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OBJECTIVE: To explore UK-based clinicians' knowledge of long-term cardiovascular disease (CVD) risks after pre-eclampsia and capture current risk management practice. STUDY DESIGN: A voluntary online survey was designed to explore clinicians' perception and management of CVD risks after pre-eclampsia. Distribution occurred May-July 2022 via social media and email. The survey assessed awareness of pre-eclampsia's association with future CVD, knowledge of published guidelines on CVD risk management after pre-eclampsia, and current practice of risk-reduction counselling. Results were analysed descriptively. MAIN OUTCOME MEASURE: Clinician knowledge of postpartum cardiovascular risk and management following pre-eclampsia. RESULTS: Of 240 respondents, 72 were midwives, 46 obstetricians, 8 cardiologists, and 114 general practitioners (GPs). Most clinicians knew that pre-eclampsia increases the risk of chronic hypertension (89 %) and stroke (75 %). Awareness was worse for heart failure (47 %) and peripheral vascular disease (55 %). Obstetricians provide CVD risk-reduction counselling to women with pre-eclampsia most frequently: 43 % always counsel and 27 % often counsel. Most other clinicians never counsel patients (midwives: 76 %, cardiologists: 75 %, GPs: 62 %). Most clinicians (84 %) were not aware of CVD risk management guidance after pre-eclampsia and 75 % of cardiologists and GPs never consider pre-eclampsia when assessing cardiovascular risk. Almost all clinicians (91 %) wished for greater education on the topic. CONCLUSIONS: This study presents the first assessment of cardiovascular risk awareness after pre-eclampsia amongst UK-based clinicians. Although most knew pre-eclampsia increases CVD risk, patient counselling was limited. Targeted educational initiatives are needed to improve the knowledge-to-practice gap and reduce CVD prevalence after pre-eclampsia.
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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).
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Citrulina , Hipertensão , Feminino , Humanos , Gravidez , Arginina , Biomarcadores , Suplementos Nutricionais , Óxido Nítrico , Estudos RetrospectivosRESUMO
OBJECTIVE: We examined whether the risk of stillbirth was related to ambient air pollution in a UK population. DESIGN: Prospective case-control study. SETTING: Forty-one maternity units in the UK. POPULATION: Women who had a stillbirth ≥28 weeks' gestation (n = 238) and women with an ongoing pregnancy at the time of interview (n = 597). METHODS: Secondary analysis of data from the Midlands and North of England Stillbirth case-control study only including participants domiciled within 20 km of fixed air pollution monitoring stations. Pollution exposure was calculated using pollution climate modelling data for NO2 , NOx and PM2.5 . The association between air pollution exposure and stillbirth risk was assessed using multivariable logistic regression adjusting for household income, maternal body mass index (BMI), maternal smoking, Index of Multiple Deprivation quintile and household smoking and parity. MAIN OUTCOME MEASURE: Stillbirth. RESULTS: There was no association with whole pregnancy ambient air pollution exposure and stillbirth risk, but there was an association with preconceptual NO2 exposure (adjusted odds ratio [aOR] 1.06, 95% CI 1.01-1.08 per microg/m3 ). Risk of stillbirth was associated with maternal smoking (aOR 2.54, 95% CI 1.38-4.71), nulliparity (aOR 2.16, 95% CI 1.55-3.00), maternal BMI (aOR 1.05, 95% CI 1.01-1.08) and placental abnormalities (aOR 4.07, 95% CI 2.57-6.43). CONCLUSIONS: Levels of ambient air pollution exposure during pregnancy in the UK, all of were beneath recommended thresholds, are not associated with an increased risk of stillbirth. Periconceptual exposure to NO2 may be associated with increased risk but further work is required to investigate this association.
