexplored during early development. The neonatal period is a critical stage for brain development and can provide key insights into the role that prenatal and early postnatal factors play in shaping sex differences in the brain. Methods: Here, we assessed on-average sex differences in global and regional brain volumes in 514 newborns aged 0–28 days (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. We also assessed sex-by-age interactions to investigate sex differences in early postnatal brain development. Results: On average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed significantly greater total cortical gray matter volumes, whilst males showed greater total white matter volumes. After controlling for total brain volume in regional comparisons, females had significantly increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and left caudate nucleus. Males had significantly increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. Significant sex-by-age interactions were noted in the left anterior cingulate gyrus and left superior temporal gyrus (posterior parts). Conclusions: Our findings demonstrate that sex differences in brain structure are already present at birth and remain comparatively stable during early postnatal development, highlighting an important role of prenatal factors in shaping sex differences in the brain. Plain Language Summary: Sex differences in the human brain have attracted substantial scientific and societal interest, but less is known about whether the brain shows sex differences at birth. Studying sex differences at birth can help to understand how prenatal factors (e.g., hormone levels before birth) and early postnatal factors (e.g., exposure to the sensory environment and caregiver interactions) contribute to shaping sex differences in the brain. In this study, we investigated on-average sex differences in brain structure in a large sample of newborn infants shortly after birth. Our findings show that several on-average differences are present at birth, suggesting that factors before birth play an important role in initiating sex differences in the brain. Highlights: At birth, males on average show significantly increased total brain volumes compared to females even after accounting for sex differences in birth weight. After controlling for total brain volume, females on average show significantly increased total cortical gray matter volumes, while males show increased total white matter volumes. After controlling for total brain volume, significant on-average sex differences are observed in regions such as the corpus callosum (F > M), bilateral parietal lobes (F > M), left anterior cingulate gyrus (F > M), left caudate nucleus (F > M), and right medial and inferior temporal gyri (M > F). Fewer global and regional volumes showed significant sex-by-age interactions, except for the left anterior cingulate gyrus (F > M) and left superior temporal gyrus (M > F). Several sex differences that have previously been observed later in development are present from birth, emphasising the key role that prenatal factors play in initiating sex differences in the brain. [ABSTRACT FROM AUTHOR]

Background Objective Search Strategy Selection Criteria Data Collection and Analysis Main Results Conclusions Health literacy, influenced by sociodemographic characteristics such as ethnicity, economic means and societal factors, affects the ways in which pregnant women maintain their health; this in turn may increase risk of adverse pregnancy outcomes.To explore what is known about the impact of personal health literacy on prevention of stillbirth and related adverse outcomes in pregnant women of low socioeconomic status or from ethnic minority backgrounds.MEDLINE, CINAHL, PsychINFO, and CENTRAL were searched as well as reference lists of included studies and gray literature.Included studies focused on personal health literacy and stillbirth prevention in women from low socioeconomic or ethnic minority backgrounds in the perinatal period.A meta‐summary approach was adopted for qualitative, observational, descriptive, and audit studies. Findings of intervention studies were extracted, and meta‐analyses were conducted where possible. The primary outcome was stillbirth; maternal mortality and neonatal mortality were secondary outcomes.Forty‐one studies were included from diverse geographical settings. The meta‐summary synthesized five abstracted statements. These recognized lower personal health literacy and greater difficulty interacting with healthcare services in the studied populations, primarily as the result of limited health knowledge, lack of positive perception towards health services, language barriers, illiteracy, and relying on friends or family members for health information. Meta‐analysis of intervention studies revealed no association