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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.

Objective: Reduced fetal movement, defined as a decrease in the frequency or strength of fetal movements as perceived by the mother, is a common reason for presentation to maternity care. Observational studies have demonstrated an association between reduced fetal movement and stillbirth and fetal growth restriction related to placental insufficiency. However, individual intervention studies have described varying results. This systematic review and meta-analysis aimed to determine whether interventions aimed at encouraging awareness of reduced fetal movement and/or improving its subsequent clinical management reduce the frequency of stillbirth or other important secondary outcomes.Data sources: Searches were conducted in MEDLINE, Embase, CINAHL, The Cochrane Library, Web of Science, and Google Scholar. Guidelines, trial registries, and gray literature were also searched. Databases were searched from inception to January 20, 2022.Study eligibility criteria: Randomized controlled trials and controlled nonrandomized studies were eligible if they assessed interventions aimed at encouraging awareness of fetal movement or fetal movement counting and/or improving the subsequent clinical management of reduced fetal movement. Eligible populations were singleton pregnancies after 24 completed weeks of gestation. The primary review outcome was stillbirth; a number of secondary maternal and neonatal outcomes were specified in the review.Methods: Risk of bias was assessed using the Cochrane Risk of Bias 2 and Risk of Bias in Non-Randomized Studies I tools for randomized controlled trials and nonrandomized studies, respectively. Variation caused by heterogeneity was assessed using I 2. Data from studies employing similar interventions were combined using random effects meta-analysis. Results: A total of 1609 citations were identified; 190 full-text articles were evaluated against the inclusion criteria, 18 studies (16 randomized controlled trials and 2 nonrandomized studies) were included. The evidence is uncertain about the effect of encouraging awareness of fetal movement on stillbirth when compared with standard care (2 studies, n=330,084) with a pooled adjusted odds ratio of 1.19 (95% confidence interval, 0.96-1.47). Interventions for encouraging awareness of fetal movement may be associated with a reduction in neonatal intensive care unit admissions and Apgar scores of Conclusion: The effect of interventions for encouraging awareness of reduced fetal movement alone or in combination with subsequent clinical management on stillbirth is uncertain. Encouraging awareness of fetal movement may be associated with reduced adverse neonatal outcomes without an increase in interventions in labor. The meta-analysis was hampered by variations in interventions, outcome reporting, and definitions. Individual studies are frequently underpowered to detect a reduction in severe, rare outcomes and no studies were included from high-burden settings. Studies from such settings are needed to determine whether interventions can reduce stillbirth.

Objectives Maternal report of reduced fetal movements (RFM) is a means of identifying fetal compromise in pregnancy. In live births RFM is associated with altered placental structure and function. Here, we explored associations between RFM, pregnancy characteristics, and the presence of placental abnormalities and fetal growth restriction (FGR) in cases of stillbirth. Methods A retrospective cohort study was carried out in a single UK tertiary maternity unit. Cases were divided into three groups: 109 women reporting RFM, 33 women with absent fetal movements (AFM) and 159 who did not report RFM before the diagnosis of stillbirth. Univariate and multivariate logistic regression was used to determine associations between RFM/AFM, pregnancy characteristics, placental insufficiency and the classification of the stillbirth. Results AFM or RFM were reported prior to diagnosis of stillbirth in 142 (47.2%) of cases. Pregnancies with RFM prior to diagnosis of stillbirth were independently associated with placental insufficiency (Odds Ratio (OR) 2.79, 95% Confidence Interval (CI) 1.84, 5.04) and were less frequently associated with maternal proteinuria (OR 0.16, 95% CI 0.07, 0.62) and previous pregnancy loss Conclusions The association between RFM and placental insufficiency was confirmed in cases of stillbirth. This provides further evidence that RFM is a symptom of placental insufficiency. Therefore, investigation after RFM should aim to identify placental dysfunction.

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.

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

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.

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

Background Around 1 in 150 babies are stillborn or die in the first month of life in the UK. Most women conceive again, and subsequent pregnancies are often characterised by feelings of stress and anxiety, persisting beyond the birth. Psychological distress increases the risk of poor pregnancy outcomes and longer-term parenting difficulties. Appropriate emotional support in subsequent pregnancies is key to ensure the wellbeing of women and families. Substantial variability in existing care has been reported, including fragmentation and poor communication. A new care package improving midwifery continuity and access to emotional support during subsequent pregnancy could improve outcomes. However, no study has assessed the feasibility of a full-scale trial to test effectiveness in improving outcomes and cost-effectiveness for the National Health Service (NHS). Methods A prospective, mixed-methods pre-and post-cohort study, in two Northwest England Maternity Units. Thirty-eight women, (≤ 20 weeks’ gestation, with a previous stillbirth, or neonatal death) were offered the study intervention (allocation of a named midwife care coordinator and access to group and online support). Sixteen women receiving usual care were recruited in the 6 months preceding implementation of the intervention. Outcome data were collected at 2 antenatal and 1 postnatal visit(s). Qualitative interviews captured experiences of care and research processes with women (n = 20), partners (n = 5), and midwives (n = 8). Results Overall recruitment was 90% of target, and 77% of women completed the study. A diverse sample reflected the local population, but non-English speaking was a barrier to participation. Study processes and data collection methods were acceptable. Those who received increased midwifery continuity valued the relationship with the care coordinator and perceived positive impacts on pregnancy experiences. However, the anticipated increase in antenatal continuity for direct midwife contacts was not observed for the intervention group. Take-up of in-person support groups was also limited. Conclusions Women and partners welcomed the opportunity to participate in research. Continuity of midwifery care was supported as a beneficial strategy to improve care and support in pregnancy after the death of a baby by both parents and professionals. Important barriers to implementation included changes in leadership, service pressures and competing priorities. Trial registration ISRCTN17447733 first registration 13/02/2018.