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Poluentes Atmosféricos , Poluição do Ar , Feminino , Gravidez , Humanos , Natimorto/epidemiologia , Estudos de Casos e Controles , Dióxido de Nitrogênio/efeitos adversos , Dióxido de Nitrogênio/análise , Placenta , Poluição do Ar/efeitos adversos , Inglaterra/epidemiologia , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análiseRESUMO
BACKGROUND: Preeclampsia shares numerous risk factors with cardiovascular diseases. Here, we aimed to assess the potential utility of high-sensitivity cardiac troponin I (hs-cTnI) values during pregnancy in predicting preeclampsia occurrence. METHODS: This study measured hs-cTnI levels in 3721 blood samples of 2245 pregnant women from 4 international, prospective cohorts. Three analytical approaches were used: (1) a cross-sectional analysis of all women using a single blood sample, (2) a longitudinal analysis of hs-cTnI trajectories in women with multiple samples, and (3) analyses of prediction models incorporating hs-cTnI, maternal factors, and the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio. RESULTS: Women with hs-cTnI levels in the upper quarter had higher odds ratios for preeclampsia occurrence compared with women with levels in the lower quarter. Associations were driven by preterm preeclampsia (odds ratio, 5.78 [95% CI, 2.73-12.26]) and remained significant when using hs-cTnI as a continuous variable adjusted for confounders. Between-trimester hs-cTnI trajectories were independent of subsequent preeclampsia occurrence. A prediction model incorporating a practical hs-cTnI level of detection cutoff (≥1.9 pg/mL) alongside maternal factors provided comparable performance with the sFlt-1/PlGF ratio. A comprehensive model including sFlt-1/PlGF, maternal factors, and hs-cTnI provided added value (cross-validated area under the receiver operator characteristic, 0.78 [95% CI, 0.73-0.82]) above the sFlt-1/PlGF ratio alone (cross-validated area under the receiver operator characteristic, 0.70 [95% CI, 0.65-0.76]; P=0.027). As assessed by likelihood ratio tests, the addition of hs-cTnI to each prediction model significantly improved the respective prediction model not incorporating hs-cTnI, particularly for preterm preeclampsia. Net reclassification improvement analyses indicated that incorporating hs-cTnI improved risk prediction predominantly by correctly reclassifying women with subsequent preeclampsia occurrence. CONCLUSIONS: These exploratory findings uncover a potential role for hs-cTnI as a complementary biomarker in the prediction of preeclampsia. After validation in prospective studies, hs-cTnI, alongside maternal factors, may either be considered as a substitute for angiogenic biomarkers in health care systems where they are sparce or unavailable, or as an enhancement to established prediction models using angiogenic markers.
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Pré-Eclâmpsia , Recém-Nascido , Gravidez , Feminino , Humanos , Fator de Crescimento Placentário , Pré-Eclâmpsia/diagnóstico , Estudos Prospectivos , Troponina I , Estudos Transversais , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , BiomarcadoresRESUMO
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.
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Beta vulgaris , Hipertensão , Adulto , Humanos , Feminino , Gravidez , Nitratos , Pressão Sanguínea , Nitritos , RNA Ribossômico 16S , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Bactérias , Suplementos NutricionaisRESUMO
Maternal cardiovascular diseases, including hypertension and cardiac conditions, are associated with poor fetal outcomes. A range of adrenergic antihypertensive and cardioprotective medications are often prescribed to pregnant women to reduce major maternal complications during pregnancy. Although these treatments are not considered teratogenic, they may have detrimental effects on fetal growth and development, as they cross the fetoplacental barrier, and may contribute to placental vascular dysregulation. Medication risk assessment sheets do not include specific advice to clinicians and women regarding the safety of these therapies for use in pregnancy and the potential off-target effects of adrenergic medications on fetal growth have not been rigorously conducted. Little is known of their effects on the fetoplacental vasculature. There is also a dearth of knowledge on adrenergic receptor activation and signalling within the endothelium and vascular smooth muscle cells of the human placenta, a vital organ in the maintenance of adequate blood flow to satisfy fetal growth and development. The fetoplacental circulation, absent of sympathetic innervation, and unique in its reliance on endocrine, paracrine and autocrine influence in the regulation of vascular tone, appears vulnerable to dysregulation by adrenergic antihypertensive and cardioprotective medications compared with the adult peripheral circulation. This semi-systematic review focuses on fetoplacental vascular expression of adrenergic receptors, associated cell signalling mechanisms and predictive consequences of receptor activation/deactivation by antihypertensive and cardioprotective medications.
