Neurodevelopmental outcomes at 2 years in children who received sildenafil therapy in utero: The STRIDER randomised controlled trial.

OBJECTIVE: Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes. DESIGN: Superiority, double-blind randomised controlled trial. SETTING: A total of 20 UK fetal medicine units. POPULATION: Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22+0 and 29+6 weeks of gestation. METHODS: Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation. MAIN OUTCOME MEASURES: All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85. RESULTS: In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm). CONCLUSIONS: Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition.

Cytology Techniques Can Provide Insight into Human Placental Structure Including Syncytiotrophoblast Nuclear Spatial Organisation.

The aim of this study was to provide the first systematic description of human placental cytology appearances and to investigate syncytiotrophoblast nuclear organisation patterns using cytology techniques. Term placentas from normal pregnancies were sampled using fine-needle aspiration (FNA) and direct scrapes. Standard histological examination was also performed to exclude pathological changes in the placentas being studied. Both Papanicolaou-stained cytospin preparations and air-dried Giemsa slides from FNA provided high-quality material for cytological assessment with good cellularity. Among the key features of the cytology preparations were villous "microbiopsies" that allowed for the three-dimensional appreciation of villous branching patterns. Cytological appearances, including nuclear characteristics of villous cytotrophoblast and syncytiotrophoblast, were also well demonstrated. In microbiopsies and detached villous trophoblast sheets, complex patterns of syncytiotrophoblast nuclear organisation, not previously described cytologically, were observed, including irregular spacing of nuclei, syncytioplasm windows and linear nuclear arrangements. This study showed that placental cytology (a) provides technically excellent material for cytological evaluation, (b) confirms the presence of complex nuclear organisational patterns in the syncytiotrophoblast by eliminating the possibility of tangential sectioning artefact, (c) provides superior nuclear detail over standard histological sections and (d) may be an untapped research resource for the investigation of normal and pathological processes because of its ability to look at the placenta in a novel way and through its potential for both ex vivo and in vivo placental sampling.

Interventions affecting the nitric oxide pathway versus placebo or no therapy for fetal growth restriction in pregnancy.

BACKGROUND: Fetal growth restriction (FGR) is a condition of poor growth of the fetus in utero. One of the causes of FGR is placental insufficiency. Severe early-onset FGR at < 32 weeks of gestation occurs in an estimated 0.4% of pregnancies. This extreme phenotype is associated with a high risk of fetal death, neonatal mortality, and neonatal morbidity. Currently, there is no causal treatment, and management is focused on indicated preterm birth to prevent fetal death. Interest has risen in interventions that aim to improve placental function by administration of pharmacological agents affecting the nitric oxide pathway causing vasodilatation. OBJECTIVES: The objective of this systematic review and aggregate data meta-analysis is to assess the beneficial and harmful effects of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or different drugs affecting this pathway against each other, in pregnant women with severe early-onset FGR. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 July 2022), and reference lists of retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or another drug affecting this pathway in pregnant women with severe early-onset FGR of placental origin, for inclusion in this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. MAIN RESULTS: We included a total of eight studies (679 women) in this review, all of which contributed to the data and analysis. The identified studies report on five different comparisons: sildenafil compared with placebo or no therapy, tadalafil compared with placebo or no therapy, L-arginine compared with placebo or no therapy, nitroglycerin compared with placebo or no therapy and sildenafil compared with nitroglycerin. The risk of bias of included studies was judged as low or unclear. In two studies the intervention was not blinded. The certainty of evidence for our primary outcomes was judged as moderate for the intervention sildenafil and low for tadalafil and nitroglycerine (due to low number of participants and low number of events). For the intervention L-arginine, our primary outcomes were not reported. Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women) Five studies (Canada, Australia and New Zealand, the Netherlands, the UK and Brazil) involving 516 pregnant women with FGR were included. We assessed the certainty of the evidence as moderate. Compared with placebo or no therapy, sildenafil probably has little or no effect on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.80 to 1.27, 5 studies, 516 women); may reduce fetal mortality (RR 0.82, 95% CI 0.60 to 1.12, 5 studies, 516 women), and increase neonatal mortality (RR 1.45, 95% CI 0.90 to 2.33, 5 studies, 397 women), although the results are uncertain for fetal and neonatal mortality as 95% confidence intervals are wide crossing the line of no effect. Tadalafil compared with placebo or no therapy (1 study, 87 women) One study (Japan) involving 87 pregnant women with FGR was included. We assessed the certainty of the evidence as low. Compared with placebo or no therapy, tadalafil may have little or no effect on all-cause mortality (risk ratio 0.20, 95% CI 0.02 to 1.60, one study, 87 women); fetal mortality (RR 0.11, 95% CI 0.01 to 1.96, one study, 87 women); and neonatal mortality (RR 0.89, 95% CI 0.06 to 13.70, one study, 83 women). L-Arginine compared with placebo or no therapy (1 study, 43 women) One study (France) involving 43 pregnant women with FGR was included. This study did not assess our primary outcomes. Nitroglycerin compared to placebo or no therapy (1 studies, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. Sildenafil citrate compared to nitroglycerin (1 study, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. AUTHORS' CONCLUSIONS: Interventions affecting the nitric oxide pathway probably do not seem to influence all-cause (fetal and neonatal) mortality in pregnant women carrying a baby with FGR, although more evidence is needed. The certainty of this evidence is moderate for sildenafil and low for tadalafil and nitroglycerin. For sildenafil a fair amount of data are available from randomised clinical trials, but with low numbers of participants. Therefore, the certainty of evidence is moderate. For the other interventions investigated in this review there are insufficient data, meaning we do not know whether these interventions improve perinatal and maternal outcomes in pregnant women with FGR.

