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

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.

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

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

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

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

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

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

Background Late stillbirth continues to affect 3–4/1000 pregnancies in high-resource settings, with even higher rates in low-resource settings. Reduced foetal movements are frequently reported by women prior to foetal death, but there remains a poor understanding of the reasons and how to deal with this symptom clinically, particularly during the preterm phase of gestation. We aimed to determine which women are at the greatest odds of stillbirth in relation to the maternal report of foetal movements in late pregnancy (≥ 28 weeks’ gestation). Methods This is an individual participant data meta-analysis of all identified case-control studies of late stillbirth. Studies included in the IPD were two from New Zealand, one from Australia, one from the UK and an internet-based study based out of the USA. There were a total of 851 late stillbirths, and 2257 controls with ongoing pregnancies. Results Increasing strength of foetal movements was the most commonly reported (> 60%) pattern by women in late pregnancy, which were associated with a decreased odds of late stillbirth (adjusted odds ratio (aOR) = 0.20, 95% CI 0.15 to 0.27). Compared to no change in strength or frequency women reporting decreased frequency of movements in the last 2 weeks had increased odds of late stillbirth (aOR = 2.33, 95% CI 1.73 to 3.14). Interaction analysis showed increased strength of movements had a greater protective effect and decreased frequency of movements greater odds of late stillbirth at preterm gestations (28–36 weeks’ gestation). Foetal hiccups (aOR = 0.45, 95% CI 0.36 to 0.58) and regular episodes of vigorous movement (aOR = 0.67, 95% CI 0.52 to 0.87) were associated with decreased odds of late stillbirth. A single episode of unusually vigorous movement was associated with increased odds (aOR = 2.86, 95% CI 2.01 to 4.07), which was higher in women at term. Conclusions Reduced foetal movements are associated with late stillbirth, with the association strongest at preterm gestations. Foetal hiccups and multiple episodes of vigorous movements are reassuring at all gestations after 28 weeks’ gestation, whereas a single episode of vigorous movement is associated with stillbirth at term.

Chronic histiocytic intervillositis (CHI) is a rare, but highly recurrent inflammatory placental lesion wherein maternal macrophages infiltrate the intervillous space. Pregnancies with CHI are at high risk of fetal growth restriction, miscarriage or stillbirth. Presently, the diagnosis can only be made after histopathological examination of the placenta. Given its proposed immunological etiology, current treatments include aspirin, heparin, and immunomodulatory agents. However, the rationale for these medications is largely based upon small case series and reports as there is a lack of larger studies investigating treatment efficacy. Therefore, this study sought to determine whether inclusion of immunomodulatory medications was effective at reducing the severity of lesions and improving pregnancy outcomes in subsequent pregnancies. Thirty-three women with a history of CHI in at least one pregnancy (index case) were identified retrospectively through medical records. Twenty-eight participants presented with a first subsequent pregnancy and a further 11 with a second subsequent pregnancy at a specialist clinic for pregnancy after loss. Data on maternal demographics, medical history, medication, pregnancy outcome, and placental pathology was collected and compared between pregnancies. Twenty-seven (69%) subsequent pregnancies were treated with at least one or both of prednisolone and hydroxychloroquine. Inclusion of at least one immunomodulatory agent in treatment regimen resulted in an almost 25% increase in overall livebirth rate (61.5 vs. 86.2%). In women treated with immunomodulatory medication a greater proportion of placentas had reduced severity of lesions compared to those treated without (86.7 vs. 33.3%, respectively). A reduction in CHI severity was associated with a 62.3% improvement in livebirth rate compared to those where severity remained unchanged in relation to the index case. These data provide preliminary evidence that the use of immunomodulatory medication in the management of CHI improves histopathological lesions and the chance of livebirth in subsequent pregnancies. Due to CHI's rarity and ethical and feasibility issues, randomized controlled trials in affected women are challenging to conduct. As a result, collaboration between centers is required in future to increase study sample sizes and elucidate the mechanisms of hydroxychloroquine and prednisolone in reducing pathology.

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.

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

Perinatal death or cerebral palsy are devastating events for families. In an attempt to prevent these pregnancy outcomes, fetal wellbeing is assessed during labour by a variety of means. In this review, the most common means to confirm fetal wellbeing, the rationale for their use and evidence of their efficacy are discussed. With respect to labour, the indications for continuous electronic fetal monitoring are presented, together with a guide to interpretation of cardiotocograph (CTG) or fetal scalp blood samples (FBS).