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Anti-Hipertensivos , Placenta , Adulto , Feminino , Humanos , Gravidez , Adrenérgicos/metabolismo , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Feto , Placenta/metabolismo , Circulação Placentária/fisiologiaRESUMO
Hypertensive disorders of pregnancy (HDP) are one of the most commonly occurring complications of pregnancy and include chronic hypertension, gestational hypertension, and pre-eclampsia. New developments in early pregnancy screening to identify women at high risk for pre-eclampsia combined with targeted aspirin prophylaxis could greatly reduce the number of affected pregnancies. Furthermore, recent advances in the diagnosis of pre-eclampsia, such as placental growth factor based testing, have been shown to improve the identification of those pregnancies at highest risk of severe complications. Evidence from trials has refined the target blood pressure and timing of delivery to manage chronic hypertension and pre-eclampsia with non-severe features, respectively. Importantly, a wealth of epidemiological data now links HDP to future cardiovascular disease and diabetes decades after an affected pregnancy. This review discusses the current guidelines and research data on the prevention, diagnosis, management, and postnatal follow-up of HDP. It also discusses the gap in knowledge regarding the long term risks for cardiovascular disease following HDP and illustrates the importance of improving adherence to postnatal guidelines to monitor hypertension and the need for more research focused on primary prevention of future cardiovascular disease in women identified as being at high risk because of HDP.
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Doenças Cardiovasculares , Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/prevenção & controle , Hipertensão Induzida pela Gravidez/diagnóstico , Hipertensão Induzida pela Gravidez/epidemiologia , Hipertensão Induzida pela Gravidez/prevenção & controle , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Fator de Crescimento Placentário , Pressão SanguíneaRESUMO
Preeclampsia is a multisystemic disorder of pregnancy that affects 250,000 pregnant individuals in the United States and approximately 10 million worldwide per annum. Preeclampsia is associated with substantial immediate morbidity and mortality but also long-term morbidity for both mother and offspring. It is now clearly established that a low dose of aspirin given daily, beginning early in pregnancy modestly reduces the occurrence of preeclampsia. Low-dose aspirin seems safe, but because there is a paucity of information about long-term effects on the infant, it is not recommended for all pregnant individuals. Thus, several expert groups have identified clinical factors that indicate sufficient risk to recommend low-dose aspirin preventive therapy. These risk factors may be complemented by biochemical and/or biophysical tests that either indicate increased probability of preeclampsia in individuals with clinical risk factors, or more importantly, identify increased likelihood in those without other evident risk. In addition, the opportunity exists to provide this population with additional care that may prevent or mitigate the short- and long-term effects of preeclampsia. Patient and provider education, increased surveillance, behavioral modification, and other approaches to improve outcomes in these individuals can improve the chance of a healthy outcome. We assembled a group with diverse, relevant expertise (clinicians, investigators, advocates, and public and private stakeholders) to develop a care plan in which providers and pregnant individuals at risk can work together to reduce the risk of preeclampsia and associated morbidities. The plan is for care of individuals at moderate to high risk for developing preeclampsia, sufficient to receive low-dose aspirin therapy, as identified by clinical and/or laboratory findings. The recommendations are presented using the GRADE methodology with the quality of evidence upon which each is based. In addition, printable appendices with concise summaries of the care plan's recommendations for patients and healthcare providers are provided. We believe that this shared approach to care will facilitate prevention of preeclampsia and its attendant short- and long-term morbidity in patients identified as at risk for development of this disorder.
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Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Pré-Eclâmpsia/etiologia , Seguimentos , Aspirina/uso terapêutico , Fatores de Risco , EscolaridadeRESUMO
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.