Aim: Pregnancy after the death of a baby is associated with numerous, varied psychological challenges for pregnant women. This study aimed to explore women’s experiences of pregnancy whilst attending a specialist antenatal service for pregnancies after a perinatal death.\ud \ud Methods: Semi-structured interviews with twenty women in a subsequent pregnancy after a perinatal death were conducted and analyzed taking an inductive thematic analysis approach.\ud \ud Results: All women expressed a heightened “awareness of risk”. Two subthemes demonstrated how increased awareness of risk affected their experience and their desire regarding antenatal and postnatal support. Women talked about stillbirth being a “quiet, unspoken subject” causing them internal conflict as they had an awareness of pregnancy complications that other people did not. Navigating subsequent pregnancies relied on them “expecting the worst and hoping for the best” in terms of pregnancy outcomes. Women viewed specialist antenatal care in pregnancy after perinatal loss favorably, as it enabled them to receive tailored care that met their needs stemming from their increased awareness of and personal expectations of risk.\ud \ud Conclusion: Women’s experiences can be used to develop models of care but further studies are required to determine to identify which components are most valued.

First paragraph: The Final Report of the Ockenden Review examined the care of 1486 families who experienced adverse outcomes in one hospital Trust in England, the majority of whom received care between 2000 and 2020 (Ockenden 2022). It describes the damaging outcomes and experiences caused by poor care for women and babies in pregnancy, labour and birth. Multiple individual actions recommended by the report are resulting in immediate and extensive changes across the maternity services in England. The report findings are relevant across the whole UK, and to international efforts to improve safety and quality in maternal and newborn care systems.

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.

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.

Background The effectiveness of screening for macrosomia is not well established. One of the critical elements of an effective screening program is the diagnostic accuracy of a test at predicting the condition. The objective of this study is to investigate the diagnostic effectiveness of universal ultrasonic fetal biometry in predicting the delivery of a macrosomic infant, shoulder dystocia, and associated neonatal morbidity in low- and mixed-risk populations. Methods and findings We conducted a predefined literature search in Medline, Excerpta Medica database (EMBASE), the Cochrane library and ClinicalTrials.gov from inception to May 2020. No language restrictions were applied. We included studies where the ultrasound was performed as part of universal screening and those that included low- and mixed-risk pregnancies and excluded studies confined to high risk pregnancies. We used the estimated fetal weight (EFW) (multiple formulas and thresholds) and the abdominal circumference (AC) to define suspected large for gestational age (LGA). Adverse perinatal outcomes included macrosomia (multiple thresholds), shoulder dystocia, and other markers of neonatal morbidity. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was carried out using the hierarchical summary receiver operating characteristic (ROC) and the bivariate logit-normal (Reitsma) models. We identified 41 studies that met our inclusion criteria involving 112,034 patients in total. These included 11 prospective cohort studies (N = 9986), one randomized controlled trial (RCT) (N = 367), and 29 retrospective cohort studies (N = 101,681). The quality of the studies was variable, and only three studies blinded the ultrasound findings to the clinicians. Both EFW >4,000 g (or 90th centile for the gestational age) and AC >36 cm (or 90th centile) had >50% sensitivity for predicting macrosomia (birthweight above 4,000 g or 90th centile) at birth with positive likelihood ratios (LRs) of 8.74 (95% confidence interval [CI] 6.84–11.17) and 7.56 (95% CI 5.85–9.77), respectively. There was significant heterogeneity at predicting macrosomia, which could reflect the different study designs, the characteristics of the included populations, and differences in the formulas used. An EFW >4,000 g (or 90th centile) had 22% sensitivity at predicting shoulder dystocia with a positive likelihood ratio of 2.12 (95% CI 1.34–3.35). There was insufficient data to analyze other markers of neonatal morbidity. Conclusions In this study, we found that suspected LGA is strongly predictive of the risk of delivering a large infant in low- and mixed-risk populations. However, it is only weakly (albeit statistically significantly) predictive of the risk of shoulder dystocia. There was insufficient data to analyze other markers of neonatal morbidity., Gordon Smith and colleagues investigate the diagnostic effectiveness of universal ultrasonic fetal biometry in predicting infant macrosomia, Author summary Why was this study done? There is a debate regarding introducing universal third-trimester screening for macrosomia. An effective screening program requires two elements: an effective test at predicting a condition and an effective intervention. There is evidence that early-term induction of labor (IOL) could reduce the rates of shoulder dystocia. However, there is no high-quality evidence regarding the diagnostic effectiveness of fetal biometry at predicting macrosomia and associated morbidity. What did the researchers do and find? We searched more than 10,000 titles and identified 41 studies including 112,034 patients that offered third-trimester ultrasounds for the prediction of macrosomia as part of universal ultrasound screening or were done in low- and mixed-risk populations. The quality of the studies was variable, and only three studies blinded the ultrasound findings to the clinicians. We found that the two most common ultrasound markers, the estimated fetal weight (EFW) and the abdominal circumference (AC), could predict the majority of macrosomic infants at birth (sensitivity >50%) with high diagnostic performance (positive LRs between 7 and 10). However, the EFW could only predict about 1 in 5 cases of shoulder dystocia (22% sensitivity) with low diagnostic performance (positive likelihood ratio of about 2). There was insufficient data to analyze other markers of neonatal morbidity. What do these findings mean? Universal third-trimester ultrasound screening will identify more pregnancies with macrosomia. However, it will not have a clinically significant effect at predicting shoulder dystocia. There is not enough evidence on the effect of ultrasound screening on neonatal morbidity. We recommend caution prior to introducing universal third-trimester screening for macrosomia, as it would increase the rates of intervention, with potential iatrogenic harm, without clear evidence that it would reduce neonatal morbidity.

