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Background: Physiological adaptations during pregnancy alter nutrient and energy metabolism. Creatine may be important for maintaining cellular energy homeostasis throughout pregnancy. However, the impact of pregnancy on endogenous and exogenous creatine availability has never been comprehensively explored., Objectives: To undertake a prospective cohort study and determine the physiological ranges of creatine and associated metabolites throughout human pregnancy., Methods: Females with a singleton low-risk pregnancy were recruited at an Australian health service. Maternal blood and urine were collected at 5-time points from 10-36 weeks of gestation, and cord blood and placental samples were collected at birth. Creatine and associated amino acids and metabolites of creatine synthesis were analyzed. Dietary data were captured to determine effects of exogenous creatine intake. Associations between creatine metabolism and neonatal growth parameters were examined., Results: Two hundred and eighty-two females were included. Maternal plasma creatine remained stable throughout pregnancy [β: -0.003 μM; 95% confidence interval (CI): -0.07, 0.07; P = 0.94], though urinary creatine declined in late gestation (β: 0.38 μM/mmol/L creatinine (CRN); 95% CI: -0.47, -0.29; P < 0.0001). Plasma guanidinoacetate (GAA; the precursor to creatine during endogenous synthesis) fell from 10-29 weeks of gestation before rising until birth (β: -0.38 μM/mmol/L CRN; 95% CI: -0.47, -0.29; P < 0.0001). Urinary GAA followed an opposing pattern (β: 2.52 μM/mmol/L CRN; 95% CI: 1.47, 3.58, P < 0.001). Animal protein intake was positively correlated with maternal plasma creatine until ∼32 weeks of gestation (β: 0.07-0.18 μM; 95% CI: 0.006, 0.25; P ≤ 0.001). There were no links between creatine and neonatal growth, but increased urinary GAA in early pregnancy was associated with a slight reduction in head circumference at birth (β: -0.01 cm; 95% CI: -0.02, -0.004; P = 0.003)., Conclusions: Although maternal plasma creatine concentrations were highly conserved, creatine metabolism appears to adjust throughout pregnancy. An ability to maintain creatine concentrations through diet and shifts in endogenous synthesis may impact fetal growth. This trial was registered at [registry name] as ACTRN12618001558213., (Copyright © 2023 American Society for Nutrition. All rights reserved.)

Excess inflammation and oxidative stress are common themes in many pathologies of pregnancy including preeclampsia and more recently severe COVID-19. The risk of preeclampsia increases following maternal infection with COVID-19, potentially relating to significant overlap in pathophysiology with endothelial, vascular and immunological dysfunction common to both. Identifying a therapy which addresses these injurious processes and stabilises the endothelial and vascular maternal system would help address the significant global burden of maternal and neonatal morbidity and mortality they cause. Sulforaphane is a naturally occurring phytonutrient found most densely within cruciferous vegetables. It has anti-inflammatory, antioxidant and immune modulating properties via upregulation of phase-II detoxification enzymes. This review will cover the common pathways shared by COVID-19 and preeclampsia and offer a potential therapeutic target via nuclear factor erythroid 2-related factor upregulation in the form of sulforaphane., Competing Interests: Declaration of competing interest All authors disclose no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: COVID-19 infection in pregnancy is associated with a higher risk of progression to severe disease, but vaccine uptake by pregnant women is hindered by persistent safety concerns. COVID-19 vaccination in pregnancy has been shown to reduce stillbirth, but its relationship with preterm birth is uncertain., Objective: This study aimed to measure the rate of COVID-19 vaccine uptake among women giving birth in Melbourne, Australia, and to compare perinatal outcomes by vaccination status., Study Design: This was a retrospective multicenter cohort study conducted after the June 2021 government recommendations for messenger RNA COVID-19 vaccination during pregnancy. Routinely collected data from all 12 public maternity hospitals in Melbourne were extracted on births at ≥20 weeks' gestation from July 1, 2021 to March 31, 2022. Maternal sociodemographic characteristics were analyzed