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Cardiomiopatias , Cardiopatias , Pré-Eclâmpsia , Humanos , Gravidez , Feminino , Pré-Eclâmpsia/epidemiologia , Resultado da Gravidez , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda , Retardo do Crescimento Fetal/epidemiologia , Cardiomiopatias/complicações , Cardiomiopatias/epidemiologiaRESUMO
Pelvic organ prolapse, urinary, bowel and sexual dysfunction, collectively called pelvic floor dysfunction (PFD) affects 1 in 3 women and has a significant public health impact. The causes of PFD are not fully understood but involve injury to connective tissue and motor nerve during childbirth. Women with PFD also have sensory nerve impairment, and it is likely this occurs during childbirth, but this has never been investigated. In the current study 150 women underwent quantitative sensory testing for vibration sensation at the vagina and clitoris, and stretch sensation at the vagina and introitus, in the third trimester, 3 and 6 months postnatal. Antenatally vibration sensation was reduced but stretch sensation was normal. Postnatally vibration sensation deteriorated whilst stretch sensation initially deteriorated but recovered by 6 months postnatal to antenatal levels (all p < 0.001). Mode of birth had a significant impact on sensation, with caesarean section appearing neuroprotective, normal vaginal birth resulted in a transient deterioration in sensation that recovered by 6 months, whilst assisted vaginal delivery was prolonged suggesting persistent neurological impairment (all p < 0.015). Further research is required to study the clinical effect of these changes on pelvic floor dysfunction in the medium and long-term.
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Cesárea , Prolapso de Órgão Pélvico , Feminino , Gravidez , Humanos , Estudos Prospectivos , Parto , Sensação/fisiologia , Parto Obstétrico , Diafragma da PelveRESUMO
Sphingolipids like sphingosine-1-phosphate (S1P) have been implicated in the pathophysiology of pre-eclampsia. We hypothesized that plasma S1P would be increased in women at high risk of developing pre-eclampsia who subsequently develop the disease. Low circulating placental growth factor (PlGF) is known to be associated with development of pre-eclampsia; so further, we hypothesized that increased S1P would be associated with concurrently low PlGF. This was a case-control study using stored maternal blood samples from 14 to 24 weeks of pregnancy, collected from 95 women at increased risk of pre-eclampsia. Pregnancy outcome was classified as uncomplicated, preterm pre-eclampsia (<37 weeks), or term pre-eclampsia. Plasma lipids were extracted and analyzed by ultraperformance liquid chromatography coupled to electrospray ionization MS/MS to determine concentrations of S1P and sphingosine. Median plasma S1P was 0.339 nmol/ml, and median sphingosine was 6.77 nmol/l. There were no differences in the plasma concentrations of S1P or sphingosine in women who subsequently developed pre-eclampsia, no effect of gestational age, fetal sex, ethnicity, or the presence of pre-existing hypertension. There was a correlation between S1P and sphingosine plasma concentration (P < 0.0001). There was no relationship between S1P or sphingosine with PlGF. Previous studies have suggested that plasma S1P may be a biomarker of pre-eclampsia. In our larger study, we failed to demonstrate there are women at high risk of developing the disease. We did not show a relationship with known biomarkers of the disease, suggesting that S1P is unlikely to be a useful predictor of the development of pre-eclampsia later in pregnancy.
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Pré-Eclâmpsia , Recém-Nascido , Gravidez , Feminino , Humanos , Masculino , Fator de Crescimento Placentário , Esfingosina , Estudos de Casos e Controles , Espectrometria de Massas em Tandem , BiomarcadoresRESUMO
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.