Purpose Many organisations, including the Royal College of Obstetricians and Gynaecologists, have recommended increasing the number of hours of consultant obstetric presence in UK National Health Service maternity units to improve patient care. St Mary’s Hospital, Manchester implemented 24-7 consultant presence in September 2014. The paper aims to discuss these issues. Design/methodology/approach To assess the impact of 24-7 consultant presence upon women and babies, a retrospective review of all serious clinical intrapartum incidents occurring between September 2011 and September 2017 was carried out by two independent reviewers; disagreements in classification were reviewed by a senior Obstetrician. The impact of consultant presence was classified in a structure agreed a priori. Findings A total of 72 incidents were reviewed. Consultants were directly involved in the care of 75.6 per cent of cases before 24-7 consultant presence compared to 96.8 per cent afterwards. Negative impact due to a lack of consultant presence fell from 22 per cent of the incidents before 24-7 consultant presence to 9.7 per cent after implementation. In contrast, positive impact of consultant presence increased from 14.6 to 32.3 per cent following the introduction of 24-7 consultant presence. Practical implications Introduction of 24-7 consultant presence reduced the negative impact caused by a lack of, or delay in, consultant presence as identified by serious untoward incident (SUI) reviews. Consultant presence was more likely to have a positive influence on care delivery. Originality/value This is the first assessment of the impact of 24-7 consultant presence on the SUIs in obstetrics.

Summary: We compared bone outcomes in adolescents with breech and cephalic presentation. Tibia bone mineral content, density, periosteal circumference, and cross-sectional moment of inertia were lower in breech presentation, and females with breech presentation had lower hip CSA. These findings suggest that prenatal loading may exert long-lasting influences on skeletal development. Introduction: Breech position during pregnancy is associated with reduced range of fetal movement, and with lower limb joint stresses. Breech presentation at birth is associated with lower neonatal bone mineral content (BMC) and area, but it is unknown whether these associations persist into later life. Methods: We examined associations between presentation at onset of labor, and tibia and hip bone outcomes at age 17 years in 1971 participants (1062 females) from a UK prospective birth cohort that recruited > 15,000 pregnant women in 1991–1992. Cortical BMC, cross-sectional area (CSA) and bone mineral density (BMD), periosteal circumference, and cross-sectional moment of inertia (CSMI) were measured by peripheral quantitative computed tomography (pQCT) at 50% tibia length. Total hip BMC, bone area, BMD, and CSMI were measured by dual-energy X-ray absorptiometry (DXA). Results: In models adjusted for sex, age, maternal education, smoking, parity, and age, singleton/multiple births, breech presentation (n = 102) was associated with lower tibial cortical BMC (− 0.14SD, 95% CI − 0.29 to 0.00), CSA (− 0.12SD, − 0.26 to 0.02), BMD (− 0.16SD, − 0.31 to − 0.01), periosteal circumference (− 0.14SD, − 0.27 to − 0.01), and CSMI (− 0.11SD, − 0.24 to 0.01). In females only, breech presentation was associated with lower hip CSA (− 0.24SD, − 0.43 to 0.00) but not with other hip outcomes. Additional adjustment for potential mediators (delivery method, birthweight, gestational age, childhood motor competence and adolescent height and body composition) did not substantially affect associations with either tibia or hip outcomes. Conclusions: These findings suggest that prenatal skeletal loading may exert long-lasting influences on skeletal size and strength but require replication.

Background Pregnancy after the death of a baby is associated with a series of emotional and psychological challenges for pregnant women and their families. Specialist antenatal services have been proposed to address the increased biomedical and psychological risks in pregnancies after perinatal death. This study aimed to explore the pregnancy and postnatal experiences of women in a pregnancy after a perinatal death who were attending a specialist antenatal service and to evaluate the economic impact of the service.Methods To explore women’s views and experiences of care during their pregnancy this study used face-to-face semi-structured interviews following a topic guide comprising of four sections (history leading to care pathway, their experience of coping with new pregnancy after loss, support and advice for others). Following inductive thematic analysis, a deductive approach was taken to map themes to Stroebe and Schutt’s Dual Process Model of Grief.A Social Return on Investment (SROI) analysis informed by contributions from a subgroup of women and staff participants. Information was obtained from focus groups discussions, questionnaires and interviews. The SROI was reported as the ratio of the value generated by the clinic and the costs of providing the service.Results Thematic analysis of interviews (n=20) described how perinatal death was a quiet, unspoken subject and that navigating subsequent pregnancies relied on expecting the worst and hoping for the best. Mapping these themes onto the Dual Process Model of Grief found being pregnant complicated the grieving process, as increased awareness of the risk of stillbirth drew parents’ focus back to loss. Attendance at a specialist service was valued; SROI analysis found that for £1 invested, £6.10 of value was generated, mostly relating to the birth of a live baby, reduced negative psychological symptoms and fewer focussed contacts with health professionals.Conclusions Specialist antenatal care in pregnancies after perinatal death was viewed favourably by parents. Women’s experiences can be used to synthesise and develop models of care that aim to meet their needs but comparative studies are required to determine whether these models are superior to routine high-risk care and to identify which components are most valued.

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.

