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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.

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

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.

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

BackgroundConcerns regarding reduced fetal movements (RFM) are reported in 5–15% of pregnancies, and RFM are associated with adverse pregnancy outcomes including fetal growth restriction and stillbirth. Studies have aimed to improve pregnancy outcomes by evaluating interventions to raise awareness of RFM in pregnancy, such as kick counting, evaluating interventions for the clinical management of RFM, or both. However, there is not currently a core outcome set (COS) for studies of RFM. This study aims to create a COS for use in research studies that aim to raise awareness of RFM and/or evaluate interventions for the clinical management of RFM.MethodsA systematic review will be conducted, to identify outcomes used in randomised and non-randomised studies with control groups that aimed to raise awareness of RFM (for example by using mindfulness techniques, fetal movement counting, or other tools such as leaflets or mobile phone applications) and/or that evaluated the clinical management of RFM.An international Delphi consensus will then be used whereby stakeholders will rate the importance of the outcomes identified in the systematic review in (i) awareness and (ii) clinical management studies. The preliminary lists of outcomes will be discussed at a consensus meeting where one final COS for awareness and management, or two discrete COS (one for awareness and one for management), will be agreed upon.DiscussionA well-developed COS will provide researchers with the minimum set of outcomes that should be measured and reported in studies that aim to quantify the effects of interventions.

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.

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

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

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

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

Background The Medical Certificate of Stillbirth (MCS) records data about a baby’s death after 24 weeks of gestation but before birth. Major errors that could alter interpretation of the MCS were widespread in two UK-based regional studies. Methods A multicentre evaluation was conducted, examining MCS issued 1 January 2018 to 31 December 2018 in 76 UK obstetric units. A systematic case-note review of stillbirths was conducted by Obstetric and Gynaecology trainees, generating individual ‘ideal MCSs’ and comparing these to the actual MCS issued. Anonymized central data analysis described rates and types of error, agreement and factors associated with major errors. Results There were 1120 MCSs suitable for assessment, with 126 additional submitted data sets unsuitable for accuracy analysis (total 1246 cases). Gestational age demonstrated ‘substantial’ agreement [K = 0.73 (95% CI 0.70–0.76)]. Primary cause of death (COD) showed ‘fair’ agreement [K = 0.26 (95% CI 0.24–0.29)]. Major errors [696/1120; 62.1% (95% CI 59.3–64.9%)] included certificates issued for fetal demise at Conclusion This study demonstrates widespread major errors in MCS completion across the UK. MCS should only be completed following structured case-note review, with particular attention on the fetal growth trajectory.

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

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

OBJECTIVE 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 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: Pregnancy has been described as a ‘teachable moment’ for behaviour change, which presents an important opportunity for health promotion within antenatal care settings. However, no pregnancy-specific model has been developed or tested in the context of health behaviour change during pregnancy. This study aimed to investigate and compare the utility of the Capability-Opportunity-Motivation Behaviour (COM-B) and Teachable Moments (TM) models, to explain health behaviour change during pregnancy, within the context of eating behaviour. Design: Longitudinal cohort studyMethods: Five hundred and sixteen women completed a survey at between 12-16 weeks gestation (T1). Follow-up data were collected at 20-24 weeks (T2), 36-40 weeks (T3), and 6-12 weeks postnatally (T4). The primary outcome was eating behaviour. To assess the utility of the COM-B model, perceived capability, opportunity, and motivation to eat healthily were measured. To assess the utility of the TM model, risk perceptions, self-image, and affective response were measured. Results: Overall, the COM-B model explained 18.4% of the variance in eating behaviour, whilst the TM model explained 9%. Both models explained the most variance in eating behaviour at T1 and T3, compared with T2 and T4. Small changes were observed in eating behaviour and the model constructs over the time period studied, although these were not clinically meaningful. Conclusions: Neither the COM-B nor TM model provide a satisfactory explanation of eating behaviour during pregnancy, however the findings suggest that certain stages of pregnancy may create more salient opportunities for behaviour change. The findings also support claims that motivation may not play a key role in directing eating behaviour during pregnancy. Further research is needed to explore the role of timing in antenatal behaviour change. The development of a pregnancy-specific model is necessary to optimise understanding of pregnancy as a teachable moment for behaviour change.