Relationship between the concentration of ergothioneine in plasma and the likelihood of developing pre-eclampsia.

Ergothioneine, an antioxidant nutraceutical mainly at present derived from the dietary intake of mushrooms, has been suggested as a preventive for pre-eclampsia (PE). We analysed early pregnancy samples from a cohort of 432 first time mothers as part of the Screening for Endpoints in Pregnancy (SCOPE, European branch) project to determine the concentration of ergothioneine in their plasma. There was a weak association between the ergothioneine levels and maternal age but none for BMI. Of these 432 women, 97 went on to develop pre-term (23) or term (74) PE. If a threshold was set at the 90th percentile of the reference range in the control population (≥462 ng/ml), only one of these 97 women (1%) developed PE, versus 96/397 (24.2%) whose ergothioneine level was below this threshold. One possible interpretation of these findings, consistent with previous experiments in a reduced uterine perfusion model in rats, is that ergothioneine may indeed prove protective against PE in humans. An intervention study of some kind now seems warranted.

Cohort profile: Improved Pregnancy Outcomes via Early Detection (IMPROvED), an International Multicentre Prospective Cohort.

Background: Improved Pregnancy Outcomes via Early Detection (IMPROvED) is a multi-centre, European phase IIa clinical study. The primary aim of IMPROvED is to enable the assessment and refinement of innovative prototype preeclampsia risk assessment tests based on emerging biomarker technologies. Here we describe IMPROvED's profile and invite researchers to collaborate. Methods: A total of 4,038 low-risk nulliparous singleton pregnancies were recruited from maternity units in Ireland (N=1,501), United Kingdom (N=1,108), The Netherlands (N=810), and Sweden (N=619) between November 2013 to August 2017. Participants were interviewed by a research midwife at ~11 weeks (optional visit), ~15 weeks, ~20 weeks, ~34 weeks' gestation (optional visit), and postpartum (within 72-hours following delivery). Findings to date: Clinical data included information on maternal sociodemographic, medical history, and lifestyle factors collected at ~15 weeks' gestation, and maternal measurements, collected at each study visit. Biobank samples included blood, urine, and hair collected at each study visit throughout pregnancy in all units plus umbilical cord/blood samples collected at birth in Ireland and Sweden. A total of 74.0% (N=2,922) had an uncomplicated pregnancy, 3.1% (N=122) developed preeclampsia, 3.6% (N=143) had a spontaneous preterm birth, and 10.5% (N=416) had a small for gestational age baby. We evaluated a panel of metabolite biomarkers and a panel of protein biomarkers at 15 weeks and 20 weeks' gestation for preeclampsia risk assessment. Their translation into tests with clinical application, as conducted by commercial entities, was hampered by technical issues and changes in test requirements. Work on the panel of proteins was abandoned, while work on the use of metabolite biomarkers for preeclampsia risk assessment is ongoing. Future plans: In accordance with the original goals of the IMPROvED study, the data and biobank are now available for international collaboration to conduct high quality research into the cause and prevention of adverse pregnancy outcomes.

