Acceptability of data linkage to identify women at risk of postnatal complication for the development of digital risk prediction tools and interventions to better optimise postnatal care, a qualitative descriptive study design.

BACKGROUND: Pregnancy acts as a cardiovascular stress test. Although many complications resolve following birth, women with hypertensive disorder of pregnancy have an increased risk of developing cardiovascular disease (CVD) long-term. Monitoring postnatal health can reduce this risk but requires better methods to identity high-risk women for timely interventions. METHODS: Employing a qualitative descriptive study design, focus groups and/or interviews were conducted, separately engaging public contributors and clinical professionals. Diverse participants were recruited through social media convenience sampling. Semi-structured, facilitator-led discussions explored perspectives of current postnatal assessment and attitudes towards linking patient electronic healthcare data to develop digital tools for identifying postpartum women at risk of CVD. Participant perspectives were gathered using post-it notes or a facilitator scribe and analysed thematically. RESULTS: From 27 public and seven clinical contributors, five themes regarding postnatal check expectations versus reality were developed, including 'limited resources', 'low maternal health priority', 'lack of knowledge', 'ineffective systems' and 'new mum syndrome'. Despite some concerns, all supported data linkage to identify women postnatally, targeting intervention to those at greater risk of CVD. Participants outlined potential benefits of digitalisation and risk prediction, highlighting design and communication needs for diverse communities. CONCLUSIONS: Current health system constraints in England contribute to suboptimal postnatal care. Integrating data linkage and improving education on data and digital tools for maternal healthcare shows promise for enhanced monitoring and improved future health. Recognised for streamlining processes and risk prediction, digital tools may enable more person-centred care plans, addressing the gaps in current postnatal care practice.

CHronic hypERtension and L-citRulline studY (CHERRY): an Early-Phase Randomised Controlled Trial in Pregnancy.

Oral supplementation with L-citrulline, which is sequentially converted to L-arginine then nitric oxide, improves vascular biomarkers and reduces blood pressure in non-pregnant, hypertensive human cohorts and pregnant mice with a pre-eclampsia-like syndrome. This early-phase randomised feasibility trial assessed the acceptability of L-citrulline supplementation to pregnant women with chronic hypertension and its effects on maternal BP and other vascular outcomes. Pregnant women with chronic hypertension were randomised at 12-16 weeks to receive 3-g L-citrulline twice daily (n = 24) or placebo (n = 12) for 8 weeks. Pregnant women reported high acceptability of oral L-citrulline. Treatment increased maternal plasma levels of citrulline, arginine and the arginine:asymmetric dimethylarginine ratio, particularly in women reporting good compliance. L-citrulline had no effect on diastolic BP (L-citrulline: - 1.82 95% CI (- 5.86, 2.22) vs placebo: - 5.00 95% CI (- 12.76, 2.76)), uterine artery Doppler or angiogenic biomarkers. Although there was no effect on BP, retrospectively, this study was underpowered to detect BP changes < 9 mmHg, limiting the conclusions about biological effects. The increase in arginine:asymmetric dimethylarginine ratio was less than in non-pregnant populations, which likely reflects altered pharmacokinetics of pregnancy, and further pharmacokinetic assessment of L-citrulline in pregnancy is advised.Trial Registration EudraCT 2015-005792-25 (2017-12-22) and ISRCTN12695929 (2018-09-20).

The effect of prone positioning on maternal haemodynamics and fetal wellbeing in the third trimester-A primary cohort study with a scoping review.

