Does a sFlt-1/PlGF ratio result > 655 before 34 weeks' gestation necessitate preterm delivery within 2 days? A retrospective observational study.

INTRODUCTION: Preeclampsia is associated with adverse perinatal outcomes, including fetal growth restriction (FGR) and preterm delivery. The maternal serum ratio of soluble fms-like tyrosine kinase receptor-1 (sFlt-1) to placental growth factor (PlGF) can be used to evaluate placental dysfunction in cases of preeclampsia and FGR. A need for delivery within 2 days has been recommended for sFlt-1/PlGF ratios > 655 (normal ratio < 38) measured before 34 weeks' gestation. However, few studies have assessed this recommendation in a real-world setting and there remains a need for further evidence-based guidance on the use of the ratio in delivery timing planning in this situation. AIM: To assess the need for delivery within 2 days associated with sFlt-1/PlGF ratios > 655 before 34 weeks' gestation. METHODS: A retrospective audit of all sFlt-1/PlGF ratio test results obtained at a single maternity hospital between September 2016 and November 2022. The primary outcome was time to delivery after recording a ratio > 655 in patients with a pregnancy between 20 + 0 and 33 + 6 weeks' gestation. Statistical analysis was performed using IBM SPSS Statistics v29.0.0.0. RESULTS: During the study period a total of 33 patients with suspected or confirmed preeclampsia and/or FGR recorded sFlt-1/PlGF ratios > 655 before 34 + 0 weeks' gestation. Amongst cases with ratios > 655, median time to delivery was 4 days (IQR 1.0-9.0), with 14 (42.4%) delivering in ≤ 2 days, 8 (24.2%) delivering between 2 and 7 days and 11 (33.3%) delivering after 7 days. A significant inverse correlation was observed between time to delivery and gestational age at the time of ratio testing (rs = -0.484, p = 0.004). DISCUSSION: This study provides updated recommendations on the use of the sFlt-1/PlGF ratio in predicting the risk of imminent delivery amongst those with high ratios > 655 measured before 34 weeks' gestation. Our results suggest that the risk of imminent delivery can be stratified based on ratio level and gestational age, which in combination with the results of other clinical assessments, can be used to plan delivery timing and allow for considerations of fetal lung maturing corticosteroid and neuroprotective magnesium sulfate therapies prior to delivery.

Reducing the Risk of Pre-Eclampsia in Women with Polycystic Ovary Syndrome Using a Combination of Pregnancy Screening, Lifestyle, and Medical Management Strategies.

Polycystic ovary syndrome (PCOS) is a multisystem disorder that presents with a variety of phenotypes involving metabolic, endocrine, reproductive, and psychological symptoms and signs. Women with PCOS are at increased risk of pregnancy complications including implantation failure, miscarriage, gestational diabetes, fetal growth restriction, preterm labor, and pre-eclampsia (PE). This may be attributed to the presence of specific susceptibility features associated with PCOS before and during pregnancy, such as chronic systemic inflammation, insulin resistance (IR), and hyperandrogenism, all of which have been associated with an increased risk of pregnancy complications. Many of the features of PCOS are reversible following lifestyle interventions such as diet and exercise, and pregnant women following a healthy lifestyle have been found to have a lower risk of complications, including PE. This narrative synthesis summarizes the evidence investigating the risk of PE and the role of nutritional factors in women with PCOS. The findings suggest that the beneficial aspects of lifestyle management of PCOS, as recommended in the evidence-based international guidelines, extend to improved pregnancy outcomes. Identifying high-risk women with PCOS will allow targeted interventions, early-pregnancy screening, and increased surveillance for PE. Women with PCOS should be included in risk assessment algorithms for PE.

Maternal serum soluble fms-like tyrosine kinase-1-to-placental growth factor ratio distinguishes growth-restricted from non-growth-restricted small-for-gestational-age fetuses.