between current interventions that aimed to increase personal health literacy and the risk of stillbirth (relative risk [RR] 1.04, 95% confidence interval [CI] 0.96–1.12), neonatal mortality (RR 0.88, 95% CI 0.75–1.03), and maternal mortality (RR 0.87, 95% CI 0.63–1.22).Various factors suggest lower personal health literacy in women of low socioeconomic status or ethnic minority, which can increase the risk of stillbirth. However, this review identified no significant impact of current health education interventions on the risk of stillbirth, or neonatal or maternal mortality. Although not directly measured, the health education interventions were anticipated to increase personal health literacy. Further research on the topic of this scoping review is warranted, particularly in lower‐resource settings and regarding the potential role of e‐literacy and organizational health literacy to improve pregnancy outcomes. To address deficits in health literacy, efforts must be made to provide pregnant women with health information in novel, accessible ways. [ABSTRACT FROM AUTHOR]

Chronic histiocytic intervillositis (CHI) is a recurrent placental lesion where maternal macrophages infiltrate the intervillous space. Its cause is unknown, though due to similarities to rejected allografts one hypothesis is that CHI represents maternal–fetal rejection. Here, virtual crossmatching was applied to healthy pregnancies and those with a history of CHI. Anti-HLA antibodies, measured by Luminex, were present in slightly more controls than CHI (8/17 (47.1%) vs 5/14 (35.7%)), but there was no significant difference in levels of sensitisation or fetal specific antibodies. Quantification of immunohistochemical staining for HLA-Class II was increased in syncytiotrophoblast of placentas with CHI (Grade 0.44 [IQR 0.1–0.7]) compared to healthy controls (0.06 [IQR 0–0.2]) and subsequent pregnancies (0.13 [IQR 0–0.3]) (P = 0.0004). HLA-Class II expression was positively related both to the severity of CHI (r = 0.67) and C4d deposition (r = 0.48). There was no difference in overall C4d and HLA-Class I immunostaining. Though increased anti-HLA antibodies were not evident in CHI, increased expression of HLA-Class II at the maternal–fetal interface suggests that they may be relevant in its pathogenesis. Further investigation of antibodies immediately after diagnosis is warranted in a larger cohort of CHI cases to better understand the role of HLA in its pathophysiology. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the risk of stillbirth in relation to (1) a previous caesarean delivery (CD) compared with those following a vaginal birth (VB); and (2) vaginal birth after caesarean (VBAC) compared with 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 with VB. The odds of intrapartum stillbirth were higher in the previous pre‐labour CD group (aOR 2.72; 95% CI 1.51–4.91) and in 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 were found for intrapartum stillbirth in women who had VBAC (aOR 0.99; 95% CI 0.48–2.06) compared with women who had a repeat CD. 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 healthcare providers to reach optimal decisions regarding mode of birth, particularly when CD is unnecessary. Linked article: This article is commented on by Pisake Lumbiganon et al., pp. 1062‐1063 in this issue. To view this mini commentary visit https://doi.org/10.1111/1471‐0528.17795. [ABSTRACT FROM AUTHOR]

Objective: We examined whether the risk of stillbirth was related to ambient air pollution in a UK population. Design: Prospective case–control study. Setting: Forty‐one maternity units in the UK. Population: Women who had a stillbirth ≥28 weeks' gestation (n = 238) and women with an ongoing pregnancy at the time of interview (n = 597). Methods: Secondary analysis of data from the Midlands and North of England Stillbirth case–control study only including participants domiciled within 20 km of fixed air pollution monitoring stations. Pollution exposure was calculated using pollution climate modelling data for NO2, NOx and PM2.5. The association between air pollution exposure and stillbirth risk was assessed using multivariable logistic regression adjusting for household income, maternal body mass index (BMI), maternal smoking, Index of Multiple Deprivation quintile and household smoking and parity. Main Outcome Measure: Stillbirth. Results: There was no association with whole pregnancy ambient air pollution exposure and stillbirth risk, but there was an association with preconceptual NO2 exposure (adjusted odds ratio [aOR] 1.06, 95% CI 1.01–1.08 per microg/m3). Risk of stillbirth was associated with maternal smoking (aOR 2.54, 95% CI 1.38–4.71), nulliparity (aOR 2.16, 95% CI 1.55–3.00), maternal BMI (aOR 1.05, 95% CI 1.01–1.08) and placental abnormalities (aOR 4.07, 95% CI 2.57–6.43). Conclusions: Levels of ambient air pollution exposure during pregnancy in the UK, all of were beneath recommended thresholds, are not associated with an increased risk of stillbirth. Periconceptual exposure to NO2 may be associated with increased risk but further work is required to investigate this association. [ABSTRACT FROM AUTHOR]