Personalized external aortic root support in aneurysm disease.

PURPOSE OF REVIEW: To bring together and annotate publications about personalised external aortic root support reported in the 18 months preceding submission. RECENT FINDINGS: The total number of personalised external aortic root support (PEARS) operations is now approaching 700 in 30 centres in Australia, Belgium, Brazil, Czech Republic, Great Britain, Greece, Ireland, Malaysia, Netherlands, New Zealand, Poland and Slovakia. There are continued reports of stability of aortic dimensions and aortic valve function with the only exceptions known being where the surgeon has deviated from the instructions for use of the device. The median root diameter of Marfan patients having PEARS was 47 mm suggesting that the existing criterion of 50 mm is due for reconsideration. The peri-operative mortality currently estimated to be less than 0.3%. The first recipient remains alive and well after 18 years. The use of PEARS as an adjunct to the Ross operation to support the pulmonary autograft is being explored in several centres. SUMMARY: The operation requires proctoring and adherence to a strict operative protocol and with those precautions excellent results are attained. The evidence and opinions provided in the cited publications indicate that PEARS is a proven and successful prophylactic operation for aortic root aneurysm.

Vocal cord dysfunction after pediatric cardiac surgery: A prospective implementation study.

Objective: To determine the incidence, outcomes, and evaluate diagnostic modalities for postoperative vocal cord dysfunction (VCD) following cardiothoracic surgery in children. Methods: A prospective mixed-methods study using principles of implementation science was completed. All patients undergoing surgery involving the aortic arch, ductus, or ligamentum arteriosum and vascular rings from September 2019 to December 2020 were enrolled. Patients underwent speech pathology assessment, laryngeal ultrasound, and flexible direct laryngoscopy. Results: Ninety-five patients were eligible for inclusion. The incidence of VCD ranged from 18% to 56% and varied according to procedure group. VCD occurred in 42% of neonates. Repair of hypoplastic aortic arch was associated with increased risk of VCD (57%; P = .002). There was no significant difference in duration of intubation, pediatric intensive care unit stay, or hospital stay. Forty percent children were able to achieve full oral feeding. Children with VCD were more likely to require nasogastric supplementary feeding at discharge (60% vs 36%; P = .044). Sixty-eight percent of patients demonstrated complete resolution of VCD at a median of 97 days postoperatively. Laryngeal ultrasound and speech pathology assessment combined had a sensitivity of 91% in comparison to flexible direct laryngoscopy. Conclusions: VCD occurred in one-third and resolved in two-thirds of patients at a median of 3 months following cardiac surgery. Aortic arch repair carried the highest risk of VCD. VCD adversely influenced feeding. Forty percent of patients achieved full oral feeding before discharge. VCD did not delay intensive care unit or hospital discharge. Speech pathology assessment and laryngeal ultrasound combined was reliable for diagnosis in most patients and was more patient friendly than flexible direct laryngoscopy.

Periconceptual and prenatal alcohol consumption and neurodevelopment at age two and five years.

OBJECTIVE: Examine the association between alcohol consumption before and during pregnancy and neurodevelopmental outcomes in the offspring at two and five years. STUDY DESIGN: Retrospective analysis of a prospective longitudinal cohort; SCOPE-BASELINE. Data on pre-conception and prenatal alcohol consumption were obtained at 15 weeks' gestation and categorised as abstinent, occasional-low (1-7units/week) and moderate-heavy (≥8units/week). Binge drinking was defined as ≥6 units/session. Outcome measures (Child Behaviour Checklist and Kaufman Brief Intelligence Test) were obtained at two and five years. Linear regression examined an alcohol consumption and Child Behaviour Checklist and Kaufman Brief Intelligence Test relationship, adjusting for several potential confounders. RESULTS: Data on alcohol consumption was available for 1,507 women. Adjusted linear regression suggested few associations: pre-pregnancy occasional-low alcohol consumption was associated with lower log externalizing Child Behaviour Checklist scores (-0.264, 95% CI: -0.009, -0.520), while pre-pregnancy moderate-high levels of alcohol consumption was associated with lower Kaufman Brief Intelligence Test verbal standard scores (-0.034, 95% CI: -0.001, -0.068) and composite IQ scores (-0.028, 95% CI: -0.056, -0.0004) at five-years. In the first trimester, moderate-high levels of alcohol consumption was associated with lower internalizing Child Behaviour Checklist scores at two-years (-0.252, 95% CI: -0.074, -0.430). No significant associations were observed between number of binge episodes pre-pregnancy or binge drinking in the first trimester and Child Behaviour Checklist or Kaufman Brief Intelligence Test. CONCLUSIONS: We did not find strong evidence of associations between pre-pregnancy and early pregnancy maternal alcohol consumption and adverse neurodevelopmental outcomes at age two and five years overall. Further research examining alcohol consumption (including binge drinking) beyond 15 weeks' gestation and subsequent neurodevelopmental outcomes is needed to examine the potential effect of alcohol consumption in later pregnancy.