Fetal growth restriction (FGR) and stillbirth are associated with placental dysfunction and inflammation and hypoxia, oxidative and nitrative stress are implicated in placental damage. Damage-associated molecular patterns (DAMPs) are elevated in pregnancies at increased risk of FGR and stillbirth and are associated with increase in pro-inflammatory placental cytokines. We hypothesised that placental insults lead to release of DAMPs, promoting placental inflammation. Placental tissue from uncomplicated pregnancies was exposed in vitro to hypoxia, oxidative or nitrative stress. Tissue production and release of DAMPs and cytokines was determined. Oxidative stress and hypoxia caused differential release of DAMPs including uric acid, HMGB1, S100A8, cell-free fetal DNA, S100A12 and HSP70. After oxidative stress pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-8, TNFα, CCL2) were increased both within explants and in conditioned culture medium. Hypoxia increased tissue IL-1α/β, IL-6, IL-8 and TNFα levels, and release of IL-1α, IL-6 and IL-8, whereas CCL2 and IL-10 were reduced. IL1 receptor antagonist (IL1Ra) treatment prevented hypoxia- and oxidative stress-induced IL-6 and IL-8 release. These findings provide evidence that relevant stressors induce a sterile inflammatory profile in placental tissue which can be partially blocked by IL1Ra suggesting this agent has translational potential to prevent placental inflammation evident in FGR and stillbirth.

Supplemental Digital Content is available in the text., Rationale: Activation of the kynurenine pathway of tryptophan catabolism by infection and inflammation contributes to the development of systemic hypotension. Commercially-available kynurenine has direct vasorelaxant effects on arteries from several species and reduces systemic blood pressure when administered to normotensive or hypertensive rats. Objectives: To determine whether kynurenine promotes relaxation of human resistance arteries from normotensive and hypertensive pregnant women and to identify the vascular mechanism of its effects. Methods and Results: In isolated omental and myometrial resistance arteries from normotensive pregnant women, kynurenine (1 mmol/L) significantly reduced U46619-induced constriction (omentum N=14, P=2.4×10−3; myometrium N=21–25, P=2.6×10−4) and relaxed preconstricted arteries (N=53, P=1.0×10−11; N=20, P=8.8×10−3). Vasorelaxation persisted following endothelium removal (N=7, P=1.6×10−4) but was completely prevented by inhibition of large-conductance Ca2+-activated K+ channels (BKCa) channels with iberiotoxin (N=9, P=5.7×10−4) or paxilline (N=10, P=2.1×10−17). Accordingly, in isolated vascular smooth muscle cells from omental arteries, kynurenine increased the BKCa current (n=5–8, P=0.022) and the amplitude of spontaneous transient outward currents (n=6, P=0.031) but did not affect spontaneous transient outward current frequency. Kynurenine also increased Ca2+ spark frequency of pressurized omental arteries (n=8, P=0.031). Vasorelaxant effects of kynurenine persisted following inhibition of ryanodine receptors (N=7, P=0.48) but were moderately reduced by inhibition of adenylate cyclase (N=9, P=0.024). In arteries from women with preeclampsia, kynurenine similarly attenuated vasoconstriction (N=15, P=1.3×10−5) and induced BKCa-mediated vasodilation (N=16, P=2.0×10−4). Vasorelaxation in response to kynurenine and a specific BKCa activator, NS11021, was absent in fetal-derived placental resistance arteries in normal pregnancy and preeclampsia. Conclusions: Kynurenine dilates systemic arteries from multiple territories via BKCa activation. Notably, the vasorelaxatory capacity of kynurenine is preserved in preeclampsia, suggesting this approach may have translational potential for the treatment of hypertension in pregnancy. The data warrant further investigation of the potential to exploit this endogenous vasorelaxant as a new treatment for hypertensive pathologies.