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.

Background The AFFIRM intervention aimed to reduce stillbirth and neonatal deaths by increasing awareness of reduced fetal movements (RFM) and implementing a care pathway when women present with RFM. Although there is uncertainty regarding the clinical effectiveness of the intervention, the aim of this analysis was to evaluate the cost-effectiveness. Methods A stepped-wedge, cluster-randomised trial was conducted in thirty-three hospitals in the United Kingdom (UK) and Ireland. All women giving birth at the study sites during the analysis period were included in the study. The costs associated with implementing the intervention were estimated from audits of RFM attendances and electronic healthcare records. Trial data were used to estimate a cost per stillbirth prevented was for AFFIRM versus standard care. A decision analytic model was used to estimate the costs and number of perinatal deaths (stillbirths + early neonatal deaths) prevented if AFFIRM were rolled out across Great Britain for one year. Key assumptions were explored in sensitivity analyses. Results Direct costs to implement AFFIRM were an estimated £95,126 per 1,000 births. Compared to standard care, the cost per stillbirth prevented was estimated to be between £86,478 and being dominated (higher costs, no benefit). The estimated healthcare budget impact of implementing AFFIRM across Great Britain was a cost increase of £61,851,400/year. Conclusions Perinatal deaths are relatively rare events in the UK which can increase uncertainty in economic evaluations. This evaluation estimated a plausible range of costs to prevent baby deaths which can inform policy decisions in maternity services. Trial registration The trial was registered with www.ClinicalTrials.gov, number NCT01777022.

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.

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 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).

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.

Background The grief associated with the death of a baby is enduring, however most women embark on another pregnancy, many in less than a year following their loss. Symptoms of anxiety and depression are reported to be increased in pregnancies after perinatal death, although effect on maternal stress is less clear. Variation between individual studies may result from differences in gestation at sampling, the questionnaire used and the type of antecedent perinatal death. We aimed to describe quantitative measures of anxiety, depression, stress and quality of life at different timepoints in pregnancies after perinatal death and in the early postnatal period. Methods Women recruited from three sites in the North-West of England. Women were asked to participate if a previous pregnancy had ended in a perinatal death. Participants completed validated measures of psychological state (Cambridge Worry Score, Edinburgh Postnatal Depression Score (EPDS), Generalized Anxiety Disorder 7-item score) and health status (EQ-5D-5L™ and EQ5D-Visual Analogue Scale) at three time points, approximately 15 weeks’ and 32 weeks’ gestation and 6 weeks postnatally. A sample of hair was taken at approximately 36 weeks’ gestation for measurement of hair cortisol in a subgroup of women. The hair sample was divided into samples from each trimester and cortisol measured by ELISA. Results In total 112 women participated in the study. Measures of anxiety and depressive symptoms decreased from the highest levels at 15 weeks’ gestation to 6-weeks postnatal (for example mean GAD-7: 15 weeks 8.2 ± 5.5, 6 weeks postnatal 4.4 ± 5.0, p Conclusions This study demonstrated heightened anxiety and depressive symptoms and elevated cortisol levels in women in pregnancies after a stillbirth or neonatal death which decrease as pregnancy progresses. Further studies are needed to determine optimal care for women to address these negative psychological consequences.

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.