BACKGROUND: Fetal growth restriction secondary to chronic placental insufficiency is a major cause of perinatal morbidity and mortality. A significant proportion of fetuses with fetal growth restriction are small for gestational age, defined as a birthweight of ≤10th percentile. However, not all small-for-gestational-age fetuses are growth restricted. Some are constitutionally small and otherwise healthy. It is important to distinguish between small-for-gestational-age fetuses with and without fetal growth restriction to ensure appropriate interventions in small-for-gestational-age fetuses with fetal growth restriction and to minimize unnecessary interventions in healthy small-for-gestational-age fetuses. The maternal serum ratio of soluble fms-like tyrosine kinase-1 and placental growth factor is an indicator of placental insufficiency in the latter half of pregnancy. As such, the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio may be a clinically useful tool to distinguish between small-for-gestational-age fetuses with and without fetal growth restriction. OBJECTIVE: This study aimed to determine whether the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio can distinguish between small-for-gestational-age fetuses with and without fetal growth restriction with a birthweight of ≤10th percentile. STUDY DESIGN: A retrospective audit of 233 singleton pregnancies delivering an infant with a birthweight of ≤10th percentile corrected for gestational age with an antenatal maternal serum soluble fms-like tyrosine kinase-1-to-placental growth factor result was performed. Fetal growth restriction was defined as a birthweight of ≤10th percentile with an umbilical artery pulsatility index of >95th percentile, fetal middle cerebral artery pulsatility index of <5th percentile, amniotic fluid index of <6 cm, and/or cerebroplacental ratio of <1st percentile. The soluble fms-like tyrosine kinase-1-to-placental growth factor ratios before delivery between fetuses with and without fetal growth restriction (121 [fetal growth restriction] vs 112 [no fetal growth restriction]) were compared. The Student t test and Fisher exact test were used to compare cases and controls. The Mann-Whitney U test, linear regression analysis, and Spearman correlation coefficient (Rho) were used to examine associations between the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio and fetal outcomes to determine whether the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio served as a prognostic marker of fetal growth restriction severity. RESULTS: The mean soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was increased in fetal growth restriction cases compared with non-fetal growth restriction controls (234.3±25.0 vs 67.4±7.7, respectively; P<.0001). When controlling for preeclampsia, which is associated with placental insufficiency, fetal growth restriction cases still demonstrated an independent increase in the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio (effect size, 0.865; 95% confidence interval, 0.509-1.220; P<.001). The soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was negatively correlated with birthweight percentiles in pregnancies delivering an infant with a birthweight of ≤10th percentile (r=-0.3565; P<.0001). This association was maintained for fetuses with fetal growth restriction (r=-0.2309; P<.05), whereas fetuses without fetal growth restriction had no significant correlation between the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio and neonatal birthweight percentiles. CONCLUSION: The soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was significantly higher in small-for-gestational-age fetuses with fetal growth restriction than small-for-gestational-age fetuses without fetal growth restriction, independent of preeclampsia. Furthermore, the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was negatively correlated with fetal growth restriction birthweight percentiles, suggesting that it may be a clinical measure of fetal growth restriction severity. Therefore, the ratio may usefully delineate fetal growth restriction from constitutionally small but otherwise healthy fetuses antenatally, allowing for timely interventions in small-for-gestational-age cases with fetal growth restriction and unnecessary interventions to be minimized in small-for-gestational-age cases without fetal growth restriction.

Association of Vascular Endothelial Growth Factors (VEGFs) with Recurrent Miscarriage: A Systematic Review of the Literature.

Recurrent miscarriage (RM) can be defined as two or more consecutive miscarriages before 20 weeks' gestation. Vascular endothelial growth factors (VEGFs) play an important role in endometrial angiogenesis and decidualization, prerequisites for successful pregnancy outcomes. We conducted a systematic review of the published literature investigating the role of VEGFs in RM. In particular, we explored the methodological inconsistencies between the published reports on this topic. To our knowledge, this is the first systematic literature review to examine the role of VEGFs in RM. Our systematic search followed PRISMA guidelines. Three databases, Medline (Ovid), PubMed, and Embase, were searched. Assessment-bias analyses were conducted using the Joanna Bigger Institute critical appraisal method for case-control studies. Thirteen papers were included in the final analyses. These studies included 677 cases with RM and 724 controls. Endometrial levels of VEGFs were consistently lower in RM cases compared to controls. There were no consistent significant findings with respect to VEGFs levels in decidua, fetoplacental tissues, and serum when RM cases were compared to controls. The interpretation of studies that explored the relationship between VEGFs and RM is hampered by inconsistencies in defining clinical, sampling, and analytical variables. To clarify the association between VEGF and RM in future studies, researchers ideally should use similarly defined clinical groups, similar samples collected in the same way, and laboratory analyses undertaken using the same methods.

Identification of biochemical biomarkers associated with premature cervical shortening in high-risk, asymptomatic pregnant women: a retrospective data analysis.