from the total birth cohort. Perinatal outcomes were compared between vaccinated and unvaccinated women for whom weeks 20 to 43 of gestation fell entirely within the 9-month data collection period. The primary outcomes were the rates of stillbirth and preterm birth (spontaneous and iatrogenic) in singleton pregnancies of at least 24 weeks' gestation, after exclusion of congenital anomalies. Secondary perinatal outcomes included the rate of congenital anomalies among infants born at ≥20 weeks' gestation and birthweight ≤third centile and newborn intensive care unit admissions among infants born without congenital anomalies at ≥24 weeks' gestation. We calculated the adjusted odds ratio of perinatal outcomes among vaccinated vs unvaccinated women using inverse propensity score-weighting regression adjustment with multiple covariates; P<.05 was considered statistically significant., Results: Births from 32,536 women were analyzed: 17,365 (53.4%) were vaccinated and 15,171 (47.6%) were unvaccinated. Vaccinated women were more likely to be older, nulliparous, nonsmoking, not requiring an interpreter, of higher socioeconomic status, and vaccinated against pertussis and influenza. Vaccination status also varied by region of birth. Vaccinated women had a significantly lower rate of stillbirth compared with unvaccinated women (0.2% vs 0.8%; adjusted odds ratio, 0.18; 95% confidence interval, 0.09-0.37; P<.001). Vaccination was associated with a significant reduction in total preterm births at <37 weeks (5.1% vs 9.2%; adjusted odds ratio, 0.60; 95% confidence interval, 0.51-0.71; P<.001), spontaneous preterm birth (2.4% vs 4.0%; adjusted odds ratio, 0.73; 95% confidence interval, 0.56-0.96; P=.02), and iatrogenic preterm birth (2.7% vs 5.2%; adjusted odds ratio, 0.52; 95% confidence interval, 0.41-0.65; P<.001). Infants born to vaccinated mothers also had lower rates of admission to the neonatal intensive care unit. There was no significant increase in the rate of congenital anomalies or birthweight ≤3rd centile in vaccinated women. Vaccinated women were significantly less likely to have an infant with a major congenital anomaly compared with the unvaccinated group (2.4% vs 3.0%; adjusted odds ratio, 0.72; 95% confidence interval, 0.56-0.94; P=.02). This finding remained significant even when the analysis was restricted to women vaccinated before 20 weeks' gestation., Conclusion: COVID-19 vaccination during pregnancy was associated with a reduction in stillbirth and preterm birth, and not associated with any adverse impact on fetal growth or development. Vaccine coverage was substantially influenced by known social determinants of health., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Activin A is a two-subunit protein belonging to the transforming growth factor β superfamily. First discovered almost three decades ago, it has since been implicated in diverse physiological roles, ranging from wound repair to reproduction. After 30 years of research, altered activin A levels are now understood to be associated with the development of various diseases, making activin A a potential therapeutic target. In pregnancy, the placenta and fetal membranes are major producers of activin A, with significantly enhanced serum concentrations now recognised as a contributor to numerous gestational disorders. Evidence now suggests that circulating levels of activin A may be clinically relevant in the early detection of pregnancy complications, including miscarriage and preeclampsia. This review aims to summarise our current understanding of activin A as a potential diagnostic marker in common pregnancy pathologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Induction of labour is one of the most common obstetric interventions globally. Balloon catheters and vaginal prostaglandins are widely used to ripen the cervix in labour induction. We aimed to compare the effectiveness and safety profiles of these two induction methods., Methods: We did an individual participant data meta-analysis comparing balloon catheters and vaginal prostaglandins for cervical ripening before labour induction. We systematically identified published and unpublished randomised controlled trials that completed data collection between March 19, 2019, and May 1, 2021, by searching the Cochrane Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and PubMed. Further trials done before March 19, 2019, were identified through a recent Cochrane review. Data