The objective of this study was to investigate the accuracy of universal third trimester umbilical artery (UA) Doppler to predict adverse pregnancy outcome at term. We searched Medline, EMBASE, the Cochrane library and ClinicalTrials.gov from inception to October 2020 and we also analyzed previously unpublished data from a prospective cohort study of nulliparous women, the Pregnancy Outcome Prediction (POP) study. We included studies that performed a third-trimester ultrasound scan in unselected, low or mixed risk populations, excluding studies which only included high risk pregnancies. Meta-analysis was performed using the hierarchal summary receiver operating characteristic curve (HSROC) analysis and bivariate logit-normal models. We identified 13 studies (including the POP study) involving 67,764 pregnancies which met our inclusion criteria. The overall quality was variable and only six studies (N = 5777 patients) blinded clinicians to the UA Doppler result. The summary sensitivity and positive likelihood ratio (LR) for small for gestational age (SGA; birthweight

Background Stillbirth prevention is an international priority - risk prediction models could individualise care and reduce unnecessary intervention, but their use requires evaluation. Objectives To identify risk prediction models for stillbirth, and assess their potential accuracy and clinical benefit in practice. Search strategy MEDLINE, Embase, DH-DATA and AMED databases were searched from inception to June 2019 using terms relevant to stillbirth, perinatal mortality and prediction models. The search was compliant with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Selection criteria Studies developing and/or validating prediction models for risk of stillbirth developed for application during pregnancy. Data collection and analysis Study screening and data extraction were conducted in duplicate, using the CHARMS checklist. Risk of bias was appraised using the PROBAST tool. Results The search identified 2751 citations. Fourteen studies reporting development of 69 models were included. Variables consistently included were: ethnicity, body mass index, uterine artery Doppler, pregnancy-associated plasma protein and placental growth factor. For almost all models there were significant concerns about risk of bias. Apparent model performance (i.e. in the development dataset) was highest in models developed for use later in pregnancy and including maternal characteristics, and ultrasound and biochemical variables, but few were internally validated and none were externally validated. Conclusions Almost all models identified were at high risk of bias. There are first-trimester models of possible clinical benefit in early risk stratification; these require validation and clinical evaluation. There were few later pregnancy models but, if validated, these could be most relevant to individualised discussions around timing of birth. Tweetable abstract Prediction models using maternal factors, blood tests and ultrasound could individualise stillbirth prevention, but existing models are at high risk of bias.

ObjectiveCurrent data on the role of the umbilical cord in pregnancy complications are conflicting; estimates of the proportion of stillbirths due to cord problems range from 3.4 to 26.7%. A systematic review and meta-analysis were undertaken to determine which umbilical cord abnormalities are associated with stillbirth and related adverse pregnancy outcomes.MethodsMEDLINE, EMBASE, CINAHL and Google Scholar were searched from 1960 to present day. Reference lists of included studies and grey literature were also searched. Cohort, cross-sectional, or case-control studies of singleton pregnancies after 20 weeks' gestation that reported the frequency of umbilical cord characteristics or cord abnormalities and their relationship to stillbirth or other adverse outcomes were included. Quality of included studies was assessed using NIH quality assessment tools. Analyses were performed in STATA.ResultsThis review included 145 studies. Nuchal cords were present in 22% of births (95% CI 19, 25); multiple loops of cord were present in 4% (95% CI 3, 5) and true knots of the cord in 1% (95% CI 0, 1) of births. There was no evidence for an association between stillbirth and any nuchal cord (OR 1.11, 95% CI 0.62, 1.98). Comparing multiple loops of nuchal cord to single loops or no loop gave an OR of 2.36 (95% CI 0.99, 5.62). We were not able to look at the effect of tight or loose nuchal loops. The likelihood of stillbirth was significantly higher with a true cord knot (OR 4.65, 95% CI 2.09, 10.37).ConclusionsTrue umbilical cord knots are associated with increased risk of stillbirth; the incidence of stillbirth is higher with multiple nuchal loops compared to single nuchal cords. No studies reported the combined effects of multiple umbilical cord abnormalities. Our analyses suggest specific avenues for future research.

Objective: To describe and explore 'gut instinct' that something was wrong in women who identified that they experienced gut instinct during pregnancy. Method: A case-control study utilising an international web-based questionnaire. Stillborn cases ( n = 146) and liveborn controls ( n = 234) answered the gut instinct question within 30 days of the pregnancy ending. Of those, 84 cases and 27 controls also provided qualitative comment data. Descriptive statistics were used for the question, with a fixed option and summative content analysis was used to analyse the comment data. Findings: In all, 110 (75%) of the stillborn cases answered "yes" to the gut instinct question vs only 28 (12%) of the controls who had a livebirth meaning the risk of stillbirth was 22.5 fold higher in those who experience "gut instinct" than in those who do not experience this feeling. Four themes were identified from the comment data namely: When the gut instinct occurred; How the gut instinct made the woman feel; Dreams and other related phenomena; Reassured by someone or something. Conclusions: Women who had a stillborn baby reported a "gut instinct" that something was wrong more frequently than mothers of a live born baby. Our findings may be influenced by recall negativity bias, and a prospective study is needed to confirm or refute our findings. The possibility that "maternal intuition" exists during pregnancy and responds to changes in fetal or placental health merits further exploration. Implications for practice: Maternity care providers should be alert to the woman when she expresses intuitive feelings, as well as asking her to report her concerns and act appropriately to assess and manage fetal wellbeing. Refereed/Peer-reviewed