INTRODUCTION: Supine sleep position is associated with stillbirth, likely secondary to inferior vena cava compression, and a reduction in cardiac output (CO) and uteroplacental perfusion. Evidence for the effects of prone position in pregnancy is less clear. This study aimed to determine the effect maternal prone position on maternal haemodynamics and fetal heart rate, compared with left lateral position. METHODS: Twenty-one women >28 weeks' gestation underwent non-invasive CO monitoring (Cheetah) every 5 minutes and continuous fetal heart rate monitoring (MONICA) in left lateral (20 minutes), prone (30 minutes), followed by left lateral (20 minutes). Anxiety and comfort were assessed by questionnaires. Regression analyses (adjusted for time) compared variables between positions. The information derived from the primary study was used in an existing mathematical model of maternal circulation in pregnancy, to determine whether occlusion of the inferior vena cava could account for the observed effects. In addition, a scoping review was performed to identify reported clinical, haemodynamic and fetal effects of maternal prone position; studies were included if they reported clinical outcomes or effects or maternal prone position in pregnancy. Study records were grouped by publication type for ease of data synthesis and critical analysis. Meta-analysis was performed where there were sufficient studies. RESULTS: Maternal blood pressure (BP) and total vascular resistance (TVR) were increased in prone (sBP 109 vs 104 mmHg, p = 0.03; dBP 74 vs 67 mmHg, p = 0.003; TVR 1302 vs 1075 dyne.s-1cm-5, p = 0.03). CO was reduced in prone (5.7 vs 7.1 mL/minute, p = 0.003). Fetal heart rate, variability and decelerations were unaltered. However, fetal accelerations were less common in prone position (86% vs 95%, p = 0.03). Anxiety was reduced after the procedure, compared to beforehand (p = 0.002), despite a marginal decline in comfort (p = 0.04).The model predicted that if occlusion of the inferior vena cava occurred, the sBP, dBP and CO would generally decrease. However, the TVR remained relatively consistent, which implies that the MAP and CO decrease at a similar rate when occlusion occurs. The scoping review found that maternal and fetal outcomes from 47 included case reports of prone positioning during pregnancy were generally favourable. Meta-analysis of three prospective studies investigating maternal haemodynamic effects of prone position found an increase in sBP and maternal heart rate, but no effect on respiratory rate, oxygen saturation or baseline fetal heart rate (though there was significant heterogeneity between studies). CONCLUSION: Prone position was associated with a reduction in CO but an uncertain effect on fetal wellbeing. The decline in CO may be due to caval compression, as supported by the computational model. Further work is needed to optimise the safety of prone positioning in pregnancy. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov (NCT04586283).

Altered Oral Nitrate Reduction and Bacterial Profiles in Hypertensive Women Predict Blood Pressure Lowering Following Acute Dietary Nitrate Supplementation.

BACKGROUND: The efficacy of dietary nitrate supplementation to lower blood pressure (BP) in pregnant women is highly variable. We aimed to investigate whether differences in oral microbiota profiles and oral nitrate-reducing capacity may explain interindividual differences in BP lowering following nitrate supplementation. METHODS: Participants recruited for this study were both pregnant and nonpregnant women, with or without hypertension (n=55). Following an overnight fast, plasma, saliva, and tongue scraping samples were collected for measurement of nitrate/nitrite concentrations, oral NaR (nitrate reductase) activity, and microbiota profiling using 16S rRNA gene sequencing. Baseline BP was measured, followed by the administration of a single dose of dietary nitrate (400 mg nitrate in 70 mL beetroot juice). Post-nitrate intervention, plasma and salivary nitrate/nitrite concentrations and BP were determined 2.5 hours later. RESULTS: Women with hypertension had significantly lower salivary nitrite concentrations (P=0.006) and reduced abundance of the nitrate-reducing taxa Veillonella(P=0.007) compared with normotensive women. Oral NaR activity was not significantly different in pregnant versus nonpregnant women (P=0.991) but tended to be lower in hypertensive compared with normotensive women (P=0.099). Oral NaR activity was associated with both baseline diastolic BP (P=0.050) and change in diastolic BP following acute nitrate intake (P=0.01, adjusted for baseline BP). CONCLUSIONS: The abundance and activity of oral nitrate-reducing bacteria impact both baseline BP as well as the ability of dietary nitrate supplementation to lower BP. Strategies to increase oral nitrate-reducing capacity could lower BP and enhance the efficacy of dietary nitrate supplementation, in pregnancy as well as in nonpregnant adults. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03930693.

Prevalence of pre-eclampsia and adverse pregnancy outcomes in women with pre-existing cardiomyopathy: a multi-centre retrospective cohort study.