relating to the combined use of the two methods were not included, only data from women with a viable, singleton pregnancy were analysed, and no exclusion was made based on parity or membrane status. We contacted authors of individuals trials and participant-level data were harmonised and recoded according to predefined definitions of variables. Risk of bias was assessed with the ROB2 tool. The primary outcomes were caesarean delivery, indication for caesarean delivery, a composite adverse perinatal outcome, and a composite adverse maternal outcome. We followed the intention-to-treat principle for the main analysis. The primary meta-analysis used two-stage random-effects models and the sensitivity analysis used one-stage mixed models. All models were adjusted for maternal age and parity. This meta-analysis is registered with PROSPERO (CRD42020179924)., Findings: Individual participant data were available from 12 studies with a total of 5460 participants. Balloon catheters, compared with vaginal prostaglandins, did not lead to a significantly different rate of caesarean delivery (12 trials, 5414 women; crude incidence 27·0%; adjusted OR [aOR] 1·09, 95% CI 0·95-1·24; I 2 =0%), caesarean delivery for failure to progress (11 trials, 4601 women; aOR 1·20, 95% CI 0·91-1·58; I 2 =39%), or caesarean delivery for fetal distress (10 trials, 4441 women; aOR 0·86, 95% CI 0·71-1·04; I 2 =0%). The composite adverse perinatal outcome was lower in women who were allocated to balloon catheters than in those allocated to vaginal prostaglandins (ten trials, 4452 neonates, crude incidence 13·6%; aOR 0·80, 95% CI 0·70-0·92; I 2 =0%). There was no significant difference in the composite adverse maternal outcome (ten trials, 4326 women, crude incidence 22·7%; aOR 1·02, 95% CI 0·89-1·18; I 2 =0%)., Interpretation: In induction of labour, balloon catheters and vaginal prostaglandins have comparable caesarean delivery rates and maternal safety profiles, but balloon catheters lead to fewer adverse perinatal events., Funding: Australian National Health and Medical Research Council and Monash Health Emerging Researcher Fellowship., Competing Interests: Declaration of interests BWM has received grants from the Australian National Health and Medical Research Council (NHMRC), personal fees from ObsEva, personal fees from Merck, personal fees from Guerbet, and grants from Merck, outside the submitted work. BWM was also an investigator for one of the trials included in the individual participant data meta-analysis. DLR has received fees to participate in advisory boards from Alexion and travel support and lecture fees from the International Society of Ultrasound in Obstetrics and Gynecology, unrelated to this work. KRP has received research grant funds from GlaxoSmithKline and consultancy fees from Janssen Pharmaceuticals unrelated to this work. WL has received research grant funds from the Norman Beischer Medical Research Foundation, unrelated to this work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The COVID-19 pandemic has been associated with a worsening of perinatal outcomes in many regions around the world. Melbourne, Australia, had one of the longest and most stringent lockdowns worldwide in 2020 while recording only rare instances of COVID-19 infection in pregnant women., Objective: This study aimed to compare the stillbirth and preterm birth rates in women who were exposed or unexposed to lockdown restrictions during pregnancy., Study Design: This was a retrospective, multicenter cohort study of perinatal outcomes in Melbourne before and during the COVID-19 lockdown. The lockdown period was defined as the period from March 23, 2020 to March 14, 2021. Routinely-collected maternity data on singleton pregnancies ≥24 weeks gestation without congenital anomalies were obtained from all the 12 public hospitals in Melbourne. We defined the lockdown-exposed cohort as those women for whom weeks 20 to 40 of gestation occurred during the lockdown and the unexposed control group as women from the corresponding calendar periods 12 and 24 months before. The main outcome measures were stillbirth, preterm birth, fetal growth restriction (birthweight < third centile), and iatrogenic preterm birth for fetal compromise. We performed multivariable logistic regression analysis to compare the odds of stillbirth, preterm birth, fetal growth restriction, and iatrogenic preterm birth for fetal compromise, adjusting for multiple covariates., Results: There were 24,817 births in the exposed group and 50,017 births in the control group. There was a significantly higher risk of preterm stillbirth in the exposed group than the control group (0.26% vs 0.18%; adjusted odds ratio, 1.49; 95% confidence interval, 1.08-2.05; P=.015). There was also a significant reduction in the preterm birth of live infants <37 weeks (5.68% vs 6.07%; adjusted odds ratio, 0.93; 95% confidence interval, 0.87-0.99; P=.02), which was largely mediated by a significant reduction in iatrogenic preterm birth (3.01% vs 3.27%; adjusted odds ratio, 0.91; 95% confidence interval, 0.83-0.99; P=.03), including iatrogenic preterm birth for fetal compromise (1.25% vs 1.51%; adjusted odds ratio, 0.82; 95% confidence interval, 0.71-0.93; P=.003). There were also significant reductions in special care nursery admissions during lockdown (11.53% vs 12.51%; adjusted odds ratio, 0.90; 95% confidence interval, 0.86-0.95; P<.0001). There was a trend to fewer spontaneous preterm births <37 weeks in the exposed group of a similar magnitude to that reported in other countries (2.69% vs 2.82%; adjusted odds ratio, 0.95; 95% confidence interval, 0.87-1.05; P=.32)., Conclusion: Lockdown restrictions in Melbourne, Australia were associated with a significant reduction in iatrogenic preterm birth for fetal compromise and a significant increase in preterm stillbirths. This raises concerns that pandemic conditions in 2020 may have led to a failure to identify and appropriately care for pregnant women at an increased risk of antepartum stillbirth. Further research is required to understand the relationship between these 2 findings and to inform our ongoing responses to the pandemic., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Research indicates that soluble fms-like tyrosine kinase 1 (sFLT-1) and placental growth factor (PLGF) have diagnostic and prognostic significance for women with preeclampsia. However, sparse research has studied these biomarkers in women with preexisting comorbidities such as chronic hypertension, diabetes mellitus, systemic lupus erythematosus and chronic kidney disease. We undertook a prospective longitudinal cohort study to compare the sFLT-1: PlGF ratio between women with and without comorbidities who did and did not go on to develop preeclampsia. We found that women with comorbidities may develop preeclampsia with a milder elevation in sFLT-1: PlGF than do women without comorbidities. This has clinical and research implications., (Copyright © 2022 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Introduction: Soluble fms-like tyrosine kinase 1 (sFLT-1), a circulating anti-angiogenic factor that binds and antagonizes placental growth factor (PlGF), appears key to preeclamptic pathophysiology. Two main sFLT-1 splice variants exist: sFLT-1 e15a and sFLT-1 i13. Total sFLT-1/PlGF ratios are increasingly used clinically; we explore whether using placental-specific sFLT-1 e15a improves test performance compared with total sFLT-1 in preeclampsia diagnosis., Methods: Consent was obtained for serum sampling from 96 women with suspected preeclampsia. Total sFLT-1 and PlGF were quantified using the B.R.A.H.M.S Kryptor Compact Plus automated immunoassay platform, and sFLT-1 e15a by custom enzyme-linked immunosorbent assay. Test performance was then assessed by subsequent diagnosis., Results: Of 96 participants, 32 did not develop preeclampsia, 32 had early-onset (<34 weeks') disease and 32 had late-onset (≥34 weeks') disease. In those with preeclampsia, median sFLT-1 and sFLT-1 e15a were significantly increased (7361.0 vs 2463.0 pg/mL, and 946.6 vs 305.4 ng/mL respectively; p < 0.001 for both), and PlGF significantly reduced (43.5 vs 154.4 pg/mL; p < 0.001) compared to those without preeclampsia. Those with early-onset, compared to late-onset, preeclampsia chiefly had lower median PlGF levels (16.0 vs 57.3; p < 0.001), which contributed to higher sFLT-1/PlGF and sFLT-1 e15a/PlGF ratios (830.1 vs 86.7, and 109258.9 vs 12608.7 respectively; p < 0.001 for both)., Discussion: sFLT-1 e15a performs comparably to total sFLT-1 in women with suspected preeclampsia, however with higher translational burden. Our results support the expanding clinical use of the sFLT-1/PlGF ratio in suspected preeclampsia, particularly early-onset, to assist with disease diagnosis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate how medical comorbidities - chronic hypertension, pre-gestational or