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.

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.

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.

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.

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.

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.

Optic nerve sonography and ophthalmic artery Doppler velocimetry in healthy pregnant women: an Australian cohort study.

PURPOSE: Maternal ocular sonography offers a window into cerebrovascular and intracranial pressure changes in pregnancy. This study aimed to determine the Doppler velocimetric variables of the ophthalmic artery, and the mean diameter of the optic nerve sheath (ONSD), in an Australian cohort of healthy pregnant women. METHODS: A prospective observational cohort study of healthy women with uncomplicated singleton pregnancies in the third trimester was undertaken in a tertiary maternity service. A single prenatal ultrasonographic examination was performed on all participants, with a postnatal examination performed on a subgroup with uncomplicated deliveries. RESULTS: Fifty women were examined at a mean gestation of 35 weeks. The mean ± SD Doppler variables in the ophthalmic artery were peak systolic velocity (PSV) 41.89 ± 13.13 cm/s, second peak velocity 20.63 ± 8.97 cm/s, end diastolic velocity 9.29 ± 5.13 cm/s, pulsatility index 1.97 ± 0.53, resistive index 0.78 ± 0.07, peak ratio (second peak velocity/PSV) 0.49 ± 0.12, while the mean ONSD was 4.34 ± 0.4 mm. None of these variables had a demonstrable relationship with gestation or mean arterial pressure (MAP), nor did the sheath diameter have a relationship with any of the Doppler variables. CONCLUSIONS: The ocular sonographic variables observed in this population are similar to those reported in other cohorts. No clear relationship could be identified in this cohort between ophthalmic artery Doppler variables and the ONSD, and between each of these variables and gestation or MAP.

Analysis of the Epigenome in Multiplex Pre-eclampsia Families Identifies SORD, DGKI, and ICA1 as Novel Candidate Risk Genes.

Pre-eclampsia is a serious heritable disorder that affects 5-8% of pregnancies worldwide. While classical genetic studies have identified several susceptibility genes they do not fully explain the heritability of pre-eclampsia. An additional contribution to risk can be quantified by examining the epigenome, in particular the methylome, which is a representation of interactions between environmental and genetic influences on the phenotype. Current array-based epigenetic studies only examine 2-5% of the methylome. Here, we used whole-genome bisulfite sequencing (WGBS) to determine the entire methylome of 13 individuals from two multiplex pre-eclampsia families, comprising one woman with eclampsia, six women with pre-eclampsia, four women with uncomplicated normotensive pregnancies and two male relatives. The analysis of WGBS profiles using two bioinformatics platforms, BSmooth and Bismark, revealed 18,909 differentially methylated CpGs and 4157 differentially methylated regions (DMRs) concordant in females. The methylation patterns support the involvement of previously reported candidate genes, including COL4A1, SLC2A4, PER3, FLT1, GPI, LCT, DDAH1, TGFB3, DLX5, and LRP1B. Statistical analysis of DMRs revealed three novel genes significantly correlated with pre-eclampsia: sorbitol dehydrogenase (SORD, p = 9.98 × 10-6), diacylglycerol kinase iota (DGKI, p = 2.52 × 10-5), and islet cell autoantigen 1 (ICA1, 7.54 × 10-3), demonstrating the potential of WGBS in families for elucidating the role of epigenome in pre-eclampsia and other complex diseases.

Whole-exome sequencing in multiplex preeclampsia families identifies novel candidate susceptibility genes.

OBJECTIVE: Preeclampsia is a common and serious heritable disorder of human pregnancy. Although there have been notable successes in identification of maternal susceptibility genes a large proportion of the heritability of preeclampsia remains unaccounted for. It is has been postulated that rare variation may account for some of this missing heritability. In this study, we performed whole-exome sequencing (WES) in multiplex families to identify rare exonic risk variants. METHODS: We conducted WES in 244 individuals from 34 Australian/New Zealand multiplex preeclampsia families. Variants were tested for association with preeclampsia using a threshold model and logistic regression. RESULTS: We found significant association for two moderately rare missense variants, rs145743393 (Padj = 0.0032, minor allele frequency = 0.016) in the chromosome 1 open reading frame 35 (C1orf35) gene, and rs34270076 (Padj = 0.0128, minor allele frequency = 0.024) in the pyroglutamylated RFamide peptide receptor (QRFPR) gene. To replicate these associations we performed imputation in our Australian genome wide association scan for preeclampsia and found no significant exonic variants in either C1orf35 or QRFPR. However, 11 variants demonstrating nominal significance (P < 0.05) in the genomic region between QRFPR and annexin A5 (ANXA5) were identified. We further leveraged publicly available genome-wide available summary data from the UK Biobank to investigate association of these two variants with the underlying clinical phenotypes of preeclampsia and detected nominal association of the QRFPR variant (rs34270076, P = 0.03) with protein levels in females. CONCLUSION: The study represents the first to use WES in multiplex families for preeclampsia and identifies two novel genes (QRFPR and C1orf35) not previously associated with preeclampsia and find nominal association of rs34270076 with protein levels, a key clinical feature of preeclampsia. We find further support for ANXA5 previously associated with pregnancy complications, including preeclampsia.