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Hipertensão , Pré-Eclâmpsia , Gravidez , Humanos , Feminino , Masculino , Remodelação Ventricular , Período Pós-PartoRESUMO
There is conflicting evidence regarding the effect of coronavirus disease (COVID-19) in pregnancy. Risk factors for COVID-19 overlap with risk factors for pregnancy complications. We aimed to assess the effects of the COVID-19 pandemic and confirmed SARS-CoV-2 infection on pregnancy outcomes. A retrospective interrupted time-series and matched cohort analysis was performed. Singleton pregnancies completed between 1st January 2016 and 31st January 2021 were included. Trends in outcomes were analysed over time. Modelled COVID-19 transmission data were applied to deliveries since 1st January 2020 to assign a risk of COVID-19 to each pregnancy, and incorporated into a regression model of birthweight. Confirmed COVID-19 cases were matched to controls delivered in the pre-pandemic period, and maternal and neonatal outcomes compared. 43,802 pregnancies were included, with 8343 in the model of birthweight. There was no increase in the risk of stillbirth (p = 0.26) or neonatal death (p = 0.64) during the pandemic. There was no association between modelled COVID-19 attack rate (%) in any trimester and birthweight (first trimester p = 0.50, second p = 0.15, third p = 0.16). 214 COVID-positive women were matched to controls. Preterm birth was more common in symptomatic cases (14/62, 22.6%) compared to asymptomatic cases (9/109, 8.3%, p = 0.008) and controls (5/62, 8.1%, p = 0.025). Iatrogenic preterm birth was more common in cases (21/214, 9.8%) than controls (9/214, 4.2%, p = 0.02). All other examined outcomes were similar between groups. There was no significant impact of COVID-19 on the examined birth outcomes available. Symptomatic COVID-19 should be considered a risk factor for preterm birth, possibly due to an increase in iatrogenic deliveries for maternal indications.
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COVID-19/epidemiologia , Modelos Biológicos , Complicações Infecciosas na Gravidez/epidemiologia , SARS-CoV-2 , Adolescente , Adulto , Inglaterra/epidemiologia , Feminino , Humanos , Gravidez , Nascimento Prematuro/epidemiologia , Estudos Retrospectivos , Natimorto/epidemiologiaRESUMO
INTRODUCTION: Guidelines disagree on the diagnostic thresholds for gestational diabetes (GDM); treatment of women with mild fasting hyperglycemia may not be cost-effective and increase unnecessary intervention. MATERIALS AND METHODS: Single-center, open-label randomized controlled feasibility trial (ISRCTN86503951). "Metformin" treatment (2 g/day) without home blood glucose monitoring (HBGM) compared to NICE "standard" diabetes prenatal care in women with fasting 5.1-5.4 mmol/L, 2H <8.5 mmol/L) at oral glucose tolerance test (OGTT). RESULTS: Process outcome: From the 173 women approached, 40/147 (27%) met the eligibility criteria and agreed to participate (non-completion n = 3). All women received dietary advice. Overall, compliance was good; with the majority of women in the treatment arm reporting missing metformin tablets less than 1-3 times/week. In the treatment arm (n = 18), median compliance (returned packets) was 65% [0-98%]; four women were unable to tolerate the full recommended dose of metformin. All women reported being satisfied with their treatment; with 9 out of 18 women (metformin arm) reporting they would choose the same treatment in a future pregnancy however 8 women reported they would want closer prenatal monitoring. Clinical outcome: Baseline characteristics and pregnancy outcomes were not different between participants and non-participants (n = 133). In women randomized to the standard care arm who performed HBGM, 15/19 were prescribed metformin based on values above target despite diet and lifestyle modifications; two women required additional insulin (10%). Data on glycemic control were available for 16/19 women; a reduction in fasting and post-prandial glucose was achieved in 15/16 from recruitment to 36 weeks. There was no change in A1C in women in the treatment arm vs the standard care arm. There was no difference in the rates of LGA between participants (n = 40) and non-participants (n = 133), although there was a reduction in the median birthweight centiles in the participants, the majority of whom received metformin treatment, compared with the non-participants (35 [IQR 12-54] vs 52 [25-78]; p = .045). DISCUSSION: Treatment with metformin in conjunction with routine care was acceptable to women with mild fasting hyperglycemia who participated in the trial, although overall recruitment to the study was low. Most women with mild fasting hyperglycemia (5.1-5.4 mmol/L) would meet the threshold for pharmacological treatment if identified as GDM based on current NICE guideline target blood glucose levels. However, given the low consent rate, it is unlikely that a future RCT comparing metformin treatment (in conjunction with routine prenatal care and without HBGM monitoring) to a diabetes prenatal clinic model of care would have the generalisability to inform the future management of this group.
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Diabetes Gestacional , Hiperglicemia , Metformina , Glicemia , Automonitorização da Glicemia , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/tratamento farmacológico , Jejum , Estudos de Viabilidade , Feminino , Humanos , Metformina/uso terapêutico , Gravidez , Cuidado Pré-NatalRESUMO
[Figure: see text].