IntroductionIn December 2019, a novel coronavirus, SARS-CoV-2, was identified. Whilst pregnant women appear to be at risk of severe infection, pre-term birth, and stillbirth, it is unclear whether placental dysfunction is a consistent feature of maternal SARS-CoV-2 infection during pregnancy. We aim to describe the immune response in placentas of women who had COVID-19 infection during pregnancy and investigate whether there are any associated morphological changes.MethodsThe placentas of women testing positive for COVID-19 during their pregnancy were compared to contemporaneous controls who were not known to have had COVID-19 during pregnancy. Samples of each placenta were sent for histopathological analysis or underwent immunohistochemical staining for CD163, CD20, CD3, CD31, and SARS-CoV-2 spike protein. A subset of samples were sent for transmission electron microscopy.ResultsThere was a significant increase in the number of CD163+ macrophages in the Post COVID group (p = 0.0020). There was no difference in the percentage of CD3+, CD20+ cells, but there was an increase in placental vascularity in the Post COVID group compared to controls (p = 0.026).There were no structural differences observed between the samples sent for EM analysis. However, one of the placentas from the Post COVID group was seen to have several large sub-apical vacuoles in the syncytiotrophoblast. We did not observe any virions within the vacuoles and SARS-CoV-2 spike protein staining was negative for the sample. Histopathological investigations indicated that there was no specific placental pathology caused by maternal COVID-19 infection in this cohort of samples.ConclusionsThis study did not confirm previous studies which describe a possible increase in cases of both maternal and fetal vascular malperfusion, and placentitis in women who had COVID-19, which were seen in association with adverse pregnancy outcomes. It remains unclear whether observed abnormalities are caused by maternal infection, or whether maternal infection exacerbates existing placental pathology; understanding why some placentas generate these abnormalities is a key goal.

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.

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

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

Blockade of the interleukin-1 (IL-1) pathway has been used therapeutically in several inflammatory diseases including arthritis and cryopyrin-associated periodic syndrome (CAPS). These conditions frequently affect women of childbearing age and continued usage of IL-1 specific treatments throughout pregnancy has been reported. IL-1 is involved in pregnancy complications and its blockade could have therapeutic potential. We systematically reviewed all reported cases of IL-1 blockade in human pregnancy to assess safety and perinatal outcomes. We searched several databases to find reports of specific blockade of the IL-1 pathway at any stage of pregnancy, excluding broad spectrum or non-specific anti-inflammatory intervention. Our literature search generated 2439 references of which 22 studies included, following extensive review. From these, 88 different pregnancies were assessed. Most (64.8%) resulted in healthy term deliveries without any obstetrical/neonatal complications. Including pregnancy exposed to Anakinra or Canakinumab, 12 (15.0%) resulted in preterm birth and one stillbirth occurred. Regarding neonatal complications, 2 cases of renal agenesis (2.5%) were observed, and 6 infants were diagnosed with CAPS (7.5%). In conclusion, this systematic review describes that IL-1 blockade during pregnancy is not associated with increased adverse perinatal outcomes, considering that treated women all presented an inflammatory disease associated with elevated risk of pregnancy complications.

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.

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.

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

Background Current methods fail to accurately predict women at greatest risk of developing fetal growth restriction (FGR) or related adverse outcomes, including stillbirth. Sexual dimorphism in these adverse pregnancy outcomes is well documented as are sex-specific differences in gene and protein expression in the placenta. Circulating maternal serum microRNAs (miRNAs) offer potential as biomarkers that may also be informative of underlying pathology. We hypothesised that FGR would be associated with an altered miRNA profile and would differ depending on fetal sex. Methods miRNA expression profiles were assessed in maternal serum (> 36 weeks’ gestation) from women delivering a severely FGR infant (defined as an individualised birthweight centile (IBC), Highlights Detection and treatment of pregnancies at high risk of fetal growth restriction (FGR) and stillbirth remains a major obstetric challenge; circulating maternal serum microRNAs (miRNAs) offer potential as novel biomarkers.Unbiased analysis of serum miRNAs in women in late pregnancy identified a specific profile of circulating miRNAs in women with a growth-restricted infant.Some altered miRNAs (miR-28-5p, miR-301a-3p) showed sexually dimorphic expression in FGR pregnancies and others a fetal-sex dependent association to a hormonal marker of placental dysfunction (miR-454-3p, miR-29c-3p).miR-301a-3p and miR-28-5p could potentially be used to predict FGR specifically in pregnancies with a male or female baby, respectively, however larger cohort studies are required.Further investigations of these miRNAs and their relationship to placental dysfunction will lead to a better understanding of the pathophysiology of FGR and why there is differing susceptibility of male and female fetuses to FGR and stillbirth. Supplementary Information The online version contains supplementary material available at 10.1186/s13293-021-00405-z.

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.