gestational diabetes and obesity - influence maternal and neonatal complications from preeclampsia., Study Design: We undertook a retrospective cohort study of women delivering in Victoria, Australia, between 2009 and 2017. We compared the likelihood of having a maternal complication before delivery or neonatal complication after birth between women with and without comorbidities. We used causal mediation analysis for neonatal outcomes to separate the effects of comorbidities and of prematurity on morbidity., Main Outcome Measures: Pregnancy complications (eclampsia; haemolysis, elevated liver enzymes, low platelets syndrome; placental abruption; stillbirth) and neonatal complications (respiratory distress syndrome; neonatal sepsis; a 5-minute APGAR < 5; neonatal intensive care unit admission)., Results: Women with comorbidities delivered at a median (interquartile range) of 37.0 (36.0-39.0) weeks gestation, earlier than women without comorbidities (38.0 (36.0-39.0) weeks, p < 0.001). Women with comorbidities were less likely than those without to suffer any pregnancy complication prior to delivery (adjusted relative risk 0.78, 95% confidence interval 0.72-0.86); however, their neonates suffered more respiratory distress syndrome (aRR 1.43, 95% CI 1.31-1.57), neonatal sepsis (aRR 1.42, 95% CI 1.17-1.72) and NICU admission (aRR 1.37, 95% CI 1.23-1.53). Earlier delivery was a major contributor to worse neonatal outcomes., Conclusions: Medical comorbidities are associated with earlier delivery among women with preeclampsia. This is associated with fewer maternal complications, but worse neonatal outcomes., (Copyright © 2021 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: Universal screening has been proposed as a strategy to identify asymptomatic individuals infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mitigate transmission., Aim: To investigate the rate of positive tests among pregnant women in Melbourne, Australia., Methods: We performed a cross-sectional prevalence study at three maternity hospitals (one tertiary referral hospital and two secondary maternities) in Melbourne, Australia. SARS-CoV-2 testing was offered to all pregnant women attending face-to-face antenatal visits and to those attending the hospital with symptoms of possible coronavirus disease, between 6th and 19th of May 2020. Testing was performed by multiplex-tandem polymerase chain reaction (PCR) on combined oropharyngeal and nasopharyngeal swabs. The primary outcome was the proportion of positive SARS-CoV-2 tests., Findings: SARS-CoV-2 testing was performed in 350 women, of whom 19 had symptoms of possible COVID-19. The median maternal age was 32 years (IQR 28-35 years), and the median gestational age at testing was 33 weeks and four days (IQR 28 weeks to 36 weeks and two days). All 350 tests returned negative results (p̂=0%, 95% CI 0-1.0%)., Conclusion: In a two-week period of low disease prevalence, the rate of asymptomatic coronavirus infection among pregnant women in Australia during the study period was negligible, reflecting low levels of community transmission., (Copyright © 2020 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.)

Background: Little evidence is available on the use of telehealth for antenatal care. In response to the COVID-19 pandemic, we developed and implemented a new antenatal care schedule integrating telehealth across all models of pregnancy care. To inform this clinical initiative, we aimed to assess the effectiveness and safety of telehealth in antenatal care., Methods: We analysed routinely collected health data on all women giving birth at Monash Health, a large health service in Victoria (Australia), using an interrupted time-series design. We assessed the impact of telehealth integration into antenatal care from March 23, 2020, across low-risk and high-risk care models. Allowing a 1-month implementation period from March 23, 2020, we compared the first 3 months of telehealth integrated care delivered between April 20 and July 26, 2020, with conventional care delivered between Jan 1, 2018, and March 22, 2020. The primary outcomes were detection and outcomes of fetal growth restriction, pre-eclampsia, and gestational diabetes. Secondary outcomes were stillbirth, neonatal intensive care unit admission, and preterm birth (birth before 37 weeks' gestation)., Findings: Between Jan 1, 2018, and March 22, 2020, 20 031 women gave birth at Monash Health during the conventional care period