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Cinurenina/farmacologia , Pré-Eclâmpsia/tratamento farmacológico , Resistência Vascular/efeitos dos fármacos , Vasodilatação , Vasodilatadores/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/antagonistas & inibidores , Inibidores de Adenilil Ciclases/farmacologia , Adulto , Bloqueadores dos Canais de Cálcio/farmacologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Indóis/farmacologia , Músculo Liso Vascular/citologia , Miométrio/irrigação sanguínea , Omento/irrigação sanguínea , Peptídeos/farmacologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Resistência Vascular/fisiologia , Vasoconstritores/antagonistas & inibidores , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
OBJECTIVE: Placental growth factor testing decreases time to recognition of preeclampsia and may reduce severe maternal adverse outcomes. This analysis aims to describe the clinical phenotype of women by PlGF concentration, and to determine the mechanism(s) underpinning the reduction in severe maternal adverse outcomes in the PARROT trial, in order to inform how PlGF testing may be optimally used within clinical management algorithms. STUDY DESIGN: This was a planned secondary analysis from the PARROT trial that compared revealed PlGF testing and management guidance with usual care in the assessment of women with suspected preterm preeclampsia. MAIN OUTCOME MEASURES: Maternal and perinatal outcomes following stratification of women by trial group, and measured PlGF concentration. RESULTS: 1006 women were included. PlGF < 100 pg/ml identified women with more marked hypertension, increased adverse maternal outcomes and preterm delivery rates, and higher rates of small for gestational age infants. There was a reduction in adverse maternal outcomes in women whose results were revealed when PlGF levels were 12-100 pg/ml compared to usual care (3.8% vs 6.9%; aOR 0.15(95% CI 0.03-0.92). There was no significant difference in gestation at delivery between concealed or revealed groups in any PlGF categories. CONCLUSION: Low PlGF concentrations are associated with severe preeclampsia. The reduction in severe adverse maternal outcomes may be mediated through quicker diagnosis and intensive surveillance, as recommended by the management algorithm for those at increased risk. PlGF is particularly beneficial in those who test 12-100 pg/ml, as these may be women with silent multi-organ disease who otherwise may go undetected.
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Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/diagnóstico , Adulto , Biomarcadores/sangue , Feminino , Idade Gestacional , Humanos , Pré-Eclâmpsia/epidemiologia , Gravidez , Resultado da Gravidez/epidemiologia , Método Simples-CegoRESUMO
Preeclampsia remains a leading cause of maternal and perinatal morbidity and mortality. Accurate prediction of preeclampsia risk would enable more effective, risk-based prenatal care pathways. Current risk assessment algorithms depend on clinical risk factors largely unavailable for first-time pregnant women. Delivering accurate preeclampsia risk assessment to this cohort of women, therefore requires for novel biomarkers. Here, we evaluated the relevance of metabolite biomarker candidates for their selection into a prototype rapid, quantitative Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) based clinical screening assay. First, a library of targeted LC-MS/MS assays for metabolite biomarker candidates was developed, using a medium-throughput translational metabolomics workflow, to verify biomarker potential in the Screening-for-Pregnancy-Endpoints (SCOPE, European branch) study. A variable pre-selection step was followed by the development of multivariable prediction models for pre-defined clinical use cases, i.e., prediction of preterm preeclampsia risk and of any preeclampsia risk. Within a large set of metabolite biomarker candidates, we confirmed the potential of dilinoleoyl-glycerol and heptadecanoyl-2-hydroxy-sn-glycero-3-phosphocholine to effectively complement Placental Growth Factor, an established preeclampsia biomarker, for the prediction of preeclampsia risk in first-time pregnancies without overt risk factors. These metabolites will be considered for integration in a prototype rapid, quantitative LC-MS/MS assay, and subsequent validation in an independent cohort.