INTRODUCTION: The reported effects of SARS-CoV-2 on pregnancy outcomes are conflicting; studies frequently overlook the placenta, which is critical for the health of the mother and infant(s). This study aimed to determine the effect of pandemic stress ± SARS CoV-2 infection on placental histopathology. METHODS: Women were recruited in Canada (n = 69); France (n = 21) or in the UK (n = 25), between March and October 2020. Historic controls (N = 20) were also included. Placenta and fetal membrane samples were collected rapidly after delivery and were fixed and stained for histopathological analysis. Maternal demographical data and obstetric outcomes were recorded. RESULTS: Over 80% of the placentas from SARS-CoV-2+ pregnancies had histopathological abnormalities: predominantly structural (71-86%) or inflammatory (9-22%), depending on geographical location. Excessive fibrin was seen in all sites, whereas deciduitis (Canada), calcifications (UK), agglutinations and chorangiosis (France) predominated in different locations. The frequency of abnormalities was significantly higher than in SARS-CoV-2 negative women (50%, p

Introduction 98% of the 2.6 million stillbirths per annum occur in low and middle income countries. However, understanding of risk factors for stillbirth in these settings is incomplete, hampering efforts to develop effective strategies to prevent deaths. Methods A cross-sectional study of eligible women on the postnatal ward at Mpilo Hospital, Zimbabwe was undertaken between 01/08/2018 and 31/03/2019 (n = 1779). Data were collected from birth records for maternal characteristics, obstetric and past medical history, antenatal care and pregnancy outcome. A directed acyclic graph was constructed with multivariable logistic regression performed to fit the corresponding model specification to data comprising singleton pregnancies, excluding neonatal deaths (n = 1734), using multiple imputation for missing data. Where possible, findings were validated against all women with births recorded in the hospital birth register (n = 1847). Results Risk factors for stillbirth included: previous stillbirth (29/1691 (2%) of livebirths and 39/43 (91%) of stillbirths, adjusted Odds Ratio (aOR) 2628.9, 95% CI 342.8 to 20,163.0), antenatal care (aOR 44.49 no antenatal care vs. > 4 antenatal care visits, 95% CI 6.80 to 291.19), maternal medical complications (aOR 7.33, 95% CI 1.99 to 26.92) and season of birth (Cold season vs. Mild aOR 14.29, 95% CI 3.09 to 66.08; Hot season vs. Mild aOR 3.39, 95% CI 0.86 to 13.27). Women who had recurrent stillbirth had a lower educational and health status (18.2% had no education vs. 10.0%) and were less likely to receive antenatal care (20.5% had no antenatal care vs. 6.6%) than women without recurrent stillbirth. Conclusion The increased risk in women who have a history of stillbirth is a novel finding in Low and Middle Income Countries (LMICs) and is in agreement with findings from High Income Countries (HICs), although the estimated effect size is much greater (OR in HICs ~ 5). Developing antenatal care for this group of women offers an important opportunity for stillbirth prevention.

Background Routine assessment in (near) term pregnancy is often inaccurate for the identification of fetuses who are mild to moderately compromised due to placental insufficiency and are at risk of adverse outcomes, especially when fetal size is seemingly within normal range for gestational age. Although biometric measurements and cardiotocography are frequently used, it is known that these techniques have low sensitivity and specificity. In clinical practice this diagnostic uncertainty results in considerable ‘over treatment’ of women with healthy fetuses whilst truly compromised fetuses remain unidentified. The CPR is the ratio of the umbilical artery pulsatility index over the middle cerebral artery pulsatility index. A low CPR reflects fetal redistribution and is thought to be indicative of placental insufficiency independent of actual fetal size, and a marker of adverse outcomes. Its utility as an indicator for delivery in women with reduced fetal movements (RFM) is unknown. The aim of this study is to assess whether expedited delivery of women with RFM identified as high risk on the basis of a low CPR improves neonatal outcomes. Secondary aims include childhood outcomes, maternal obstetric outcomes, and the predictive value of biomarkers for adverse outcomes. Methods International multicentre cluster randomised trial of women with singleton pregnancies with RFM at term, randomised to either an open or concealed arm. Only women with an estimated fetal weight ≥ 10th centile, a fetus in cephalic presentation and normal cardiotocograph are eligible and after informed consent the CPR will be measured. Expedited delivery is recommended in women with a low CPR in the open arm. Women in the concealed arm will not have their CPR results revealed and will receive routine clinical care. The intended sample size based on the primary outcome is 2160 patients. The primary outcome is a composite of: stillbirth, neonatal mortality, Apgar score Discussion The CEPRA trial will identify whether the CPR is a good indicator for delivery in women with perceived reduced fetal movements. Trial registration Dutch trial registry (NTR), trial NL7557. Registered 25 February 2019.