Implications of the introduction of new criteria for the diagnosis of gestational diabetes: a health outcome and cost of care analysis.

OBJECTIVE: To identify effects on health outcomes from implementing new criteria diagnosing gestational diabetes mellitus(GDM) and to analyse costs-of-care associated with this change. DESIGN: Quasi-experimental study comparing data from the calendar year before (2014) and after (2016) the change. SETTING: Single, tertiary-level, university-affiliated, maternity hospital. PARTICIPANTS: All women giving birth in the hospital, excluding those with pre-existing diabetes or multiple pregnancy. MAIN OUTCOME MEASURES: Primary outcomes were caesarean section, birth weight >90th percentile for gestation, hypertensive disorder of pregnancy and preterm birth less than 37 weeks. A number of secondary outcomes reported to be associated with GDM were also analysed.Care packages were derived for those without GDM, diet-controlled GDM and GDM requiring insulin. The institutional Business Reporting Unit data for average occasions of service, pharmacy schedule for the costs of consumables and medications, and Medicare Benefits Schedule ultrasound services were used for costing each package. All costs were estimated in figures from the end of 2016 negating the need to adjust for Consumer Price Index increases. RESULTS: There was an increase in annual incidence of GDM of 74% without overall improvements in primary health outcomes. This incurred a net cost increase of AUD$560 093. Babies of women with GDM had lower rates of neonatal hypoglycaemia and special care nursery admissions after the change, suggesting a milder spectrum of disease. CONCLUSION: New criteria for the diagnosis of GDM have increased the incidence of GDM and the overall cost of GDM care. Without obvious changes in short-term outcomes, validation over other systems of diagnosis may require longer term studies in cohorts using universal screening and treatment under these criteria.

Clinical features and outcomes of pregnancies complicated by pre-ecplampsia necessitating in-utero transfer.

OBJECTIVES: Pre-eclampsia (PE) is associated with significant risks of adverse perinatal outcomes, often necessitating transfer to a higher level of care for specialist perinatal management. In Victoria, Australia, the Paediatric Infant Perinatal Emergency Retrieval (PIPER) coordinates in-utero transfers of high-risk pregnancies. Our objectives were to report the clinical features and outcomes of women referred to PIPER with a primary diagnosis of PE, and subsequently transferred in-utero. STUDY DESIGN: A retrospective audit of consecutive pregnancies referred to PIPER in 2013-2014 with a primary diagnosis of pre-eclampsia, ≥20 weeks' gestation and transferred in-utero. MAIN OUTCOME MEASURES: Severity of disease, gestational age, transfer details and outcome until 7 days post transfer. RESULTS: Over two years, 244 women were referred to PIPER with PE; 199 (82%) were subsequently transferred in-utero. Severe PE was diagnosed in 146 (73%) women. Overall, 64% presented 'early' (<32 weeks' gestation). Only 6% were ≥37 weeks. All but 2 women <32 weeks were transferred to a tertiary perinatal centre, compared with 39% of women ≥32 weeks. Within 7 days, 153/199 (77%) delivered, 10% remained in-patients and 12.5% were discharged. There were 165 livebirths and 3 stillbirths, with a mean gestational age of 30.7 weeks (SD 3.3 weeks). Twenty-nine women required high dependency or intensive care admission. No maternal deaths were reported. CONCLUSION: Women referred to PIPER predominantly presented with early onset, severe PE and most delivered within 7 days of transfer. Data from this study provides important information for obstetric service planning in Victoria and comparable regions.

Low-dose aspirin treatment enhances the adhesion of preeclamptic decidual mesenchymal stem/stromal cells and reduces their production of pro-inflammatory cytokines.