Currently, pregnant women are screened using ultrasound to perform gestational aging, typically at around 12 weeks' gestation, and around the middle of pregnancy. Ultrasound scans thereafter are performed for clinical indications only.We sought to assess the case for offering universal late pregnancy ultrasound to all nulliparous women in the UK. The main questions addressed were the diagnostic effectiveness of universal late pregnancy ultrasound to predict adverse outcomes and the cost-effectiveness of either implementing universal ultrasound or conducting further research in this area.We performed diagnostic test accuracy reviews of five ultrasonic measurements in late pregnancy. We conducted cost-effectiveness and value-of-information analyses of screening for fetal presentation, screening for small for gestational age fetuses and screening for large for gestational age fetuses. Finally, we conducted a survey and a focus group to determine the willingness of women to participate in a future randomised controlled trial.We searched MEDLINE, EMBASE and the Cochrane Library from inception to June 2019.The protocol for the review was designed a priori and registered. Eligible studies were identified using keywords, with no restrictions for language or location. The risk of bias in studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Health economic modelling employed a decision tree analysed via Monte Carlo simulation. Health outcomes were from the fetal perspective and presented as quality-adjusted life-years. Costs were from the perspective of the public sector, defined as NHS England, and the costs of special educational needs. All costs and quality-adjusted life-years were discounted by 3.5% per annum and the reference case time horizon was 20 years.Umbilical artery Doppler flow velocimetry, cerebroplacental ratio, severe oligohydramnios and borderline oligohydramnios were all either non-predictive or weakly predictive of the risk of neonatal morbidity (summary positive likelihood ratios between 1 and 2) and were all weakly predictive of the risk of delivering a small for gestational age infant (summary positive likelihood ratios between 2 and 4). Suspicion of fetal macrosomia is strongly predictive of the risk of delivering a large infant, but it is only weakly, albeit statistically significantly, predictive of the risk of shoulder dystocia. Very few studies blinded the result of the ultrasound scan and most studies were rated as being at a high risk of bias as a result of treatment paradox, ascertainment bias or iatrogenic harm. Health economic analysis indicated that universal ultrasound for fetal presentation only may be both clinically and economically justified on the basis of existing evidence. Universal ultrasound including fetal biometry was of borderline cost-effectiveness and was sensitive to assumptions. Value-of-information analysis indicated that the parameter that had the largest impact on decision uncertainty was the net difference in cost between an induced delivery and expectant management.The primary literature on the diagnostic effectiveness of ultrasound in late pregnancy is weak. Value-of-information analysis may have underestimated the uncertainty in the literature as it was focused on the internal validity of parameters, which is quantified, whereas the greatest uncertainty may be in the external validity to the research question, which is unquantified.Universal screening for presentation at term may be justified on the basis of current knowledge. The current literature does not support universal ultrasonic screening for fetal growth disorders.We describe proof-of-principle randomised controlled trials that could better inform the case for screening using ultrasound in late pregnancy.This study is registered as PROSPERO CRD42017064093.This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inUltrasound scans allow doctors to check on the health of an unborn infant. Usually, all pregnant women receive a scan at about 3 months and about 5 months of pregnancy. After that, women are offered a scan during birth only if they have risk factors or if a problem develops. Problems can arise in the later stages of pregnancy, including issues with the infant’s growth or whether or not the infant is breech. Some of these problems may be prevented if a scan is carried out, but scans can also be inaccurate. When they are, a woman may receive unnecessary treatment, which could even harm her or her infant. In this study we set out to review previous research about how good ultrasound scanning is at detecting infants who may be born with a condition. This study focused on detecting if the infant was too big or too small. Unfortunately, much of the previous research was not carried out to a high standard. Scanning can detect the size of a infant relatively well, but it is much less clear if scanning can predict complications that may harm the infant during birth. We also studied the costs and outcomes of scanning. We calculated the extra cost required to scan every woman and compared this with the extra benefits from preventing complications. One thing that ultrasound scans detect is whether the infant is presenting head first or bottom first (a ‘breech presentation’), as infants presenting breech have high risks of complications. Scanning all women to check whether or not their infant is presenting breech seems to be cost-effective and the cost savings may even be higher than the cost of implementation, although this depends on how much the scan would cost. Whether or not it is worthwhile scanning all infants to see if they are above or below the thresholds for normal size is less clear. A larger research study could provide more reliable numbers from which to draw a conclusion. We show how such a study could be designed, so that a single study could tell us both how well scans can predict adverse outcomes and how helpful this information is.

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.

Background Stillbirth remains a major concern across the globe and in some high-resource countries, such as the UK; efforts to reduce the rate have achieved only modest reductions. One third of stillborn babies are small for gestational age (SGA), and these pregnancies are also at risk of neonatal adverse outcomes and lifelong health problems, especially when delivered preterm. Current UK clinical guidance advocates regular monitoring and early term delivery of the SGA fetus; however, the most appropriate regimen for surveillance of these babies remains unclear and often leads to increased intervention for a large number of these women. This pilot trial will determine the feasibility of a large-scale trial refining the risk of adverse pregnancy outcome in SGA pregnancies using biomarkers of placental function sFlt-1/PlGF, identifying and intervening in only those deemed at highest risk of stillbirth. Methods PLANES is a randomised controlled feasibility study of women with an SGA fetus that will be conducted at two tertiary care hospitals in the UK. Once identified on ultrasound, women will be randomised into two groups in a 3:1 ratio in favour of sFlt-1/PlGF ratio led management vs standard care. Women with an SGA fetus and a normal sFlt-1/PlGF ratio will have a repeat ultrasound and sFlt-1/PlGF ratio every 2 weeks with planned birth delayed until 40 weeks. In those women with an SGA fetus and an abnormal sFlt-1/PlGF ratio, we will offer birth from 37 weeks or sooner if there are other concerning features on ultrasound. Women assigned to standard care will have an sFlt-1/PlGF ratio taken, but the results will be concealed from the clinical team, and the woman’s pregnancy will be managed as per the local NHS hospital policy. This integrated mixed method study will also involve a health economic analysis and a perspective work package exploring trial feasibility through interviews and questionnaires with participants, their partners, and clinicians. Discussion Our aim is to determine feasibility through the assessment of our ability to recruit and retain participants to the study. Results from this pilot study will inform the design of a future large randomised controlled trial that will be adequately powered for adverse pregnancy outcome. Such a study would provide the evidence needed to guide future management of the SGA fetus. Trial registration ISRCTN58254381. Registered on 4 July 2019

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.

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.