In preeclampsia, vasospasm, oxidative stress, endothelial dysfunction, and immune dysregulation are key mediators of maternal disease. A new time-of-disease treatment is needed with the potential to treat these areas of pathophysiology. A review of the literature has indicated that metabolites of the kynurenine pathway have the potential to; (i) induce vasorelaxation of resistance arteries and reduce blood pressure; (ii) exert antioxidant effects and reduce the effects of poly-ADP ribose polymerase activation (iii) prevent endothelial dysfunction and promote endothelial nitric oxide production; (iv) cause T cell differentiation into tolerogenic regulatory T cells and induce apoptosis of pro-inflammatory Th1 cells. This has led to the hypothesis that increasing Kynurenine pathway activity may offer a new treatment strategy for preeclampsia.

RESUME Objectif L'objectif principal de la presente declaration de consensus est d'elaborer des enonces de consensus qui guideront la pratique clinique et des recommandations pour les soins prenataux et les soins intrapartum, et les considerations psychosociales dont il faut tenir compte pour prendre soin des femmes enceintes ayant des antecedents de mortinaissance. Utilisateurs cibles Les cliniciens participant a la prise en charge obstetrique des femmes ayant des antecedents de mortinaissance ou d'autres formes de deces perinatal. Population cible Les femmes et les familles recevant des soins apres une grossesse s'etant soldee par une mortinaissance ou une autre forme de deces perinatal. Evidence La presente directive clinique resume la litterature publiee et enonce un consensus general sur la prise en charge des grossesses suivant une mortinaissance ou un deces perinatal. Nous avons interroge les bases de donnees MEDLINE, Embase et Cochrane au moyen des mots-cles : « previous stillbirth », « perinatal loss » et « subsequent pregnancy ». Nous avons ensuite etudie les resultats et lu les articles pertinents. Nous avons egalement consulte les references des articles retenus et les documents citant des etudes pertinentes. Les donnees ont ensuite ete presentees pendant une reunion de consensus, et les enonces ont ete formules. En raison du manque de donnees probantes, nous avons egalement consulte les cheminements de soins de cliniques specialisees. Validation Le contenu et les lignes directrices ont ete elabores par les auteurs principaux en consultation avec les participants a la rencontre. Le Conseil d'administration de la Societe des obstetriciens et gynecologues du Canada a approuve la version finale avant publication. La qualite des donnees probantes a ete evaluee au moyen des criteres de l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) [tableau 1]. L'interpretation des recommandations solides et conditionnelles est decrite dans le tableau 2. Le resume des conclusions peut etre fourni sur demande. Avantages, inconvenients, couts Nous avons explore une approche multidisciplinaire de prestation des soins prenataux et intrapartum aux femmes et aux familles ayant des antecedents de mortinaissance ou de deces perinatal. Bien qu'il manque de donnees probantes dans ce domaine, certains membres du groupe de travail fournissent ces soins a des femmes et a des familles dans plusieurs pays et nous ont fait part de leurs connaissances et de leurs experiences dans le but de guider les soins. Mis-a-jour Une revue des donnees probantes sera menee cinq ans apres la publication de la presente directive clinique afin d'evaluer si une mise a jour complete ou partielle s'impose. Cependant, si de nouvelles donnees probantes importantes sont publiees avant la fin du cycle de cinq ans, le processus pourrait etre accelere afin que certaines recommandations soient mises a jour rapidement. Commanditaires La presente directive clinique a ete elaboree a l'aide de ressources financees par la Societe des obstetriciens et gynecologues du Canada et le Programme pour les femmes et les bebes du Centre Sunnybrook des sciences et la sante tableau 1,2. Declarations sommaires et recommandations 1Le principal facteur de risque de mortinaissance recurrente est le fait d'avoir des antecedents de mortinaissance. Le risque de recurrence des femmes peut etre stratifie en fonction de la cause connue de la mortinaissance initiale et des autres facteurs de risque maternels connus (qualite des preuves : elevee). 2Au moment de la mortinaissance, des tests devraient etre menes selon le tableau clinique. Tous les parents devraient se voir offrir une autopsie ou un examen equivalent, un examen pathologique du placenta, un depistage genetique de source fœtale et une recherche d'hemorragie fœto-maternelle (qualite des preuves : moyenne). 