and 2292 women gave birth during the telehealth integrated care period. Of 20 154 antenatal consultations provided in the integrated care period, 10 731 (53%) were delivered via telehealth. Overall, compared with the conventional care period, no significant differences were identified in the integrated care period with regard to the number of babies with fetal growth restriction (birthweight below the 3rd percentile; 2% in the integrated care period vs 2% in the conventional care period, p=0·72, for low-risk care models; 5% in the integrated care period vs 5% in the conventional care period, p=0·50 for high-risk care models), number of stillbirths (1% vs 1%, p=0·79; 2% vs 2%, p=0·70), or pregnancies complicated by pre-eclampsia (3% vs 3%, p=0·70; 9% vs 7%, p=0·15), or gestational diabetes (22% vs 22%, p=0·89; 30% vs 26%, p=0·06). Interrupted time-series analysis showed a significant reduction in preterm birth among women in high-risk models (-0·68% change in incidence per week [95% CI -1·37 to -0·002]; p=0·049), but no significant differences were identified in other outcome measures for low-risk or high-risk care models after telehealth integration compared with conventional care., Interpretation: Telehealth integrated antenatal care enabled the reduction of in-person consultations by 50% without compromising pregnancy outcomes. This care model can help to minimise in-person interactions during the COVID-19 pandemic, but should also be considered in post-pandemic health-care models., Funding: None., Competing Interests: Declaration of interests BWM is a consultant for Guerbet, and has received research grants from Guerbet and Merck. KRP has received consultancy fees from Janssen. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The diagnostic criteria for preeclampsia have evolved from the traditional definition of de novo hypertension and proteinuria to a broader definition of hypertension with evidence of end-organ dysfunction. Although this change is endorsed by various societies such as the International Society for the Study of Hypertension in Pregnancy and the American College of Obstetricians and Gynecologists, there remains controversy with regard to the implementation of broader definitions and the most appropriate definition of end-organ dysfunction., Objective: This study aimed to assess the impact of different diagnostic criteria for preeclampsia on rates of disease diagnosis, disease severity, and adverse outcomes and to identify associations between each component of the different diagnostic criteria and adverse pregnancy outcomes., Study Design: We performed a retrospective cohort study of singleton pregnancies at Monash Health between January 1, 2016 and July 31, 2018. Within this population, all cases of gestational hypertension and preeclampsia were reclassified according to the International Society for the Study of Hypertension in Pregnancy 2001, American College of Obstetricians and Gynecologists 2018, and International Society for the Study of Hypertension in Pregnancy 2018 criteria. Differences in incidence of preeclampsia and maternal and perinatal outcomes were compared between the International Society for the Study of Hypertension in Pregnancy 2001 group and the extra cases identified by American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018. Outcomes assessed included biochemical markers of preeclampsia, a composite of adverse maternal outcomes, and a composite of adverse perinatal outcomes. Multiple logistic regression analysis was also performed to assess each component of the American College of Obstetricians and Gynecologists 2018 and International Society for the Study of Hypertension in Pregnancy 2018 criteria and their associations with adverse maternal and perinatal outcomes., Results: Of 22,094 pregnancies, 751 (3.4%) women had preeclampsia as defined by any of the 3 criteria. Compared with International Society for the Study of Hypertension in Pregnancy 2001, the American College of Obstetricians and Gynecologists 2018 criteria identified an extra 42 women (n=654 vs n=696, 6.4% relative increase) with preeclampsia, and International Society for the Study of Hypertension in Pregnancy 2018 identified an extra 97 women (n=654 vs n=751, 14.8% relative increase). The additional women identified by International Society for the Study of Hypertension in Pregnancy 2018 exhibited a milder form of disease with lower rates of severe hypertension (62.4% vs 