Early cost-effectiveness analysis of screening for preeclampsia in nulliparous women: A modelling approach in European high-income settings.

BACKGROUND: Preeclampsia causes substantial maternal and perinatal morbidity and mortality and significant societal economic impact. Effective screening would facilitate timely and appropriate prevention and management of preeclampsia. OBJECTIVES: To develop an early cost-effectiveness analysis to assess both costs and health outcomes of a new screening test for preeclampsia from a healthcare payer perspective, in the United Kingdom (UK), Ireland, the Netherlands and Sweden. METHODS: A decision tree over a 9-month time horizon was developed to explore the cost-effectiveness of the new screening test for preeclampsia compared to the current screening strategy. The new test strategy is being developed so that it can stratify healthy low risk nulliparous women early in pregnancy to either a high-risk group with a risk of 1 in 6 or more of developing preeclampsia, or a low-risk group with a risk of 1 in 100 or less. The model simulated 25 plausible scenarios in a hypothetical cohort of 100,000 pregnant women, in which the sensitivity and specificity of the new test were varied to set a benchmark for the minimum test performance that is needed for the test to become cost-effective. The input parameters and costs were mainly derived from published literature. The main outcome was incremental costs per preeclampsia case averted, expressed as an incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty. RESULTS: Base case results showed that the new test strategy would be more effective and less costly compared to the current situation in the UK. In the Netherlands, the majority of scenarios would be cost-effective from a threshold of €50,000 per preeclampsia case averted, while in Ireland and Sweden, the vast majority of scenarios would be considered cost-effective only when a threshold of €100,000 was used. In the best case analyses, ICERs were more favourable in all four participating countries. Aspirin effectiveness, prevalence of preeclampsia, accuracy of the new screening test and cost of regular antenatal care were identified as driving factors for the cost-effectiveness of screening for preeclampsia. CONCLUSION: The results indicate that the new screening test for preeclampsia has potential to be cost-effective. Further studies based on proven accuracy of the test will confirm whether the new screening test is a cost-effective additional option to the current situation.

The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice.

All units managing hypertensive pregnant women should maintain and review uniform departmental management protocols and conduct regular audits of maternal & fetal outcomes. The cause(s) of pre-eclampsia and the optimal clinical management of the hypertensive disorders of pregnancy remain uncertain; therefore, we recommend that every hypertensive pregnant woman be offered an opportunity to participate in research, clinical trials and follow-up studies.

Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations.

Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized human trophoblst cells) cell invasion in a Hippo-signaling-dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA (Ras homolog gene family, member A)/ROCK (Rho-associated protein kinase) induced actin polymerization. Mutation-based YAP-5SA (S61A, S109A, S127A, S164A, S381A) demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

Implementation of a novel vocal cord dysfunction management pathway using the consolidated framework for implementation research.

Every year in Australia over a thousand children who are born with congenital heart disease require surgical intervention. Vocal cord dysfunction (VCD) can be an unavoidable and potentially devastating complication of surgery for congenital heart disease. Structured, multidisciplinary care pathways help to guide clinical care and reduce mortality and morbidity. An implementation study was conducted to embed a novel, multidisciplinary management pathway into practice using the consolidated framework for implementation research (CFIR). The goal of the pathway was to prepare children with postoperative vocal cord dysfunction to safely commence and transition to oral feeding. Education sessions to support pathway rollout were completed with clinical stakeholders. Other implementation strategies used included adaptation of the pre-procedural pathway to obtain consent, improving the process of identifying patients on the VCD pathway, and nominating a small team who were responsible for the ongoing monitoring of patients following recruitment. Implementation success was evaluated according to compliance with pathway defined management. Our study found that while there were several barriers to pathway adoption, implementation of the pathway was feasible despite pathway adaptations that were required in response to COVID-19.