3Les femmes ayant des antecedents de mortinaissance presentent aussi un risque accru d'autres issues defavorables de la grossesse, comme l'accouchement premature, le poids insuffisant a la naissance et le decollement placentaire (qualite des preuves : moyenne). 4Lors de la visite initiale, si la mortinaissance precedente n'a pas fait l'objet d'une investigation adequate, il convient de noter qu'aucun test universel n'est recommande. Les antecedents cliniques et les examens au moment de la mortinaissance devraient guider les tests au cas par cas (qualite des preuves : moyenne). 5L'evaluation biochimique de la fonction placentaire et l'examen Doppler de l'artere uterine systematiques ne sont pas universellement recommandes en raison de leur faible valeur predictive et de leur inutilite dans l'ajustement de la stratification du risque, puisque le risque de recurrence est deja eleve (qualite des preuves : moyenne). 6L'aspirine a faible dose peut reduire le risque de deces perinatal chez les femmes a risque d'insuffisance placentaire. Certaines femmes ayant des antecedents de mortinaissance peuvent se trouver dans cette categorie (qualite des preuves : elevee). 7Les femmes ayant des antecedents de mortinaissance peuvent etre a risque de retard de croissance fœtal durant la grossesse subsequente et peuvent tirer avantage d'echographies repetees pour mesurer la croissance (qualite des preuves : elevee). Bien qu'il y ait peu de donnees probantes appuyant les examens systematiques du profil biophysique, la surveillance accrue peut etre benefique pour certaines femmes et leurs familles, mais elle peut causer de l'anxiete chez d'autres. La frequence et le calendrier de surveillance fœtale devraient etre determines en fonction des antecedents medicaux, des circonstances entourant la mortinaissance initiale et des preferences des parents (qualite des preuves : moyenne). 8Les decisions quant au moment de l'accouchement devraient tenir compte des circonstances entourant la mortinaissance precedente, du tableau clinique de la grossesse en cours et de l'etat emotionnel de la femme et de sa famille, ainsi que des inconvenients connus de l'accouchement avant 39 semaines. Dans certains cas precis, l'accouchement a terme precoce (de 37 a 39 semaines) peut etre pertinent. Il n'existe pas de donnees probantes appuyant l'accouchement avant 37 semaines pour le facteur de risque de mortinaissance seulement (qualite des preuves : moyenne). 9Les familles sont particulierement touchees par une mortinaissance anterieure. Cet evenement change leur vie, et entraine des couts psychologiques, physiques et sociaux continus qui persistent durant la grossesse subsequente et par la suite. Les besoins psychosociaux des familles sont accrus durant les grossesses suivant une mortinaissance. Les systemes et processus actuels de prise en charge de la grossesse devraient chercher a bien repondre a ces besoins (qualite des preuves : elevee). 10La prestation adequate des soins comprend du soutien des soins et des services medicaux et psychosociaux coherents et prodigues en temps opportun par des equipes de soins competentes et connues des familles qui connaissent bien les consequences persistantes d'une mortinaissance sur les grossesses subsequentes. Tous les soins offerts aux familles ayant vecu une mortinaissance devraient etre axes sur la protection et la promotion de la sante de la femme et de sa famille, et sur les choix eclaires (qualite des preuves : elevee). 11Le soutien par les pairs est souvent benefique pour les parents qui vivent une grossesse apres une mortinaissance. Les fournisseurs de soins devraient discuter des options de soutien par les pairs et les encourager a s'en prevaloir (qualite des preuves : moyenne). 12Les femmes et les familles qui ont vecu une mortinaissance sont tres susceptibles d'avoir besoin de soutien emotionnel, et toute la famille devrait se voir offrir des possibilites de soutien durant la grossesse et la periode postpartum. De nombreuses sequelles psychologiques sont associees aux grossesses suivant une mortinaissance, notamment la depression, le stress post-traumatique et l'anxiete. Chez certaines personnes, des taux eleves de symptomes d'anxiete et de depression sont presents tout au long de la grossesse et apres la naissance. Les reactions au deuil sont aussi variees et devraient etre reconnues. Les fournisseurs de soins devraient faire valoir les forces de la famille et offrir un depistage psychosocial, un suivi cible, des aiguillages et un traitement, au besoin (qualite des preuves : elevee).