Preeclampsia (PE) is a hypertensive disorder of human pregnancy. Low-dose aspirin (acetylsalicylic acid) (60-150 mg/day) is used to prevent PE when taken early in pregnancy. The effect of aspirin on term PE remains uncertain. Abnormal placentation is a hallmark of PE and leads to increased placental oxidative stress, which triggers the release of anti-angiogenic factors that cause local damage to the decidual vasculature. The damage subsequently spreads systemically and culminates in maternal clinical symptoms. Decidua basalis mesenchymal stem/stromal cells (DMSCs) reside in a vascular microenvironment. In PE, DMSCs are exposed to abnormally high levels of oxidative stress and circulating inflammatory factors from the maternal blood. We previously showed that colony-forming unit ability and resistance to oxidative stress in DMSCs are reduced in MSCs derived from term PE pregnancies (PE-DMSCs). The action, if any, of aspirin on term PE-DMSCs has not been reported. In this study, aspirin (5 µg/mL) was found to significantly increase PE-DMSC adhesion compared to untreated PE-DMSCs and gestation-matched control DMSCs (p value < 0.001) but had no effect on PE-DMSC proliferation. ELISA analysis showed that aspirin significantly decreased the production of inflammatory cytokines IFN-γ (p value < 0.05) and IL-8 (p value < 0.001) in PE-DMSCs. In addition, aspirin treatment increased the antioxidant capacity of PE-DMSCs compared with the untreated group (p value < 0.05). This study is the first to reveal a novel, beneficial action of aspirin on PE-DMSCs from term PE pregnancies by improving their adhesion, suppressing their production of pro-inflammatory cytokines production, and increasing their antioxidant capacity. KEY MESSAGES: Preeclampsia (PE) is a serious hypertensive disorder of pregnancy. The risk of PE is reduced by aspirin but the mechanism is poorly understood. Decidua basalis mesenchymal stem/stromal cells (DMSCs) are abnormal in PE. Aspirin treatment improves multiple functions of PE-DMSCs. Improved DMSC function may contribute to the beneficial effect of aspirin.

Assessing the sensitivity of placental growth factor and soluble fms-like tyrosine kinase 1 at 36 weeks' gestation to predict small-for-gestational-age infants or late-onset preeclampsia: a prospective nested case-control study.

BACKGROUND: Fetal growth restriction is a disorder of placental dysfunction with three to four-fold increased risk of stillbirth. Fetal growth restriction has pathophysiological features in common with preeclampsia. We hypothesised that angiogenesis-related factors in maternal plasma, known to predict preeclampsia, may also detect fetal growth restriction at 36 weeks' gestation. We therefore set out to determine the diagnostic performance of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and the sFlt-1:PlGF ratio, measured at 36 weeks' gestation, in identifying women who subsequently give birth to small-for-gestational-age (SGA; birthweight <10th centile) infants. We also aimed to validate the predictive performance of the analytes for late-onset preeclampsia in a large independent, prospective cohort. METHODS: A nested 1:2 case-control study was performed including 102 cases of SGA infants and a matched group of 207 controls; and 39 cases of preeclampsia. We determined the diagnostic performance of each angiogenesis-related factor, and of their ratio, to detect SGA infants or preeclampsia, for a predetermined 10% false positive rate. RESULTS: Median plasma levels of PlGF at 36 weeks' gestation were significantly lower in women who subsequently had SGA newborns (178.5 pg/ml) compared to normal birthweight controls (326.7 pg/ml, p < 0.0001). sFlt-1 was also higher among SGA cases, but this was not significant after women with concurrent preeclampsia were excluded. The sensitivity of PlGF to predict SGA infants was 28.8% for a 10% false positive rate. The sFlt-1:PlGF ratio demonstrated better sensitivity for preeclampsia than either analyte alone, detecting 69.2% of cases for a 10% false positive rate. CONCLUSIONS: Plasma PlGF at 36 weeks' gestation is significantly lower in women who subsequently deliver a SGA infant. While the sensitivity and specificity of PlGF currently limit clinical translation, our findings support a blood-based biomarker approach to detect late-onset fetal growth restriction. Thirty-six week sFlt-1:PlGF ratio predicts 69.2% of preeclampsia cases, and could be a useful screening test to triage antenatal surveillance.

Transferable Matrixes Produced from Decellularized Extracellular Matrix Promote Proliferation and Osteogenic Differentiation of Mesenchymal Stem Cells and Facilitate Scale-Up.

Decellularized extracellular matrixes (dECM) derived from mesenchymal stem cell (MSC) cultures have recently emerged as cell culture substrates that improve the proliferation, differentiation, and maintenance of MSC phenotype during ex vivo expansion. These biomaterials have considerable potential in the fields of stem cell biology, tissue engineering, and regenerative medicine. Processing the dECMs into concentrated solutions of biomolecules that enable the useful properties of the native dECM to be transferred to a new surface via a simple adsorption step would greatly increase the usefulness and impact of this technology. The development of such solutions, hereafter referred to as transferable matrixes, is the focus of this article. In this work, we produced transferable matrixes from dECM derived from two human placental MSC cell lines (DMSC23 and CMSC29) using pepsin digestion (P-ECM), urea extraction (U-ECM), and mechanical homogenization in acetic acid (AA-ECM). Native dECMs improved primary DMSC proliferation as well as osteogenic and adipogenic differentiation, compared with traditional expansion procedures. Interestingly, tissue culture plastic coated with P-ECM was able to replicate the proliferative effects of native dECM, while U-ECM was able to replicate osteogenic differentiation. These data illustrate the feasibility of producing dECM-derived transferable matrixes that replicate key features of the native matrixes and show that different processing techniques produce transferable matrixes with varying bioactivities. Additionally, these transferable matrixes are able to coat 1.3-5.2 times the surface area covered by the native dECM, facilitating scale-up of this technology.