44.3%; P<.01) and magnesium sulfate use (11.9% vs 4.1%; P<.05) and a trend toward lower rates of adverse maternal outcomes (9.8% vs 4.1%). These women also delivered at a later gestation, and their babies had a lower number of neonatal intensive care unit admissions and adverse perinatal outcomes. Objective features such as fetal growth restriction, thrombocytopenia, renal and liver impairment, and proteinuria were associated with an increased risk of adverse maternal and perinatal outcomes, whereas subjective neurologic features demonstrated poorer associations., Conclusion: Implementation of broader definitions of preeclampsia will result in an increased incidence of disease diagnosis. However, because women who exclusively fulfill the new criteria have a milder phenotype of the disease, it remains uncertain whether this will translate to improved outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Placental mitochondrial dysfunction contributes to the oxidative stress that underlies preeclampsia. Here, we assessed whether sulforaphane (SFN) could improve syncytiotrophoblast mitochondrial function after in vitro hypoxic and superoxide injury., Methods: Placental cytotrophoblasts were isolated from healthy term placentae (n = 12) and incubated for 48 h in 8% O 2  ± 1 μM SFN before acute (4hrs) or chronic (24hrs) hypoxic (1% O 2 ), or superoxide (xanthine/xanthine oxidase) injury. Cytotrophoblasts were also isolated from preeclamptic placentae (n = 5) and cultured in 8% O 2  ± 1 μM SFN. Mitochondrial respiration was measured using the Seahorse MitoStress XF assay. Cells were stained with mitotracker red to assess mitochondrial membrane health and mitochondrial gene expression assessed using RT-qPCR., Results: SFN prevented significant reductions in syncytiotrophoblast mitochondrial maximal respiration, spare respiratory capacity, basal respiration and ATP production following acute hypoxia. Chronic hypoxia only reduced maximal and spare respiratory capacity. SFN prevented these negative changes and increased respiration overall. Alternatively, acute superoxide injury significantly increased mitochondrial maximal respiration and spare respiratory capacity. SFN treatment further increased basal respiration following superoxide injury and prevented significant decreases in ATP production and coupling efficiency. In preeclamptic placentae, SFN significantly increased mitochondrial maximal respiration, spare respiratory capacity, basal respiration and ATP production, and decreased proton leak. SFN up-regulated mRNA expression of mitochondrial complexes and corrected an up-regulation in fission gene expression observed after hypoxic-superoxide injury. Finally, preliminary results suggest SFN prevented hypoxia-induced impairment of mitochondrial membrane structure., Discussion: SFN mitigated hypoxia and superoxide induced changes to syncytiotrophoblast mitochondrial function in vitro, and improved mitochondrial respiration in trophoblast cells from preeclamptic placentae., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Placental growth factor (PlGF), total soluble fms-like tyrosine-kinase 1 (sFlt-1) and its placental-specific variant, sFlt-1 e15a, show promise as biomarkers for the prediction and diagnosis of preeclampsia. This study describes the degradation of PlGF, sFlt-1 and sFlt-1 e15a within maternal serum and plasma to assist clinical implementation. Whole blood was refrigerated at 4 °C for up to 48 h prior to centrifugation for isolation of plasma and serum. PlGF and sFlt-1 were quantified using the B.R.A.H.M.S Kryptor Compact PLUS; sFlt-1 e15a via a custom ELISA. All three analytes are stable for at least 48 h at 4 °C. Serum and plasma performed comparably., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Preeclampsia is a serious complication affecting 5-8% of pregnancies. Central to its pathogenesis is placental hypoxia and inflammation which leads to secretion of soluble fms-like tyrosine kinase 1 (sFlt-1). sFlt-1 causes widespread endothelial dysfunction. The molecular mechanisms regulating sFlt-1 production remain poorly understood. Recently, a binding site for the nuclear factor activated T cells (NFAT) transcription factor has been found on fms-like tyrosine kinase 1 (FLT-1) promoter., Methods: We assessed whether inhibiting NFAT impacts FLT-1, sFlt-1 and cytokine expression, as well as sFlt-1 secretion in primary cytotrophoblasts, placental explants and human umbilical vein endothelial