BackgroundStillbirth 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.ObjectivesTo collate and evaluate systematic reviews of factors associated with stillbirth in order to identify variables relevant to prediction model development.Search strategyMEDLINE, Embase, DARE and Cochrane Library databases and reference lists were searched up to November 2019.Selection criteriaWe included systematic reviews of association of individual variables with stillbirth without language restriction.Data collection and analysisAbstract 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.ResultsThe 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.ConclusionWe 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 abstractReview shows key predictors for use in developing models predicting stillbirth include age, prior pregnancy outcome and PAPP-A, PLGF and Uterine artery Doppler.

Introduction: Late-gestation adverse pregnancy outcome is associated with reduced placental villous vascularity but rarely with a frankly abnormal umbilical artery Doppler waveform. The clinical utility of umbilical artery Doppler velocimetry in late gestation is limited by poor understanding of what aspect(s) of placental structure and function the impedance reflects. We hypothesized that placental arterial circulation impedance reflects placental vascularity and arterial function.Material and methods: This was a secondary analysis of data from the FEMINA2 study, a study of pregnancy outcome after reduced fetal movement. Forty-three pregnancies that delivered within 7 days of ultrasound assessment were examined. Impedance was quantified by pulsatility index (PI) from umbilical, chorionic plate arteries, and intra-placental arteries. Site-specific PI was compared with villous vascularity (CD31 immunostaining) and placental arterial function (wire myography) by regression analysis (P < .01) where factor analysis suggested potential co-variance (Eigen value > 2).Results: Pulsatility index decreased with proximity to the placental microvasculature (P < .0001). Intra-placental artery PI correlated significantly with vessel number (R2 = 0.40, P = .0007). No significant relations between umbilical or chorionic plate artery PI and villous vascularity were found (P ≥ .11 and P ≥ .042). No significant co-variance was suggested between PI at any Doppler sampling site and ex vivo placental arterial function indices. Measurement reliability (intraclass correlation coefficient) was highest in the umbilical artery (PI 0.75 and 0.50 for intra- and interoperator reliability, respectively) and lowest in the intra-placental arteries (PI 0.55 and 0.41, respectively). Systematic bias in umbilical artery PI was observed between observers, but not at other Doppler sampling sites.Conclusions: More vascular placentas ex vivo are associated with reduced intra-placental artery Doppler impedance in utero. Although umbilical (but not intra-placental) artery Doppler PI is associated with adverse outcome after reduced fetal movement, this predictive ability does not appear to be through assessment of placental vascularity or chorionic plate arterial function. The inferior reliability of intra-placental artery Doppler, although similar to previously published reliability of umbilical artery Doppler, impairs its ability to detect subtle differences in placental vascularity, and must be significantly improved before it could be considered a clinically useful test.

BackgroundAntepartum fetal monitoring aims to assess fetal development and wellbeing throughout pregnancy. Current methods utilised in clinical practice are intermittent and only provide a ‘snapshot’ of fetal wellbeing, thus key signs of fetal demise could be missed. Continuous fetal monitoring (CFM) offers the potential to alleviate these issues by providing an objective and longitudinal overview of fetal status. Various CFM devices exist within literature; this review planned to provide a systematic overview of these devices, and specifically aimed to map the devices’ design, performance and factors which affect this, whilst determining any gaps in development.MethodsA systematic search was conducted using MEDLINE, EMBASE, CINAHL, EMCARE, BNI, Cochrane Library, Web of Science and Pubmed databases. Following the deletion of duplicates, the articles’ titles and abstracts were screened and suitable papers underwent a full-text assessment prior to inclusion in the review by two independent assessors.ResultsThe literature searches generated 4,885 hits from which 43 studies were included in the review. Twenty-four different devices were identified utilising four suitable CFM technologies: fetal electrocardiography, fetal phonocardiography, accelerometry and fetal vectorcardiography. The devices adopted various designs and signal processing methods. There was no common means of device performance assessment between different devices, which limited comparison. The device performance of fetal electrocardiography was reduced between 28 to 36 weeks’ gestation and during high levels of maternal movement, and increased during night-time rest. Other factors, including maternal body mass index, fetal position, recording location, uterine activity, amniotic fluid index, number of fetuses and smoking status, as well as factors which affected alternative technologies had equivocal effects and require further investigation.ConclusionsA variety of CFM devices have been developed, however no specific approach or design appears to be advantageous due to high levels of inter-device and intra-device variability.

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.