Introduction: Women with a prior stillbirth or a history of recurrent first trimester miscarriages are at increased risk of adverse pregnancy outcomes. However, little is known about the impact of a second trimester pregnancy loss on subsequent pregnancy outcome. This review investigated if second trimester miscarriage or termination for medical reason or fetal anomaly (TFMR/TOPFA) is associated with future adverse pregnancy outcomes. Material and methods: A systematic review of observational studies was conducted. Eligible studies included women with a history of a second trimester miscarriage or termination for medical reasons and their pregnancy outcomes in the subsequent pregnancy. Where comparative studies were identified, studies which compared subsequent pregnancy outcomes for women with and without a history of second trimester loss or TFMR/TOPFA were included. The primary outcome was livebirth, and secondary outcomes included: miscarriage (first and second trimester), termination of pregnancy, fetal growth restriction, cesarean section, preterm birth, pre‐eclampsia, antepartum hemorrhage, stillbirth and neonatal death. Studies were excluded if exposure was nonmedical termination or if related to twins or higher multiple pregnancies. Electronic searches were conducted using the online databases (MEDLINE, Embase, PubMed and The Cochrane Library) and searches were last updated on June 16, 2023. Risk of bias was assessed using the Newcastle‐Ottawa scale. Where possible, meta‐analysis was undertaken. PROSPERO registration: CRD42023375033. Results: Ten studies were included, reporting on 12 004 subsequent pregnancies after a second trimester pregnancy miscarriage. No studies were found on outcomes after second trimester TFMR/TOPFA. Overall, available data were of "very low quality" using GRADE assessment. Meta‐analysis of cohort studies generated estimated outcome frequencies for women with a previous second trimester loss as follows: live birth 81% (95% CI: 64–94), miscarriage 15% (95% CI: 4–30, preterm birth 13% [95% CI: 6–23]).The pooled odds ratio for preterm birth in subsequent pregnancy after second trimester loss in case–control studies was OR 4.52 (95% CI: 3.03–6.74). Conclusions: Very low certainty evidence suggests there may be an increased risk of preterm birth in a subsequent pregnancy after a late miscarriage. However, evidence is limited. Larger, higher quality cohort studies are needed to investigate this potential association. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to create core outcome sets (COSs) for use in research studies relating to the awareness and clinical management of reduced fetal movement (RFM). Design: Delphi survey and consensus process. Setting: International. Population: A total of 128 participants (40 parents, 19 researchers and 65 clinicians) from 16 countries. Methods: A systematic literature review was conducted to identify outcomes in studies of interventions relating to the awareness and the clinical management of RFM. Using these outcomes as a preliminary list, stakeholders rated the importance of these outcomes for inclusion in COSs for studies of: (i) awareness of RFM; and (ii) clinical management of RFM. Main outcome measures: Preliminary lists of outcomes were discussed at consensus meetings where two COSs (one for studies of RFM awareness and one for studies of clinical management of RFM). Results: The first round of the Delphi survey was completed by 128 participants, 66% of whom (n = 84) completed all three rounds. Fifty outcomes identified by the systematic review, after multiple definitions were combined, were voted on in round one. Two outcomes were added in round one, and as such 52 outcomes were voted on in two lists in rounds two and three. The COSs for studies of RFM awareness and clinical management are comprised of eight outcomes (four maternal and four neonatal) and 10 outcomes (two maternal and eight neonatal), respectively. Conclusions: These COSs provide researchers with the minimum set of outcomes to be measured and reported in studies relating to the awareness and the clinical management of RFM. [ABSTRACT FROM AUTHOR]