Reliably predicting spontaneous preterm birth remains challenging, therefore it persists as a major contributor to perinatal morbidity and mortality. The use of biomarkers to predict premature cervical shortening, a recognised risk factor for spontaneous preterm birth, is yet to be fully explored in current literature. This study evaluates seven cervicovaginal biochemical biomarkers as possible predictors of premature cervical shortening. Asymptomatic, high-risk women (n = 131) presenting to a specialised preterm birth prevention clinic were analysed through a retrospective data analysis. Cervicovaginal biochemical biomarker concentrations were obtained, and the shortest cervical length measurement, up to 28 weeks' gestation, was recorded. Associations between biomarker concentration and cervical length were then analysed. Of the seven biochemical biomarkers, Interleukin-1 Receptor Antagonist and Extracellular Matrix Protein-1 had statistically significant relationships with cervical shortening below 25 mm. Further investigation is required to validate these findings and any downstream clinical utility, with intentions to improve perinatal outcomes.IMPACT STATEMENTWhat is already known on this subject? Preterm birth is a major cause of perinatal morbidity and mortality. A woman's risk of delivering preterm is currently stratified using historical risk factors, mid-gestation cervical length, and biochemical biomarkers such as foetal fibronectin.What do the results of this study add? In a cohort of high-risk, asymptomatic pregnant women, two cervicovaginal biochemical biomarkers, Interleukin-1 Receptor Antagonist and Extracellular Matrix Protein-1, displayed associations with premature cervical shortening.What are the implications of these findings for clinical practice and/or further research? Further investigation into the possible clinical utility of these biochemical biomarkers is warranted, with a view to improving preterm birth prediction and antenatal resource utilisation, thereby reducing the burden of preterm birth and its sequelae in a cost-effective manner.

Diagnosis or prognosis? An umbrella review of mid-trimester cervical length and spontaneous preterm birth.

BACKGROUND: Cervical length is widely used to assess a woman's risk of spontaneous preterm birth (SPTB). OBJECTIVES: To summarise and critically appraise the evidence from systematic reviews on the prognostic capacity of transvaginal sonographic cervical length in the second trimester in asymptomatic women with singleton or twin pregnancy. SEARCH STRATEGY: Searches were performed in Medline, Embase, CINAHL and grey literature from 1 January 1995 to 6 July 2021, including keywords 'cervical length', 'preterm birth', 'obstetric labour, premature', 'review' and others, without language restriction. SELECTION CRITERIA: We included systematic reviews including women who did not receive treatments to reduce SPTB risk. DATA COLLECTION AND ANALYSIS: From 2472 articles, 14 systematic reviews were included. Summary statistics were independently extracted by two reviewers, tabulated and analysed descriptively. The ROBIS tool was used to evaluate risk of bias of included systematic reviews. MAIN RESULTS: Twelve reviews performed meta-analyses: two were reported as systematic reviews of prognostic factor studies, ten used diagnostic test accuracy methodology. Ten systematic reviews were at high or unclear risk of bias. Meta-analyses reported up to 80 combinations of cervical length, gestational age at measurement and definition of preterm birth. Cervical length was consistently associated with SPTB, with a likelihood ratio for a positive test of 1.70-142. CONCLUSIONS: The ability of cervical length to predict SPTB is a prognostic research question; systematic reviews typically analysed diagnostic test accuracy. Individual participant data meta-analysis using prognostic factor research methods is recommended to better quantify how well transvaginal ultrasonographic cervical length can predict SPTB.

Genomic variation associated with cardiovascular disease progression following preeclampsia: a systematic review.

Background: Women with a history of preeclampsia (PE) have been shown to have up to five times the risk of developing later-life cardiovascular disease (CVD). While PE and CVD are known to share clinical and molecular characteristics, there are limited studies investigating their shared genomics (genetics, epigenetics or transcriptomics) variation over time. Therefore, we sought to systematically review the literature to identify longitudinal studies focused on the genomic progression to CVD following PE. Methods: A literature search of primary sources through PubMed, Scopus, Web of Science and Embase via OVID was performed. Studies published from January 1, 1980, to July 28, 2023, that investigated genomics in PE and CVD were eligible for inclusion. Included studies were screened based on Cochrane systematic review guidelines in conjunction with the PRISMA 2020 checklist. Eligible articles were further assessed for quality using the Newcastle-Ottawa scale. Results: A total of 9,231 articles were screened, with 14 studies subjected to quality assessment. Following further evaluation, six studies were included for the final review. All six of these studies were heterogeneous in regard to CVD/risk factor as outcome, gene mapping approach, and in different targeted genes. The associated genes were RGS2, LPA, and AQP3, alongside microRNAs miR-122-5p, miR-126-3p, miR-146a-5p, and miR-206. Additionally, 12 differentially methylated regions potentially linked to later-life CVD following PE were identified. The only common variable across all six studies was the use of a case-control study design. Conclusions: Our results provide critical insight into the heterogeneous nature of genomic studies investigating CVD following PE and highlight the urgent need for longitudinal studies to further investigate the genetic variation underlying the progression to CVD following PE.