Assuntos
Biomarcadores/sangue , Metabolômica/métodos , Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/diagnóstico , Adulto , Austrália , Estudos de Casos e Controles , Cromatografia Líquida , Diagnóstico Precoce , Feminino , Glicerol/sangue , Humanos , Idade Materna , Análise Multivariada , Nova Zelândia , Pré-Eclâmpsia/sangue , Gravidez , Segundo Trimestre da Gravidez/sangue , Espectrometria de Massas em TandemRESUMO
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.
Assuntos
Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Enalapril/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Pré-Eclâmpsia/fisiopatologia , Adulto , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Tosse/induzido quimicamente , Método Duplo-Cego , Ecocardiografia , Enalapril/efeitos adversos , Exantema/induzido quimicamente , Estudos de Viabilidade , Feminino , Hemodinâmica/fisiologia , Humanos , Recém-Nascido , Gravidez , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the maldevelopment of a maternal-placental blood supply capable of providing for the growth requirements of the fetus in later pregnancy, without exerting undue stress on maternal body systems. Here, we review normal development of a placental bed with a safe and adequate blood supply and a villous placenta-blood interface from which nutrients and oxygen can be extracted for the growing fetus. We consider disease mechanisms that are intrinsic to the maternal environment, the placenta or the interaction between the two. Systemic signalling from the endocrine placenta targets the maternal endothelium and multiple organs to adjust metabolism for an optimal pregnancy and later lactation. This signalling capacity is skewed when placental damage occurs and can deliver a dangerous pathogenic stimulus. We discuss the placental secretome including glycoproteins, microRNAs and extracellular vesicles as potential biomarkers of disease. Angiomodulatory mediators, currently the only effective biomarkers, are discussed alongside non-invasive imaging approaches to the prediction of disease risk. Identifying the signs of impending pathology early enough to intervene and ameliorate disease in later pregnancy remains a complex and challenging objective.
Assuntos
Retardo do Crescimento Fetal/fisiopatologia , Placentação/fisiologia , Pré-Eclâmpsia/fisiopatologia , Complicações na Gravidez/fisiopatologia , Biomarcadores , Decídua/fisiopatologia , Desenvolvimento Embrionário , Endométrio/fisiopatologia , Feminino , Desenvolvimento Fetal , Feto/irrigação sanguínea , Humanos , Placenta/irrigação sanguínea , Doenças Placentárias/fisiopatologia , Gravidez , Transdução de Sinais , Trofoblastos/fisiologiaRESUMO
BACKGROUND: Small-for-gestational-age (SGA) is a significant cause of morbidity and mortality, and there are currently few preventive strategies. AIM: The aim of this study was to investigate the relationship between maternal folic acid supplement (FAS) use pre-conception through to the second trimester, and small-for-gestational age (SGA) and birth size parameters. STUDY DESIGN: Women were recruited as part of the Screening for Pregnancy Endpoints (SCOPE) international prospective multi-centre cohort study: New Zealand, Australia, United Kingdom and Ireland. Information on FAS use pre-conception, during the first trimester and at 15 ± 1 weeks' gestation was collected via interview administered questionnaire. Participants were followed through to delivery. Pregnancy outcome data and birth measurements were collected within 72 h of birth. Multivariable regression analysis was used to investigate relationships between FAS and outcomes, adjusting for maternal sociodemographic and lifestyle factors. SUBJECTS: Nulliparous women with singleton pregnancies. OUTCOME MEASURES: SGA (<10th customised birthweight centile). RESULTS: 5606 women were included. SGA prevalence was 11.3%. Pre-conception FAS was associated with a significantly lower risk of SGA: aOR = 0.82 (95% CI: 0.67-01.00 p = 0.047). Although the association between FAS at 15 weeks' gestation and SGA did not reach significance, FAS at 15 weeks was associated with a significantly higher customised birthweight centile (ß 2.56 (95% CI: 0.87-4.26; p = 0.003). There was no significant effect of FAS on large-for-gestational-age births or head circumference. CONCLUSIONS: In this international cohort, FAS was positively associated with fetal growth, without increasing risks associated with LGA. Further studies are required to confirm whether continuing FAS beyond the first trimester might lower the risk of SGA.