Introduction: Our study evaluated how a history of stillbirth in either of the first two pregnancies affects the risk of having a stillbirth or other adverse pregnancy outcomes in the third subsequent pregnancy. Material and Methods: We used the Swedish Medical Birth Register to define a population‐based cohort of women who had at least three singleton births from 1973 to 2012. The exposure of interest was a history of stillbirth in either of the first two pregnancies. The primary outcome was subsequent stillbirth in the third pregnancy. Secondary outcomes included: preterm birth, preeclampsia, placental abruption and small‐for‐gestational‐age infant. Adjusted logistic regression was performed including maternal age, body mass index, smoking, diabetes and hypertension. A sensitivity analysis was performed excluding stillbirths associated with congenital anomalies, pregestational and gestational diabetes, hypertension and preterm stillbirths. Results: The study contained data on 1 316 175 births, including 8911 stillbirths. Compared with women who had two live births, the highest odds of stillbirth in the third pregnancy were observed in women who had two stillbirths (adjusted odds ratio [aOR] 11.40, 95% confidence interval [95% CI] 2.75–47.70), followed by those who had stillbirth in the second birth (live birth–stillbirth) (aOR 3.59, 95% CI 2.58–4.98), but the odds were still elevated in those whose first birth ended in stillbirth (stillbirth–live birth) (aOR 2.35, 1.68, 3.28). Preterm birth, pre‐eclampsia and placental abruption followed a similar pattern. The odds of having a small‐for‐gestational‐age infant were highest in women whose first birth ended in stillbirth (aOR 1.93, 95% CI 1.66–2.24). The increased odds of having a stillbirth in a third pregnancy when either of the earlier births ended in stillbirth remained when stillbirths associated with congenital anomalies, pregestational and gestational diabetes, hypertension or preterm stillbirths were excluded. However, when preterm stillbirths were excluded, the strength of the association was reduced. Conclusions: Even when they have had a live‐born infant, women with a history of stillbirth have an increased risk of adverse pregnancy outcomes; this cannot be solely accounted for by the recurrence of congenital anomalies or maternal medical disorders. This suggests that women with a history of stillbirth should be offered additional surveillance for subsequent pregnancies. [ABSTRACT FROM AUTHOR]

Key recommendations A combination of mifepristone and a prostaglandin preparation should usually be recommended as the first‐line intervention for induction of labour (Grade B). A single 200 milligram dose of mifepristone is appropriate for this indication, followed by: 24+0–24+6 weeks of gestation – 400 micrograms buccal/sublingual/vaginal/oral of misoprostol every 3 hours; 25+0–27+6 weeks of gestation – 200 micrograms buccal/sublingual/vaginal/oral of misoprostol every 4 hours; from 28+0 weeks of gestation – 25–50 micrograms vaginal every 4 hours, or 50–100 micrograms oral every 2 hours [Grade C]. There is insufficient evidence available to recommend a specific regimen of misoprostol for use at more than 28+0 weeks of gestation in women who have had a previous caesarean birth or transmural uterine scar [Grade D]. Women with more than two lower segment caesarean births or atypical scars should be advised that the safety of induction of labour is unknown [Grade D]. Staff should be educated in discussing mode of birth with bereaved parents. Vaginal birth is recommended for most women, but caesarean birth will need to be considered for some [Grade D]. A detailed informed discussion should be undertaken with parents of both physical and psychological aspects of a vaginal birth versus a caesarean birth [Grade C]. Parents should be cared for in an environment that provides adequate safety according to individual clinical circumstance, while meeting their needs to grieve and feel supported in doing so (GPP). Clinical and laboratory tests should be recommended to assess maternal wellbeing (including coagulopathy) and to determine the cause of fetal death, the chance of recurrence and possible means of avoiding future pregnancy complications [Grade D]. Parents should be advised that with full investigation (including postmortem and placental histology) a possible or probable cause can be found in up to three‐quarters of late intrauterine fetal deaths [Grade B]. All parents should be offered cytogenetic testing of their baby, which should be performed after written consent is given (GPP). Parents should be advised that postmortem examination can provide information that can sometimes be crucial to the management of future pregnancy [Grade B]. A single 200 milligram dose of mifepristone is appropriate for this indication, followed by: 24+0–24+6 weeks of gestation – 400 micrograms buccal/sublingual/vaginal/oral of misoprostol every 3 hours; 25+0–27+6 weeks of gestation – 200 micrograms buccal/sublingual/vaginal/oral of misoprostol every 4 hours; from 28+0 weeks of gestation – 25–50 micrograms vaginal every 4 hours, or 50–100 micrograms oral every 2 hours [Grade C]. [ABSTRACT FROM AUTHOR]