Successful pregnancy outcomes following intravenous immunoglobulin treatment in a woman with a previous fetal death in utero due to gestational alloimmune liver disease: A case report.

Gestational alloimmune liver disease resulting in neonatal haemochromatosis is a rare but often lethal neonatal and fetal condition and is the leading cause of fetal and neonatal liver injury. Chelation-antioxidant treatment, intravenous immunoglobulin therapy and exchange transfusions, as well as liver transplantation have been used as treatments for the affected newborn at birth. In the reported case, a woman with previous neonatal death at 34 weeks of gestation due to gestational alloimmune liver disease commenced weekly doses of intravenous immunoglobulin (1 mg/kg) from 15 weeks in a subsequent pregnancy. A healthy baby boy was delivered following induction of labour at 36 weeks and 5 days of gestation. Following the same protocol, another healthy baby boy was delivered at 37 weeks of gestation. This case report emphasises the clinical utility of antenatal prophylaxis with intravenous immunoglobulin in women at high risk of recurrent gestational alloimmune liver disease.

Mesenchymal Stem/Stromal Cells and Their Role in Oxidative Stress Associated with Preeclampsia.

Preeclampsia (PE) is a serious medically important disorder of human pregnancy, which features de novo pregnancy-induced hypertension and proteinuria. The severe form of PE can progress to eclampsia, a convulsive, life-threatening condition. When placental growth and perfusion are abnormal, the placenta experiences oxidative stress and subsequently secretes abnormal amounts of certain pro-angiogenic factors (eg, PlGF) as well as anti-angiogenic factors (eg, sFlt-1) that enter the maternal circulation. The net effect is damage to the maternal vascular endothelium, which subsequently manifests as the clinical features of PE. Other than delivery of the fetus and placenta, curative treatments for PE have not yet been forthcoming, which reflects the complexity of the clinical syndrome. A major source of reactive oxygen species that contributes to the widespread maternal vascular endothelium damage is the PE-affected decidua. The role of decidua-derived mesenchymal stem/stromal cells (MSC) in normotensive and pathological placenta development is poorly understood. The ability to respond to an environment of oxidative damage is a "universal property" of MSC but the biological mechanisms that MSC employ in response to oxidative stress are compromised in PE. In this review, we discuss how MSC respond to oxidative stress in normotensive and pathological conditions. We also consider the possibility of manipulating the oxidative stress response of abnormal MSC as a therapeutic strategy to treat preeclampsia.

Prior term delivery increases risk of subsequent recurrent preterm birth: An unexpected finding.

BACKGROUND: Women with a prior pregnancy at term are generally considered to be at reduced risk for subsequent spontaneous preterm birth (sPTB), whereas a previous sPTB is a major predictor for a future sPTB. AIMS: The objective of this study was to investigate the risk of recurrent sPTB in women with a prior term birth and a subsequent sPTB. MATERIALS AND METHODS: This is a retrospective cohort study conducted at St Thomas' Hospital in London, UK. There were 430 women included: 230 with a term birth (caesarean section or vaginal delivery) preceding a sPTB (term + sPTB group) and 200 with a prior sPTB only (sPTB only group). The primary outcome was sPTB, <37 weeks gestation. RESULTS: Of the term + sPTB group, 38.7% (89/230) had a recurrent sPTB compared to 20% (40/200) in the sPTB only group (P < 0.0001), with a relative risk (RR) of 1.9. Of women who had a term caesarean section and a subsequent PTB, 50% (30/60) had a further sPTB (RR 2.5 compared to the sPTB only group), while 34.7% (59/170) of women who had a term vaginal birth and subsequent sPTB, had a further sPTB (RR 1.7 compared to the sPTB only group). CONCLUSION: In women who have had a previous sPTB, the risk of a recurrence is much higher than in women with a prior term birth. The aetiology of PTB may be different in this subgroup of women and needs to be further elucidated to determine how best to identify and treat them.

Evaluation of epigenetic age calculators between preeclampsia and normotensive pregnancies in an Australian cohort.