cells (HUVECs). We investigated whether NFAT is regulated by hypoxia in primary cytotrophoblasts. We characterised the expression of NFAT1-4 in preterm preeclamptic compared to gestationally matched placentas., Results: Inhibiting NFAT reduced FLT-1 and sFlt-1 splice variant e15a transcription, concordant with reduced total sFlt-1 and sFlt-1 e15a secretion from primary human cytotrophoblasts. This effect appeared tissue specific as inhibiting NFAT did not change sFlt-1 secretion from endothelial cells. Inhibiting NFAT also reduced transcription of inflammatory cytokines IL-1β and IL-10 in primary cytotrophoblasts. NFAT1 and NFAT3 mRNA expression were significantly increased under hypoxia (1% O 2 ). Inhibiting NFAT under hypoxia significantly reduced FLT-1 and sFlt-1 e15a transcription, but did not reduce sFlt-1 secretion. NFAT mRNA and protein localisation was not different in preeclamptic compared to gestationally matched placenta., Discussion: NFAT positively regulates placental FLT-1 and sFlt-1 e15a, secretion of sFlt-1 and inflammatory cytokine expression. It may be involved in the pathophysiology of preeclampsia., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding., Methods: In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532., Findings: Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=0·04). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0·005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -2·0 [95% CI -12·0 to 7·0]; p=0·50). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=0·23), with fewer RBC units transfused (mean 1·2 [SD 2·1] vs 1·9 [2·8]; difference -0·7 [-1·6 to 0·3]; p=0·12), although these differences were not significant. We noted no significant difference in clinical outcomes., Interpretation: A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding., Funding: NHS Blood and Transplant Research and Development., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Soluble endoglin is an anti-angiogenic protein that is released from the placenta and contributes to both maternal endothelial dysfunction and the clinical features of severe preeclampsia. The mechanism through which soluble endoglin is released from the placenta is currently unknown; however, recent work in colorectal cancer identified matrix metalloproteinase 14 (MMP-14) as the cleavage protease of endoglin. To determine whether this is also the mechanism responsible for soluble endoglin release in preeclampsia, we investigated the expression of MMP-14 within the placenta and the effects of its inhibition on soluble endoglin release. Placentas were obtained from severe, early onset preeclamptic pregnancies (n = 8) and gestationally matched preterm controls (n = 8). MMP-14 was predominately localized to the syncytiotrophoblast. Results from a proximity ligation assay showed protein interactions between endogenous MMP-14 and endoglin within the preeclamptic placenta. To demonstrate that this interaction produces soluble endoglin, we treated trophoblastic BeWo cells with either a broad-spectrum MMP inhibitor (GM6001) or MMP-14 siRNA. Both treatments produced a decrease in soluble endoglin (P ≤ 0.05). Treatment of mice bearing BeWo xenografts with GM6001 decreased circulating soluble endoglin levels in mouse serum (P ≤ 0.05). These findings indicate that MMP-14 is the likely cleavage protease of endoglin in the setting of preeclampsia. This approach provides a novel method for the development of potential therapeutics to reduce circulating soluble endoglin and ameliorate the clinical features of severe preeclampsia., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Two liver biopsies were performed 6 months apart in each of 29 patients with alcoholic liver disease. Hepatic aldehyde dehydrogenase activity was measured on each occasion. The patients were seen regularly and their alcohol consumption was assessed independently. Hepatic aldehyde dehydrogenase activity was unchanged in 17 patients who continued to drink to excess; it rose in 10 patients who significantly reduced their alcohol intake; and it fell dramatically in 2 patients who were virtually abstinent initially, but then began drinking heavily. These results clearly demonstrate that alcohol consumption itself depresses hepatic aldehyde dehydrogenase activity. It is unlikely that the low hepatic aldehyde dehydrogenase activity reported in alcoholics represents a primary abnormality predisposing to alcoholism or alcoholic liver disease.