Background Pre-eclampsia and being born small for gestational age are associated with significant maternal and neonatal morbidity and mortality. Placental dysfunction is a key pathological process underpinning these conditions; thus, markers of placental function have the potential to identify pregnancies ending in pre-eclampsia, fetal growth restriction, and the birth of a small for gestational age infant. Primary objective To assess the predictive ability of late pregnancy (after 24 weeks’ gestation) tests in isolation or in combination for adverse pregnancy outcomes associated with placental dysfunction, including pre-eclampsia, fetal growth restriction, delivery of a SGA infant (more specifically neonatal growth restriction), and stillbirth. Methods Studies assessing the ability of biochemical tests of placental function and/or ultrasound parameters in pregnant women beyond 24 weeks’ gestation to predict outcomes including pre-eclampsia, stillbirth, delivery of a SGA infant (including neonatal growth restriction), and/or fetal growth restriction will be identified by searching the following databases: EMBASE, MEDLINE, Cochrane CENTRAL, Web of Science, CINAHL, ISRCTN registry, UK Clinical Trials Gateway, and WHO International Clinical Trials Portal. Any study design in which the biomarker and ultrasound scan potential predictors have been assessed after 24 weeks’ gestation but before diagnosis of outcomes (pre-eclampsia, fetal growth restriction, SGA (including neonatal growth restriction), and stillbirth) will be eligible (this would include randomized control trials and nested prospective case-control and cohort studies), and there will be no restriction on the background risk of the population. All eligible studies will be assessed for risk of bias using the modified QUADAS-2 tool. Meta-analyses will be undertaken using the ROC models to estimate and compare test discrimination and reclassification indices to test calibration. Validation will be explored by comparing consistency across studies. Discussion This review will assess whether current published data reporting either a single or combination of tests in late pregnancy can accurately predict adverse pregnancy outcome(s) associated with placental dysfunction. Accurate prediction could allow targeted management and possible intervention for high-risk pregnancies, ultimately avoiding adverse outcomes associated with placental disease. Systematic review registration PROSPERO CRD42018107049

Background and objectivesSleep-disordered breathing (SDB) affects up to one third of women during late pregnancy and is associated with adverse pregnancy outcomes, including hypertension, diabetes, impaired fetal growth, and preterm birth. However, it is unclear if SDB is associated with late stillbirth (≥28 weeks' gestation). The aim of this study was to investigate the relationship between self-reported symptoms of SDB and late stillbirth.MethodsData were obtained from five case-control studies (cases 851, controls 2257) from New Zealand (2 studies), Australia, the United Kingdom, and an international study. This was a secondary analysis of an individual participant data meta-analysis that investigated maternal going-to-sleep position and late stillbirth, with a one-stage approach stratified by study and site. Inclusion criteria: singleton, non-anomalous pregnancy, ≥28 weeks' gestation. Sleep data ('any' snoring, habitual snoring ≥3 nights per week, the Berlin Questionnaire [BQ], sleep quality, sleep duration, restless sleep, daytime sleepiness, and daytime naps) were collected by self-report for the month before stillbirth. Multivariable analysis adjusted for known major risk factors for stillbirth, including maternal age, body mass index (BMI kg/m2), ethnicity, parity, education, marital status, pre-existing hypertension and diabetes, smoking, recreational drug use, baby birthweight centile, fetal movement, supine going-to-sleep position, getting up to use the toilet, measures of SDB and maternal sleep patterns significant in univariable analysis (habitual snoring, the BQ, sleep duration, restless sleep, and daytime naps). Registration number: PROSPERO, CRD42017047703.ResultsIn the last month, a positive BQ (adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 1.02-2.04), sleep duration >9 hours (aOR 1.82, 95% CI 1.14-2.90), daily daytime naps (aOR 1.52, 95% CI 1.02-2.28) and restless sleep greater than average (aOR 0.62, 95% CI 0.44-0.88) were independently related to the odds of late stillbirth. 'Any' snoring, habitual snoring, sleep quality, daytime sleepiness, and a positive BQ excluding the BMI criterion, were not associated.ConclusionA positive BQ, long sleep duration >9 hours, and daily daytime naps last month were associated with increased odds of late stillbirth, while sleep that is more restless than average was associated with reduced odds. Pregnant women may be reassured that the commonly reported restless sleep of late pregnancy may be physiological and associated with a reduced risk of late stillbirth.

Friedman and colleagues1 outline a vision of the learning health system founded on the sharing of data and achieved through alignment of information technology, advanced analytics and clinical expertise. The Institute of Medicine2 recognises the potential of the learning health system to generate new information automatically during the delivery of healthcare, offering continual opportunities to improve healthcare processes for the benefit of public health. The learning health system is promoted as a mechanism to accelerate the adoption of effective treatments into clinical practice, shortening the extended delay3 from publication of research findings to implementation. Furthermore, it harbours the ambition to deliver personalised medicine to each service user, rather than the systematic provision of identical care to groups of patients who share the same characteristics. Worldwide escalating costs in healthcare provision due to demographic changes, compounded by ongoing use of ineffective tests and treatments, make it critically important to harness the efficiency gains of a learning health system. Of its many potential characteristics, one distinct attribute of the learning health system is to enable efficient investigation of whether strategies promoting implementation of best practice (such as educational initiatives or care bundles) actually work. A systematic review identifying a low frequency of reports on the evaluation and impact of learning health systems4 prompted us here to reconsider the central requirements for evaluation of improvement interventions within the learning health system. Here, we reflect on two recent implementation studies, both using efficiencies of the learning health system (minimising data acquisition and relying heavily on data acquisition from existing medical records), to illustrate the key issues arising when incorporating this type of research into the learning health system. In this paper, we argue that the presence of infrastructure which facilitates data sharing, combined with appropriate research design, analysis and reporting, …