Advanced biological aging, as assessed through DNA methylation markers, is associated with several complex diseases. The associations between maternal DNA methylation age and preeclampsia (PE) have not been fully assessed. The aim of this study was to examine if increased maternal DNA methylation age (DNAmAge) was shown to be accelerated in women with PE when compared to women who had normotensive pregnancies. The case/control cohort available for study consisted of 166 women (89 with normotensive pregnancy, 77 with PE) recruited previously at the Royal Women's Hospital in Melbourne, Australia. DNA methylation profiles were obtained using the Illumina EPIC Infinium array for analysis of genomic DNA isolated from whole blood. These profiles were used to calculate seven estimates of DNAmAge and included (1) Horvath, (2) Hannum, (3) Horvath Skin and Blood, (4) Wu, (5) PhenoAge, (6) telomere length and (7) GrimAge and its surrogate measures. Three measures of DNA methylation age acceleration were calculated for all seven measures using linear regression. Pearson's correlation was performed to investigate associations between chronological age and DNAmAge. Differences between chronological age and DNAmAge and epigenetic age acceleration were investigated using t-tests. No significant difference was observed for chronological age between women with PE (age = 30.53 ± 5.68) and women who had normotensive pregnancies (age = 31.76 ± 4.76). All seven DNAmAge measures were significantly correlated (p < 0.001) with chronological age. After accounting for multiple testing and investigating differences in DNAmAge between normotensive women and women with PE, only Wu DNAmAge was significant (p = 0.001). When examining differences for epigenetic age acceleration between PE and normotensive women Hannum, Wu, and PhenoAge DNAmAge estimates (p < 0.001) were significant for both epigenetic age acceleration and intrinsic acceleration models. We found that accelerated maternal DNAmAge is increased in women with PE in some models of epigenetic aging. This research underlines the importance for further investigation into the potential changes of differential DNA methylation in PE.

Previous term emergency caesarean section is a risk factor for recurrent spontaneous preterm birth; a retrospective cohort study.

OBJECTIVES: Emergency caesarean sections (EmCS), particularly those performed in the second stage of labour, have been associated with a risk of subsequent preterm birth. More worrying is that the risk of sPTB recurrence appears to be high in women who have had a second stage EmCS and a subsequent sPTB. However, there is a paucity of evidence regarding the risk of recurrence in women who have had a prior term EmCS at any stage of labour followed by a sPTB. This study aims to investigate the relationship between all term in labour EmCS and the risk of recurrent spontaneous preterm birth (sPTB). STUDY DESIGN: This is an observational, retrospective cohort study conducted at St Thomas' Hospital, a tertiary-level maternity hospital in London, United Kingdom. 259 women were included; 59 women with a term in labour EmCS preceding a sPTB (EmCS group) and 200 women with a prior sPTB only (control group). The initial EmCS was further categorised into first stage (FS)-EmCS or second stage (SS)-EmCS. Primary outcome was sPTB in Pregnancy C < 37 weeks' gestation. Secondary outcomes included sPTB < 34 weeks' and < 24 weeks' gestation. RESULTS: 54% (32/59) of the EmCS group had a recurrent sPTB < 37 weeks compared to 20% (40/200) of the control women (p < 0.0001) with a relative risk of 2.71 [95%CI 1.87-3.87]). Of women who had a SS-EmCS and a subsequent PTB, 61.9% (13/21) had a further sPTB (RR 3.0 [95%CI, 1.8-4.5] compared to control women). In addition, there is nearly a 6-fold increased risk of a recurrent sPTB or midtrimester loss < 24 weeks' gestation in these women (RR 5.65 [95%CI2.6-12.0]). CONCLUSIONS: In women who have had a previous sPTB in which a term in labour EmCS is a risk factor, the risk of a further sPTB is much higher than in those women where a prior sPTB is the sole risk factor. Furthermore, EmCS at both the first and second stage of labour are associated with a increased risk of recurrent sPTB. Further work should ascertain which women who have had a prior term EmCS are at risk of sPTB and recurrence, and how best to identify and treat them.

Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia.

Preeclampsia is associated with significant morbidity and mortality for mother and baby. Although around 30% of all pregnancies are evaluated for preeclampsia, diagnosis is difficult, especially in patients who have overlying symptoms from other diseases. Discovery of circulating angiogenic factors in the pathogenesis of preeclampsia has been a major advance for both diagnosis and prognosis. The anti-angiogenic factor, soluble fms-like tyrosine kinase 1 (sFlt-1) and the pro-angiogenic factor, placental growth factor (PlGF), can be measured in plasma and serum and are usually reported as a ratio, which specifically relates to the onset and severity of preeclampsia. The sFlt-1/PlGF ratio has a very high negative predictive value in ruling out the development of preeclampsia within 7 days among women with suspected preeclampsia. Currently, there is no clear consensus on the practical use of angiogenic biomarkers in the detection and management of preeclampsia in routine clinical practice. While major international clinical guidelines exist, they do not define which specific parameters signal patient admission, or outpatient evaluation of suspected preeclampsia, and most clinicians follow local practices. Better guidance is needed on risk stratification among women with suspected preeclampsia, as well as among women at high risk for preeclampsia. Prediction of adverse outcomes in women, after the clinical diagnosis of preeclampsia, is also important. This report has been developed following a meeting of international experts and aims to guide clinicians in the management of pregnant women at risk of preeclampsia using the sFlt-1/PlGF ratio test.