Estrogen and COVID-19 symptoms: Associations in women from the COVID Symptom Study.

It has been widely observed that adult men of all ages are at higher risk of developing serious complications from COVID-19 when compared with women. This study aimed to investigate the association of COVID-19 positivity and severity with estrogen exposure in women, in a population based matched cohort study of female users of the COVID Symptom Study application in the UK. Analyses included 152,637 women for menopausal status, 295,689 women for exogenous estrogen intake in the form of the combined oral contraceptive pill (COCP), and 151,193 menopausal women for hormone replacement therapy (HRT). Data were collected using the COVID Symptom Study in May-June 2020. Analyses investigated associations between predicted or tested COVID-19 status and menopausal status, COCP use, and HRT use, adjusting for age, smoking and BMI, with follow-up age sensitivity analysis, and validation in a subset of participants from the TwinsUK cohort. Menopausal women had higher rates of predicted COVID-19 (P = 0.003). COCP-users had lower rates of predicted COVID-19 (P = 8.03E-05), with reduction in hospital attendance (P = 0.023). Menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P = 2.22E-05) for HRT users alone. The findings support a protective effect of estrogen exposure on COVID-19, based on positive association between predicted COVID-19 with menopausal status, and negative association with COCP use. HRT use was positively associated with COVID-19, but the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential unaccounted for confounders and comorbidities.

Physiological track-and-trigger/early warning systems for use in maternity care.

BACKGROUND: A considerable challenge for maternity care providers is recognising clinical deterioration early in pregnant women. Professional bodies recommend the use of clinical assessment protocols or evaluation tools, commonly referred to as physiological track-and-trigger systems (TTS) or early warning systems (EWS), as a means of helping maternity care providers recognise actual or potential clinical deterioration early. TTS/EWS are clinician-administered (midwife, obstetrician), bedside physiological assessment protocols, charts or tools designed to record routinely assessed clinical parameters; that is, blood pressure, temperature, heart rate, urine output and mental/neurological alertness. In general, these systems involve the application of scores or alert indicators to the observed physiological parameters based on their prespecified limits of normality. The overall system score or alert limit is then used to assist the maternity care provider identify a need to escalate care. This, in turn, may allow for earlier intervention(s) to alter the course of the emerging critical illness and ultimately reduce or avoid mortality and morbidity sequelae. OBJECTIVES: To evaluate the clinical- and cost-effectiveness of maternal physiological TTS/EWS on pregnancy, labour and birth, postpartum (up to 42 days) and neonatal outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (28 May 2021), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (7 June 2021), OpenGrey, the ProQuest Dissertations and Theses database (7 June 2021), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials (RCTs), including cluster-RCTs, comparing physiological TTS/EWS with no system or another system. Participants were women who were pregnant or had given birth within the previous 42 days, at high risk and low risk for pregnancy, labour and birth, and postpartum complications. DATA COLLECTION AND ANALYSIS: Two review authors (VS and MN) independently assessed all identified papers for inclusion and performed risk of bias assessments. Any discrepancies were resolved through discussion and consensus. Data extraction was also conducted independently by two review authors (VS and MN) and checked for accuracy. We used the summary odds ratio (OR) with 95% confidence intervals (CIs) to present the results for dichotomous data and the mean difference (MD) with 95% CI to present the results for continuous data. MAIN RESULTS: We included two studies, a parallel RCT involving 700 women and a stepped-wedge cluster trial involving 536,233 women. Both studies were published in 2019, and both were conducted in low-resource settings. The interventions were the 'Saving Mothers Score' (SMS) and the CRADLE Vital Sign Alert (VSA) device, and both interventions were compared with standard care. Both studies had low or unclear risk of bias on all seven risk of bias criteria. Evidence certainty, assessed using GRADE, ranged from very low to moderate certainty, mainly due to other bias as well as inconsistency and imprecision. For women randomised to TTS/EWS compared to standard care there is probably little to no difference in maternal death (OR 0.80, 95% CI 0.30 to 2.11; 1 study, 536,233 participants; moderate-certainty evidence). Use of TTS/EWS compared to standard care may reduce total haemorrhage (OR 0.36, 95% CI 0.19 to 0.69; 1 study, 700 participants; low-certainty evidence). For women randomised to TTS/EWS compared to standard care there may be little to no difference in sepsis (OR 0.21, 95% CI 0.02 to 1.80; 1 study, 700 participants; low-certainty evidence), eclampsia (OR 1.50, 95% CI 0.74 to 3.03; 2 studies, 536,933 participants; low-certainty evidence) and HELLP (OR 0.21, 95% CI 0.01 to 4.40; 1 study, 700 participants; very low-certainty evidence), and probably little to no difference in maternal admission to the intensive care unit (ICU) (OR 0.78, 95% CI  0.53 to 1.15; 2 studies, 536,933 participants; moderate-certainty evidence). Use of TTS/EWS compared to standard care may reduce a woman's length of hospital stay (MD -1.21, 95% CI -1.78 to -0.64; 1 study, 700 participants; low-certainty evidence) but may result in little to no difference in neonatal death (OR 1.06, 95% CI 0.62 to 1.84; 1 study, 700 participants; low-certainty evidence). Cost-effectiveness measures were not measured in either of the two studies.  AUTHORS' CONCLUSIONS: Use of TTS/EWS in maternity care may be helpful in reducing some maternal outcomes such as haemorrhage and maternal length of hospital stay, possibly through early identification of clinical deterioration and escalation of care. The evidence suggests that the use of TTS/EWS compared to standard care probably results in little to no difference in maternal death and may result in little to no difference in neonatal death. Both of the included studies were conducted in low-resource settings where the use of TTS/EWS might potentially confer a different effect to TTS/EWS use in high-resource settings. Further high-quality trials in high- and middle-resource settings, as well as in discrete populations of high- and low-risk women, are required.