Background Biomarkers of placental function can potentially aid the diagnosis and prediction of pregnancy complications. This randomised controlled pilot trial assessed whether for women with reduced fetal movement (RFM), intervention directed by the measurement of a placental biomarker in addition to standard care was feasible and improved pregnancy outcome compared with standard care alone. Methods Women aged 16–50 years presenting at eight UK maternity units with RFM between 36+0 and 41+0 weeks’ gestation with a viable singleton pregnancy and no indication for immediate delivery were eligible. Participants were randomised 1:1 in an unblinded manner to standard care and a biomarker blood test result revealed and acted on (intervention arm) or standard care where the biomarker result was not available (control arm). The objectives were to determine the feasibility of a main trial by recruiting 175–225 participants over 9 months and to provide proof of concept that informing care by measurement of placental biomarkers may improve outcome. Feasibility was assessed via the number of potentially eligible women, number recruited, reasons for non-recruitment and compliance. Proof of concept outcomes included the rates of the induction of labour and caesarean birth, and a composite adverse pregnancy outcome. Results Overall, 2917 women presented with RFM ≥ 36 weeks, 352 were approached to participate and 216 (61%) were randomised (intervention n = 109, control n = 107). The main reason for not approaching women was resource/staff issues (n = 1510). Ninety-seven women declined the trial, mainly due to not liking blood tests (n = 24) or not wanting to be in a trial (n = 21). Compliance with the trial interventions was 100% in both arms. Labour was induced in 97 (45%) participants (intervention n = 49, control n = 48), while 17 (9%) had planned caesarean sections (intervention n = 9, control n = 8). Overall, 9 (8%) babies in the intervention arm had the composite adverse pregnancy outcome versus 4 (4%) in the control arm. Conclusions A main trial using a placental biomarker in combination with delivery, as indicated by the biomarker, in women with RFM is feasible. The frequency of adverse outcomes in this population is low, hence, a large sample size would be required along with consideration of the most appropriate outcome measures. Trial registration ISRCTN, ISRCTN12067514; registered 8 September 2017.

Background: Hypertensive disorders of pregnancy are major causes of global maternal, fetal and neonatal morbidity and mortality. This research aimed to develop and validate multivariable prediction models for composite adverse maternal outcomes and neonatal outcomes in severe preeclampsia for use in low-resource settings. Methods: This was a retrospective cross-sectional study. Predictor variables with a p

The placenta is one of the most exciting organs. It is dynamic; its morphology and function continuously develop and adjust over its brief life span. It mediates the physiology of two distinct yet highly interconnected individuals. The pathology that develops in the placenta, and the adaptations the placenta undergoes to mitigate this pathology, may influence the later life health of the mother and baby (Circ Res, 116, 2015, 715; Hum Reprod Update, 17, 2011, 397; Nutr Rev 71, 2013, S88; Placenta, 36, 2015, S20). Pathological placenta examination may reveal macroscopic and microscopic patterns that provide valuable information to the obstetricians, neonatologists, and pediatricians caring for the family. The placenta often plays a key role in understanding adverse fetal outcomes such as hypoxic brain injury, cerebral palsy, fetal growth restriction, stillbirth, and neonatal death (Placenta, 35, 2014, 552; Placenta, 52, 2017, 58; Placenta, 30, 2009, 700; Obstet Gynecol, 114, 2009, 809; Clin Perinatol, 33, 2006, 503; Pediatr Dev Pathol, 11, 2008, 456; Arch Pathol Lab Med, 124, 2000, 1785). Moreover, it may help to understand the pathophysiology of pregnancy, improve management of subsequent pregnancies, and assist in medicolegal assessment. Placental pathologic examination may even provide evidence of susceptibility to adult-onset diseases such as diabetes (Pediatr Dev Pathol, 6, 2003, 54; Diabetes Metab, 36, 2010, 682; BJOG, 113, 2006, 1126; Int J Gynaecol Obstet, 104, 2009, S25; Zentralbl Gynakol, 97, 1975, 875). Pathologic examination of the placenta may thus be of tremendous value, particularly for those women experiencing an adverse pregnancy outcome. However, this potential utility may be entirely wasted, if the findings are not communicated in an effective manner to the appropriate clinicians. An optimized, readily understandable report of pathological findings is essential for clinical utility.