Pre-eclampsia is associated with postnatal cardiac dysfunction; however, the nature of this relationship remains uncertain. This multicentre retrospective cohort study aimed to determine the prevalence of pre-eclampsia in women with pre-existing cardiac dysfunction (left ventricular ejection fraction < 55%) and explore the relationship between pregnancy outcome and pre-pregnancy cardiac phenotype. In this cohort of 282 pregnancies, pre-eclampsia prevalence was not significantly increased (4.6% [95% C.I 2.2-7.0%] vs. population prevalence of 4.6% [95% C.I. 2.7-8.2], p = 0.99); 12/13 women had concurrent obstetric/medical risk factors for pre-eclampsia. The prevalence of preterm pre-eclampsia (< 37 weeks) and fetal growth restriction (FGR) was increased (1.8% vs. 0.7%, p = 0.03; 15.2% vs. 5.5%, p < 0.001, respectively). Neither systolic nor diastolic function correlated with pregnancy outcome. Antenatal ß blockers (n = 116) were associated with lower birthweight Z score (adjusted difference - 0.31 [95% C.I. - 0.61 to - 0.01], p = 0.04). To conclude, this study demonstrated a modest increase in preterm pre-eclampsia and significant increase in FGR in women with pre-existing cardiac dysfunction. Our results do not necessarily support a causal relationship between cardiac dysfunction and pre-eclampsia, especially given the population's background risk status. The mechanism underpinning the relationship between cardiac dysfunction and FGR merits further research but could be influenced by concomitant ß blocker use.

Postnatal cardiovascular morbidity following preterm pre-eclampsia: An observational study.

OBJECTIVE: To explore the nature of postnatal cardiovascular morbidity following pregnancies complicated by preterm pre-eclampsia and investigate associations between pregnancy characteristics and maternal postnatal cardiovascular function. STUDY DESIGN: This was an observational sub-study of a single-centre feasibility randomised double-blind placebo-controlled trial (https://www. CLINICALTRIALS: gov; NCT03466333), involving women with preterm pre-eclampsia, delivering before 37 weeks. Eligible women underwent echocardiography, arteriography and blood pressure monitoring within three days of birth, six weeks and six months postpartum. Correlations between pregnancy and cardiovascular characteristics were assessed using Spearman's correlation. MAIN OUTCOME MEASURES: The prevalence of cardiovascular dysfunction and remodelling six months following preterm pre-eclampsia. RESULTS: Forty-four women completed the study. At six months, 27 (61 %) had diastolic dysfunction, 33 (75 %) had raised total vascular resistance (TVR) and 18 (41 %) had left ventricular remodelling. Sixteen (46 %) women had de novo hypertension by six months and only two (5 %) women had a completely normal echocardiogram. Echocardiography did not change significantly from six weeks to six months. Earlier gestation at delivery and lower birthweight centile were associated with worse six-month diastolic dysfunction (E/E': rho = -0.39, p = 0.001 & rho = -0.42, p = 0.005) and TVR (rho = -0.34, p = 0.02 & rho = -0.37, p = 0.01). CONCLUSIONS: Preterm pre-eclampsia is associated with persistent cardiovascular morbidity-six months postpartum in the majority of women. These cardiovascular changes have significant implications for long-term cardiovascular health. The graded severity of diastolic dysfunction and TVR with worsening pre-eclampsia phenotype suggests a dose-effect. However, the mechanistic link remains uncertain.

Postnatal Enalapril to Improve Cardiovascular Function Following Preterm Preeclampsia (PICk-UP):: A Randomized Double-Blind Placebo-Controlled Feasibility Trial.

Hypertensive disease in pregnancy is associated with future cardiovascular disease and, therefore, provides an opportunity to identify women who could benefit from targeted interventions aimed at reducing cardiovascular morbidity. This study focused on the highest-risk group, women with preterm preeclampsia, who have an 8-fold risk of death from future cardiovascular disease. We performed a single-center feasibility randomized controlled trial of 6 months' treatment with enalapril to improve postnatal cardiovascular function. Echocardiography and hemodynamic measurements were performed at baseline (<3 days), 6 weeks, and 6 months postdelivery on 60 women. At randomization, 88% of women had diastolic dysfunction, and 68% had concentric remodeling/hypertrophy. No difference was seen in total vascular resistance (P=0.59) or systolic function (global longitudinal strain: P=0.14) between groups at 6 months. However, women treated with enalapril had echocardiographic measurements consistent with improved diastolic function (E/E'[the ratio of early mitral inflow velocity and early mitral annular diastolic velocity]: P=0.04) and left ventricular remodeling (relative wall thickness: P=0.01; left ventricular mass index: P=0.03) at 6 months, compared with placebo. Urinary enalapril was detectable in 85% and 63% of women in the enalapril arm at 6 weeks and 6 months, respectively. All women responded positively to taking enalapril in the future. Our study confirmed acceptability and feasibility of the study protocol with a recruitment to completion rate of 2.2 women per month. Importantly, postnatal enalapril treatment was associated with improved echocardiographic measurements; these early improvements have the potential to reduce long-term cardiovascular disease risk. A definitive, multicenter randomized controlled trial is now required to confirm these findings. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT03466333.