Late/post-term decidual basalis-derived mesenchymal stem/stromal cells show evidence of advanced ageing and downregulation of microRNA-516b-5p.

INTRODUCTION: The placenta is a short-lived organ, yet it shows signs of progressive ageing in the third trimester. Studies of ageing chorionic placental tissue have recently flourished, providing evidence of advanced ageing of tissues in the late/post-term (L/PT) period of gestation. However, ageing of the maternal aspect of the maternal-fetal interface, specifically the decidua basalis, is poorly understood. Here, we investigated whether the L/PT period was associated with advanced ageing and exhaustion of important decidua basalis mesenchymal stem/stromal cells (DMSCs) functions. METHODS: In this study, DMSCs were isolated and characterised from early term (ET) and L/PT placental tissue and they were then investigated by employing various MSC potency and ageing assays. RNA sequencing was also performed to screen for specific microRNAs that are associated with stem cell exhaustion and ageing between ET- and L/PT-DMSCs. RESULTS: L/PT-DMSCs, when compared to ET-DMSCs, showed significantly lower cell proliferation and a significant higher level of cell apoptosis. L/PT-DMSCs showed significantly lower resistance to oxidative stress and a significant decrease in antioxidant capacity compared with ET-DMSCs. Western blot analysis revealed increased expression of the stress-mediated P-p38MAPK protein in L/PT-DMSCs. RNA Sequencing showed microRNA (miR) miR-516b-5p, was present at significantly lower levels in L/PT-DMSCs. Inhibition of miR-516b-5p in ET-DMSCs revealed a decline in the ability of the inhibited cells to survive in extended cell culture. DISCUSSION: These data provide the first evidence of advanced ageing and exhaustion of important stem cell functions in L/PT-DMSCs, and the involvement of specific miRs in the DMSC ageing process.

Hypertensive disorders of pregnancy (HDP) management pathways: results of a Delphi survey to contextualise international recommendations for Indonesian primary care settings.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are a significant contributor to the high maternal mortality rate in Indonesia. At the moment, limited guidelines are available to assist primary care providers in managing HDP cases. A previous review of 16 international HDP guidelines has identified opportunities for improving HDP management in Indonesian primary care, but it has not determined the suitability of the recommendations in practice. This study aims to achieve consensus among the experts regarding the recommendations suitability and to develop HDP pathways in Indonesian primary care. METHODS: Maternal health experts, including GPs, midwives, nurses, medical specialists and health policy researchers from Indonesia and overseas were recruited for the study. They participated in a consensus development process that applied a mix of quantitative and qualitative questions in three Delphi survey rounds. At the first and second-round survey, the participants were asked to rate their agreement on whether each of 125 statements about HDP and HDP management is appropriate for use in Indonesian primary care settings. The third-round survey presented the drafts of HDP pathways and sought participants' agreement and further suggestions. The participants' agreement scores were calculated with a statement needing a minimum of 70% agreement to be included in the HDP pathways. The participants' responses and suggestions to the free text questions were analysed thematically. RESULTS: A total of 52 participants were included, with 48, 45 and 37 of them completing the first, second and third round of the survey respectively. Consensus was reached for 115 of the 125 statements on HDP definition, screening, management and long-term follow-up. Agreement scores for the statements ranged from 70.8-100.0%, and potential implementation barriers of the pathways were identified. Drafts of HDP management pathways were also agreed upon and received suggestions from the participants. CONCLUSIONS: Most evidence-based management recommendations achieved consensus and were included in the developed HDP management pathways, which can potentially be implemented in Indonesian settings. Further investigations are needed to explore the acceptability and feasibility of the developed HDP pathways in primary care practice.

The addition of fetal scalp blood lactate measurement as an adjunct to cardiotocography to reduce caesarean sections during labour: The Flamingo randomised controlled trial.