Purpose Each year approximately 3,200 women have a stillbirth in the UK. Although national evidence-based guidance has existed since 2010, case reviews continue to identify suboptimal clinical care and communication with parents. Inconsistencies in management include induction and management of labour and the frequency of investigation after stillbirth. The paper aims to discuss these issues. Design/methodology/approach An audit of stillbirths was performed in 2014 in 13 maternity units in the North West of England, this confirmed variation in practice described nationally. An integrated care pathway (ICP) was developed from national guidelines to enable optimal care for the management of stillbirth, reduce variation, standardise investigations and coordinate patient-focussed care. This was launched in 2015 and updated in 2016 to resolve the issues that were apparent after implementation. Findings Each participating unit had commenced using the ICP by May 2015. Following implementation there were changes in care, most notably from diverse methods for the induction of labour to guideline-directed induction of labour. There were trends towards better care in terms of information given, choices offered, more appropriate analgesia in labour and improved post-delivery investigation for cause. Staff feedback about the ICP was positive. Practical implications The use of this ICP improved care for women who had a stillbirth and their families. Issues with implementing a changed care pathway meant that further iterations were required, ongoing improvement is expected following the refinement of the ICP. Originality/value ICPs have been used for various clinical conditions. However, this is the first example of their use in women who had a stillbirth.

The National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Stillbirth and the Perinatal Society of Australia and New Zealand (PSANZ) have recently partnered in updating an important clinical practice guideline, Care of pregnant women with decreased fetal movements. This guideline offers 12 recommendations and a suggested care pathway, with the aim to improve the quality of care for women reporting decreased fetal movements through an evidence-based approach. Adoption of the guideline by clinicians and maternity hospitals could result in earlier identification of higher-risk pregnancies, improved perinatal health outcomes for women and their babies, and reduced stillbirth rates.

Introduction Presentation with decreased fetal movement (DFM) is associated with fetal growth restriction and stillbirth. Some studies report that DFM is frequent among overweight or obese mothers. We aimed to determine the significance and associations of fetal movements in women of increased body size. Material and methods This systematic review was conducted in accordance with the PRISMA statement and the protocol was registered with PROSPERO (CRD42016046352). Major databases were explored from inception to September 2017, using a predefined search strategy. We restricted inclusion to studies published in English and considered studies of any design that compared fetal movements in women of increased and normal body size. Two authors independently extracted data and assessed quality. Results We included 23 publications from 19 observational studies; data were extracted from 10 studies. Increased maternal body size was not associated with altered perception of fetal movement (four studies, 95 women, very low-quality evidence), but was associated with increased presentation for DFM (two cohort studies, 20 588 women, OR 1.56, 95% CI 1.27-1.92: three case-control studies, 3445 women, OR 1.32, 95% CI 1.12-1.54; low-quality evidence). Among women with DFM, increased maternal body size was associated with increased risk of stillbirth and fetal growth restriction (one study, 2168 women, very low-quality evidence). Conclusions This systematic review identified limited evidence that women with increased body size are more likely to present with DFM but do not have impaired perception of fetal movements. In women with DFM, increased body size is associated with worse pregnancy outcome, including stillbirth.

Introduction: Antepartum stillbirth is often preceded by detectable signs of fetal compromise, including changes in fetal heart rate and movement. It is hypothesised that continuous fetal monitoring could detect these signs more accurately and objectively than current forms of fetal monitoring and allow for timely intervention. This systematic review aimed to explore available evidence on women’s experiences of continuous fetal monitoring to investigate its acceptability prior to clinical implementation and to inform clinical studies. Material and methods: Systematic searching of four electronic databases (Embase, PsycINFO, MEDLINE and CINAHL), using key terms defined by initial scoping searches, identified a total of 35 studies. Following title and abstract screening by two independent researchers five studies met the inclusion criteria. Studies were not excluded based on language, methodology or quality assessment. An integrative methodology was used to synthesise qualitative and quantitative data together. Results: Forms of continuous fetal monitoring used included Monica AN24 monitors (n=4) and phonocardiography (n=1). Four main themes were identified: practical limitations of the device, negative emotions, positive perceptions and device implementation. Continuous fetal monitoring was reported to have high levels of participant satisfaction and was preferred by women to intermittent cardiotocography. Conclusion: This review suggests that continuous fetal monitoring is acceptedby women. However, it has also highlighted both the paucity and heterogeneity of current studies and suggests further research should be conducted into women’s experiences of continuous fetal monitoring before such devices can be used clinically.

Objectives Early-onset severe preeclampsia is associated with significant maternal and perinatal morbidity and mortality especially in low-resource settings, where women have limited access to antenatal care. This dataset was generated from a retrospective cross-sectional study carried out at Mpilo Central Hospital, covering the period February 1, 2016 to July 30, 2018. The aim of the study was to determine the incidence of early-onset severe preeclampsia and eclampsia, and associated risk factors in a low-resource setting. The reason for examining the incidence of preeclampsia specifically in a low-resource setting; was to document it as women in these settings appear to suffer from poor outcomes. Data description The dataset contains data of 238 pregnant women who had a diagnosis of early onset severe preeclampsia/eclampsia. There were 243 babies from singleton and twin gestations. There were five sets of twins. There were 21,505 live births during the study period giving an incidence of 1.1%. The dataset contains data on maternal socio-demographic, signs and symptoms, therapeutic interventions and mode of delivery, adverse outcomes characteristics, and fetal characteristics. This large dataset can be used to calculate the incidence and risk factors for adverse maternal and fetal outcomes or develop predictive models in severe preeclampsia/eclampsia.