Effects of dietary nitrate supplementation, from beetroot juice, on blood pressure in hypertensive pregnant women: A randomised, double-blind, placebo-controlled feasibility trial.

Chronic hypertension in pregnancy is associated with significant adverse pregnancy outcomes, increasing the risk of pre-eclampsia, fetal growth restriction and preterm birth. Dietary nitrate, abundant in green leafy vegetables and beetroot, is reduced in vivo to nitrite and subsequently nitric oxide, and has been demonstrated to lower blood pressure, improve vascular compliance and enhance blood flow in non-pregnant humans and animals. The primary aims of this study were to determine the acceptability and efficacy of dietary nitrate supplementation, in the form of beetroot juice, to lower blood pressure in hypertensive pregnant women. In this double-blind, placebo-controlled feasibility trial, 40 pregnant women received either daily nitrate supplementation (70 mL beetroot juice, n = 20) or placebo (70 mL nitrate-depleted beetroot juice, n = 20) for 8 days. Blood pressure, cardiovascular function and uteroplacental blood flow was assessed at baseline and following acute (3 h) and prolonged (8 days) supplementation. Plasma and salivary samples were collected for analysis of nitrate and nitrite concentrations and acceptability of this dietary intervention was assessed based on questionnaire feedback. Dietary nitrate significantly increased plasma and salivary nitrate/nitrite concentrations compared with placebo juice (p < 0.001), with marked variation between women. Compared with placebo, there was no overall reduction in blood pressure in the nitrate-treated group; however there was a highly significant correlation between changes in plasma nitrite concentrations and changes in diastolic blood pressure in the nitrate-treated arm only (r = -0.6481; p = 0.0042). Beetroot juice supplementation was an acceptable dietary intervention to 97% of women. This trial confirms acceptability and potential efficacy of dietary nitrate supplementation in pregnant women. Conversion of nitrate to nitrite critically involves oral bacterial nitrate reductase activities. We speculate that differences in efficacy of nitrate supplementation relate to differences in the oral microbiome, which will be investigated in future studies.

'To test or not to test', the arguments for and against thrombophilia testing in obstetrics.

Clinicians increasingly investigate women for thrombophilias due to their associations with venous thromboembolism and placenta-mediated pregnancy complication. These associations, however, are modest and based largely on retrospective data from studies with heterogeneous classifications and populations, leading to discordance between evidence and guidelines. Current evidence suggests a contributory rather than causative role for thrombophilia in placenta-mediated pregnancy complication and venous thromboembolism. With little evidence of benefit from antithrombotic therapy in placenta-mediated pregnancy complication, thrombophilia screening remains controversial. Given the low absolute risk of placenta-mediated pregnancy complication and gestational venous thromboembolism with heritable thrombophilia, universal screening is inappropriate. Selective screening for antiphospholipid syndrome is supported by robust evidence of benefit. Conversely, selective screening for heritable thrombophilia has not been shown to effectively manage placenta-mediated pregnancy complication. Therefore, at present heritable thrombophilia screening is not warranted for placenta-mediated pregnancy complication. Until we have better evidence from better stratified patient groups, caution should remain if we wish to practice evidence-based medicine.

Dietary interventions for fetal growth restriction - therapeutic potential of dietary nitrate supplementation in pregnancy.