BACKGROUND: Fetal scalp blood sampling for lactate measurement (FBSLM) is sometimes used to assist in identification of the need for expedited birth in the presence of an abnormal cardiotocograph (CTG). However, there is no randomised controlled trial evidence to support this. AIM: To determine whether adding FBSLM reduces the risk of birth by emergency caesarean section in labours complicated by an abnormal CTG, compared with CTG without FBS. MATERIAL AND METHODS: Labouring women at a tertiary maternity hospital in Melbourne, Australia with a singleton, cephalic presentation, at ≥37 weeks gestation with an abnormal CTG pattern were randomised to the intervention (n = 61), with intermittent FBSLM in addition to CTG monitoring, or control (CTG without FBS, n = 62). The primary outcome was rate of birth by caesarean section. Secondary outcomes included overall operative birth and fetal and neonatal safety endpoints. TRIAL REGISTRATION: ACTRN12611000172909. RESULTS: The smaller than anticipated sample was unable to demonstrate an effect from adding FBSLM to CTG monitoring on birth by caesarean section vs monitoring by CTG without FBS (25/61 and 28/62 respectively, P = 0.64, risk ratio 0.91, 95% confidence intervals 0.60-1.36). One newborn infant in the CTG group met the criteria for the composite neonatal outcome of death or serious outcome, neonatal encephalopathy, five-minute Apgar score < 4, neonatal resuscitation, admission to neonatal intensive care unit for 96 h or more. CONCLUSION: We were unable to provide robust evidence of the effectiveness of FBSLM to improve the specificity of the CTG in the assessment of fetal wellbeing.

Preterm birth prediction in asymptomatic women at mid-gestation using a panel of novel protein biomarkers: the Prediction of PreTerm Labor (PPeTaL) study.

BACKGROUND: Accurate prediction of spontaneous preterm labor/preterm birth in asymptomatic women remains an elusive clinical challenge because of the multi-etiological nature of preterm birth. OBJECTIVE: The aim of this study was to develop and validate an immunoassay-based, multi-biomarker test to predict spontaneous preterm birth. MATERIALS AND METHODS: This was an observational cohort study of women delivering from December 2017 to February 2019 at 2 maternity hospitals in Melbourne, Australia. Cervicovaginal fluid samples were collected from asymptomatic women at gestational week 16+0-24+0, and biomarker concentrations were quantified by enzyme-linked immunosorbent assay. Women were assigned to a training cohort (n = 136) and a validation cohort (n = 150) based on chronological delivery dates. RESULTS: Seven candidate biomarkers representing key pathways in utero-cervical remodeling were discovered by high-throughput bioinformatic search, and their significance in both in vivo and in vitro studies was assessed. Using a combination of the biomarkers for the first 136 women allocated to the training cohort, we developed an algorithm to stratify term birth (n = 124) and spontaneous preterm birth (n = 12) samples with a sensitivity of 100% (95% confidence interval, 76-100%) and a specificity of 74% (95% confidence interval, 66-81%). The algorithm was further validated in a subsequent cohort of 150 women (n = 139 term birth and n = 11 preterm birth), achieving a sensitivity of 91% (95% confidence interval, 62-100%) and a specificity of 78% (95% confidence interval, 70-84%). CONCLUSION: We have identified a panel of biomarkers that yield clinically useful diagnostic values when combined in a multiplex algorithm. The early identification of asymptomatic women at risk for preterm birth would allow women to be triaged to specialist clinics for further assessment and appropriate preventive treatment.

Decidual mesenchymal stem/stromal cell-derived extracellular vesicles ameliorate endothelial cell proliferation, inflammation, and oxidative stress in a cell culture model of preeclampsia.