A case report of mass and pressure: the utility of contrast echocardiography.

BACKGROUND: Diagnostic dilemmas in an unwell neonate can require the use of enhanced imaging modalities, especially in post-operative cardiac disease. CASE SUMMARY: A neonate presented a diagnostic challenge following the repair of complex transposition of the great arteries, when an echogenic mass was noted in the region of the left atrial appendage on two-dimensional echocardiography, in the context of a monitoring line (left atrial line) inserted directly through this area. Although the pressure monitoring on this line suggested elevated left atrial pressure, the neonate was clinically and haemodynamically stable. Contrast echocardiography was used to investigate this further and found the mass to be extracardiac. CONCLUSION: Contrast echocardiography is a simple and readily available tool for further echocardiographic delineation of structures, although needs to be performed carefully and the results interpreted logically.

Glycerophospholipid and detoxification pathways associated with small for gestation age pathophysiology: discovery metabolomics analysis in the SCOPE cohort.

INTRODUCTION: Small for gestational age (SGA) may be associated with neonatal morbidity and mortality. Our understanding of the molecular pathways implicated is poor. OBJECTIVES: Our aim was to determine the metabolic pathways involved in the pathophysiology of SGA and examine their variation between maternal biofluid samples. METHODS: Plasma (Cork) and urine (Cork, Auckland) samples were collected at 20 weeks' gestation from nulliparous low-risk pregnant women participating in the SCOPE study. Women who delivered an SGA infant (birthweight < 10th percentile) were matched to controls (uncomplicated pregnancies). Metabolomics (urine) and lipidomics (plasma) analyses were performed using ultra performance liquid chromatography-mass spectrometry. Features were ranked based on FDR adjusted p-values from empirical Bayes analysis, and significant features putatively identified. RESULTS: Lipidomics plasma analysis revealed that 22 out of the 33 significantly altered lipids annotated were glycerophospholipids; all were detected in higher levels in SGA. Metabolomic analysis identified reduced expression of metabolites associated with detoxification (D-Glucuronic acid, Estriol-16-glucuronide), nutrient absorption and transport (Sulfolithocholic acid) pathways. CONCLUSIONS: This study suggests higher levels of glycerophospholipids, and lower levels of specific urine metabolites are implicated in the pathophysiology of SGA. Further research is needed to confirm these findings in independent samples.