INTRODUCTION Retrospective studies have reported an association between a single episode of significantly increased fetal movements (IFMs) and stillbirth after 28 weeks' gestation. This prospective study aimed to report the outcome of pregnancies associated with maternal perception of IFMs and determine whether this symptom is associated with adverse pregnancy outcome, a pathological intrauterine environment or placental dysfunction. MATERIAL AND METHODS Women reporting IFMs after 28 weeks' gestation were recruited from St Mary's Hospital, Manchester and Liverpool Women's Hospital, UK, between 1 November 2017 and 1 May 2019. Demographic and clinical information were obtained and an ultrasound scan was performed to assess fetal biometry, liquor volume and umbilical artery Doppler. Maternal serum samples were collected for analysis of placentally derived biomarkers using ELISA. After delivery, maternal and fetal outcome data were collected and placentas and umbilical cord blood were obtained for analysis using immunohistochemistry and ELISA, respectively. Placental and serum samples were matched by gestation and maternal characteristics to participants with normal fetal activity. RESULTS Seventy-seven women presented with IFM, representing 0.45% of the maternity population; 64 women consented to participate in the study, of which 7 (10.9%) experienced adverse pregnancy outcome: birthweight

Background Advanced maternal age (≥35 years) is associated with increased rates of adverse pregnancy outcome. Better understanding of underlying pathophysiological processes may improve identification of older mothers who are at greatest risk. This study aimed to investigate changes in oxidative stress and inflammation in older women and identify clinical and biochemical predictors of adverse pregnancy outcome in older women. Methods The Manchester Advanced Maternal Age Study (MAMAS) was a multicentre, observational, prospective cohort study of 528 mothers. Participants were divided into three age groups for comparison 20–30 years (n = 154), 35–39 years (n = 222) and ≥ 40 years (n = 152). Demographic and medical data were collected along with maternal blood samples at 28 and 36 weeks’ gestation. Multivariable analysis was conducted to identify variables associated with adverse outcome, defined as one or more of: small for gestational age ( Results Maternal smoking was associated with adverse outcome irrespective of maternal age (Adjusted Odds Ratio (AOR) 4.22, 95% Confidence Interval (95%CI) 1.83, 9.75), whereas multiparity reduced the odds (AOR 0.54, 95% CI 0.33, 0.89). In uncomplicated pregnancies in older women, lower circulating anti-inflammatory IL-10, IL-RA and increased antioxidant capacity (TAC) were seen. In older mothers with adverse outcome, TAC and oxidative stress markers were increased and levels of maternal circulating placental hormones (hPL, PlGF and sFlt-1) were reduced (p Conclusions This study identified alterations in circulating inflammatory and oxidative stress markers in older women with adverse outcome providing preliminary evidence of mechanistic links. Further, larger studies are required to determine if these markers can be developed into a predictive model of an individual older woman’s risk of adverse pregnancy outcome, enabling a reduction in stillbirth rates whilst minimising unnecessary intervention.

Chronic histiocytic intervillositis (CHI) is a pregnancy disorder characterized by infiltration of maternal macrophages into the intervillous space of the human placenta, often with accompanying perivillous fibrin deposition. CHI is associated strongly with foetal growth restriction and increased risk of miscarriage and stillbirth. Although rare, affecting 6 in every 10 000 pregnancies beyond 12 weeks’ gestation, the rate of recurrence is high at 25%–100%. To date, diagnosis of CHI can only be made post‐delivery upon examination of the placenta due to a lack of diagnostic biomarkers, and criteria vary across publications. No treatment options have shown proven efficacy, and CHI remains a serious obstetric conundrum. Although its underlying aetiology is unclear, due to the presence of maternal macrophages and the reported increased incidence in women with autoimmune disease, CHI is hypothesized to be an inappropriate immune response to the semi‐allogeneic foetus. Given this lack of understanding, treatment approaches remain experimental with limited rationale. However, there is recent evidence that immunosuppression and antithrombotic therapies may be effective in preventing recurrence of associated adverse pregnancy outcomes. With similarities noted between the pathological features of CHI and acute rejection of solid organ transplants, further investigation of this hypothesis may provide a basis for tackling CHI and other immune‐related placental conditions. This review will explore parallels between CHI and allograft rejection and identify areas requiring further confirmation and exploitation of this comparison.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, was first identified after a cluster of cases in Wuhan, China in December 2019. Whether vertical transmission or placental pathology might occur following maternal infection during pregnancy remains unknown. This review aimed to summarise all studies that examined the placenta or neonates following infection with SARS-CoV-2, or closely related highly pathogenic coronavirus (SARS-CoV-1, or the Middle East respiratory syndrome coronavirus (MERS-CoV)). Structured literature searches found 50 studies that met the inclusion criteria. Twenty studies reported placental histopathology findings in third trimester placentas following maternal SARS-CoV-2 infection. Using the Amsterdam Consensus criteria to categorise the histopathology results, evidence of both fetal vascular malperfusion (35.3% of cases; 95% Confidence Interval (CI) 27.7–43.0%) and maternal vascular malperfusion (46% of cases; 95% CI 38.0–54.0%) were reported, along with evidence of inflammation in the placentas (villitis 8.7% cases, intervillositis 5.3% of cases, chorioamnionitis 6% of cases). The placental pathologies observed in SARS-CoV-2 were consistent with findings following maternal SARS-CoV-1 infection. Of those tested, a minority of neonates (2%) and placental samples tested positive for SARS-CoV-2 infection (21%). Limited conclusions can be drawn about the effect of maternal SARS-CoV-2 infection on placental pathology as most lack control groups and the majority of reports followed third trimester infection. Collaboration to maximise the number of samples examined will increase the reliability and generalisability of findings. A better understanding of the association between maternal SARS-CoV-2 infection and placental pathology will inform maternity care during the coronavirus pandemic., Highlights • Placental findings following maternal COVID-19, SARS or MERS were reviewed. • Minority of infants (2%) and placentas (21%) tested were positive for COVID-19. • Fetal and maternal vascular malperfusion were most frequently noted following COVID-19. • Minority of placentas demonstrated inflammatory lesions. • The association between maternal COVID infection and placental pathology is unclear.