Oxidative stress and endothelial dysfunction contribute substantially to the pathogenesis of preeclampsia (PE). Decidual mesenchymal stem/stromal cells (DMSC), reportedly reduce endothelial cell dysfunction and alleviate PE-like symptoms in a murine model. However, as a therapeutic strategy, the use of whole DMSC presents significant technical limitations, which may be overcome by employing DMSC-secreted extracellular vesicles (DMSC_EV). DMSC_EV restoration of endothelial dysfunction through a paracrine effect may alleviate the clinical features of PE. OBJECTIVE: To determine whether DMSC-secreted, extracellular vesicles (DMSC_EV) restore endothelial cell function and reduce oxidative stress. METHODS: DMSC were isolated from the placentae of uncomplicated term pregnancies and DMSC_EV prepared by ultracentrifugation. Human umbilical vein endothelial cells (HUVEC) were treated with bacterial lipopolysaccharide (LPS), or with serum from PE patients, to model the effects of PE. DMSC_EV were then added to treated HUVEC and their growth profiles, inflammatory state, and oxidative stress levels measured. RESULTS: DMSC_EV displayed characteristic features of extracellular vesicles. In both LPS- and PE serum-treatment models, addition of DMSC_EV significantly increased HUVEC cell attachment and proliferation, and significantly reduced production of pro-inflammatory cytokine IL-6. The addition of DMSC_EV to LPS-treated HUVEC had no significant effect on total antioxidant capacity, superoxide dismutase levels or on lipid peroxidation levels. In contrast, the addition of DMSC_EV to PE serum-treated HUVEC resulted in a significant reduction in levels of lipid peroxidation. CONCLUSION: Addition of DMSC_EV had beneficial effects in both LPS- and PE serum- treated HUVEC but the two treatment models to induce endothelial cell dysfunction showed differences. The LPS treatment of HUVEC model may not accurately model the endothelial cell dysfunction characteristic of PE. Human cell culture models of PE show that DMSC_EV improve endothelial cell dysfunction in PE, but testing in in vivo models of PE is required.

Functional changes in decidual mesenchymal stem/stromal cells are associated with spontaneous onset of labour.

Ageing and parturition share common pathways, but their relationship remains poorly understood. Decidual cells undergo ageing as parturition approaches term, and these age-related changes may trigger labour. Mesenchymal stem/stromal cells (MSCs) are the predominant stem cell type in the decidua. Stem cell exhaustion is a hallmark of ageing, and thus ageing of decidual MSCs (DMSCs) may contribute to the functional changes in decidual tissue required for term spontaneous labour. Here, we determine whether DMSCs from patients undergoing spontaneous onset of labour (SOL-DMSCs) show evidence of ageing-related functional changes compared with those from patients not in labour (NIL-DMSCs), undergoing Caesarean section. Placentae were collected from term (37-40 weeks of gestation), SOL (n = 18) and NIL (n = 17) healthy patients. DMSCs were isolated from the decidua basalis that remained attached to the placenta after delivery. DMSCs displayed stem cell-like properties and were of maternal origin. Important cell properties and lipid profiles were assessed and compared between SOL- and NIL-DMSCs. SOL-DMSCs showed reduced proliferation and increased lipid peroxidation, migration, necrosis, mitochondrial apoptosis, IL-6 production and p38 MAPK levels compared with NIL-DMSCs (P < 0.05). SOL- and NIL-DMSCs also showed significant differences in lipid profiles in various phospholipids (phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine), sphingolipids (ceramide, sphingomyelin), triglycerides and acyl carnitine (P < 0.05). Overall, SOL-DMSCs had altered lipid profiles compared with NIL-DMSCs. In conclusion, SOL-DMSCs showed evidence of ageing-related reduced functionality, accumulation of cellular damage and changes in lipid profiles compared with NIL-DMSCs. These changes may be associated with term spontaneous labour.

Early Pregnancy Screening for Women at High-Risk of GDM Results in Reduced Neonatal Morbidity and Similar Maternal Outcomes to Routine Screening.

The Australasian Diabetes in Pregnancy Society recommends screening high-risk women for gestational diabetes mellitus (GDM) before 24 weeks gestation, under the assumption that an earlier diagnosis and opportunity to achieve normoglycemia will minimize adverse outcomes. However, little evidence exists for this recommendation. The study objective was to compare the pregnancy outcomes of high-risk women diagnosed with GDM before 24 weeks gestation and routinely diagnosed women after 24 weeks gestation. A retrospective audit was conducted of all pregnancies diagnosed with GDM using International Association of Diabetes and Pregnancy Study Groups criteria over 12 months at a tertiary Australian hospital. Adverse perinatal outcomes were compared between "Early GDM" diagnosed before 24 weeks (n = 133) and "Late GDM" diagnosed from 24 weeks (n = 636). Early GDM had a significantly lower newborn composite outcome frequency (hypoglycemia, birth trauma, NICU/SCN admission, stillbirth, neonatal death, respiratory distress, and phototherapy) compared to Late GDM (20.3% vs. 30.0%, p = 0.02). Primary cesarean, hypertensive disorders, postpartum hemorrhage, birthweight >90th percentile, macrosomia, and preterm birth frequencies were not significantly different between groups. Therefore, high-risk women diagnosed with GDM in early pregnancy were not more likely to have an adverse outcome compared to routinely diagnosed women. As they are a high-risk group, this may indicate a possible benefit to the early diagnosis of GDM.