Fetal growth restriction (FGR) affects around 5% of pregnancies and is associated with significant short- and long-term adverse outcomes. A number of factors can increase the risk of FGR, one of which is poor maternal diet. In terms of pathology, both clinically and in many experimental models of FGR, impaired uteroplacental vascular function is implicated, leading to a reduction in the delivery of oxygen and nutrients to the developing fetus. Whilst mechanisms underpinning impaired uteroplacental vascular function are not fully understood, interventions aimed at enhancing nitric oxide (NO) bioavailability remain a key area of interest in obstetric research. In addition to endogenous NO production from the amino acid l-arginine, via nitric oxide synthase (NOS) enzymes, research in recent years has established that significant NO can be derived from dietary nitrate, via the 'alternative NO pathway'. Dietary nitrate, abundant in green leafy vegetables and beetroot, can increase NO bioactivity, conferring beneficial effects on cardiovascular function and blood flow. Given the beneficial effects of dietary nitrate supplementation to date in non-pregnant humans and animals, current investigations aim to assess the therapeutic potential of this approach in pregnancy to enhance NO bioactivity, improve uteroplacental vascular function and increase fetal growth.

Management of inherited thrombophilia in pregnancy.

Adverse pregnancy outcomes, such as pregnancy loss and pre-eclampsia, are associated with thrombotic mechanisms and thrombophilia. Antithrombotic interventions, particularly low-molecular-weight heparin, have been investigated in women identified by previous pregnancy outcome; however, the results have been inconsistent. This may reflect heterogeneity of both the study groups and the disease processes resulting in inadequate stratification to guide antithrombotic interventions. Furthermore, the variation in gestation at initiation of low-molecular-weight heparin treatment might be important. Despite limited evidence of efficacy, low-molecular-weight heparin is often used in an attempt to prevent these complications, owing to the lack of other effective treatments and its perceived safety in pregnancy. Research is required to better understand the disease processes, identify possible biomarkers and thereby more homogeneous groups for targeted treatment.

Thrombophilia and Pregnancy Complications.

There is a paucity of strong evidence associated with adverse pregnancy outcomes and thrombophilia in pregnancy. These problems include both early (recurrent miscarriage) and late placental vascular-mediated problems (fetal loss, pre-eclampsia, placental abruption and intra-uterine growth restriction). Due to poor quality case-control and cohort study designs, there is often an increase in the relative risk of these complications associated with thrombophilia, particularly recurrent early pregnancy loss, late fetal loss and pre-eclampsia, but the absolute risk remains very small. It appears that low-molecular weight heparin has other benefits on the placental vascular system besides its anticoagulant properties. Its use is in the context of antiphospholipid syndrome and recurrent pregnancy loss and also in women with implantation failure to improve live birth rates. There is currently no role for low-molecular weight heparin to prevent late placental-mediated complications in patients with inherited thrombophilia and this may be due to small patient numbers in the studies involved in summarising the evidence. There is potential for low-molecular weight heparin to improve pregnancy outcomes in women with prior severe vascular complications of pregnancy such as early-onset intra-uterine growth restriction and pre-eclampsia but further high quality randomised controlled trials are required to answer this question.

Pulmonary thrombo-embolism in pregnancy: diagnosis and management.

KEY POINTS: Venous thromboembolism (VTE) in pregnancy remains a leading cause of direct maternal mortality in the developed world and identifiable risk factors are increasing in incidence.VTE is approximately 10-times more common in the pregnant population (compared with non-pregnant women) with an incidence of 1 in 1000 and the highest risk in the postnatal period.If pulmonary imaging is required, ventilation perfusion scanning is usually the preferred initial test to detect pulmonary embolism within pregnancy. Treatment should be commenced on clinical suspicion and not be withheld until an objective diagnosis is obtained.The mainstay of treatment for pulmonary thromboembolism in pregnancy is anticoagulation with low molecular weight heparin for a minimum of 3 months in total duration and until at least 6 weeks postnatal. Low molecular weight heparin is safe, effective and has a low associated bleeding risk. EDUCATIONAL AIMS: To inform readers about the current guidance for diagnosis and management of pulmonary thromboembolism in pregnancy.To highlight the risks of venous thromboembolism during pregnancy.To introduce the issues surrounding management of pulmonary thromboembolism around labour and delivery.