Should We Add Pravastatin to Aspirin for Preeclampsia Prevention in High-risk Women?
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ABSTRACT:
SUBMITTER: Marrs CC
PROVIDER: S-EPMC5250542 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
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Should We Add Pravastatin to Aspirin for Preeclampsia Prevention in High-risk Women?
Marrs Caroline C CC Costantine Maged M MM
Clinical obstetrics and gynecology 20170301 1
Preeclampsia is a multisystem disorder that affects 3% to 5% of pregnant women and remains a significant source of short-term and long-term maternal and neonatal mortality and morbidity. Many professional societies recommend the use of low-dose aspirin to prevent preeclampsia in high-risk women. Owing to the similarities in pathophysiology between preeclampsia and atherosclerotic cardiovascular disease, and the encouraging data from preclinical and pilot clinical studies, pravastatin has been pr ...[more]
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Project description:Preeclampsia complicates approximately 3-5% of pregnancies and remains one of the major causes of maternal and neonatal morbidity. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Attempts at prevention of preeclampsia using various supplements and classes of medications have failed or had limited success, and they were not convincing enough to lead to widespread adoption of any particular strategy. Contrary to the experience with preeclampsia, prevention of cardiovascular mortality and other cardiovascular events in nonpregnant patients using 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, or statins, is widely accepted. Pravastatin and other statins have been shown to reverse various pathophysiologic pathways associated with preeclampsia, such as angiogenic imbalance, endothelial injury, inflammation, and oxidative stress. These beneficial effects are likely to contribute substantially to preventing preeclampsia and provide biological plausibility for the use of pravastatin in this setting. Pravastatin has favorable safety and pharmacokinetic profiles. In addition, animal studies and human pregnancy exposure data do not support teratogenicity claims for pravastatin. Therefore, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network started a pilot trial to collect maternal--fetal safety data and to evaluate pravastatin pharmacokinetics when used as a prophylactic daily treatment in high-risk pregnant women (identifier NCT01717586, clinicaltrials.gov).
| S-EPMC3880675 | biostudies-literature
Project description:BackgroundPreeclampsia complicates approximately 3-5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking.ObjectiveAs an initial step in evaluating the utility of pravastatin in preventing preeclampsia and after consultation with the US Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia.Study designWe conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12(0/7) and 16(6/7) weeks' gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (clinicaltrials.gov identifier NCT01717586).ResultsTen women assigned to pravastatin and 10 to placebo completed the trial. There were no differences between the 2 groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared with postpartum. Four subjects in the placebo group developed preeclampsia compared with none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at the time of delivery were below the lower limit of quantification of the assay. Pravastatin use was associated with a more favorable pregnancy angiogenic profile.ConclusionThis study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.
| S-EPMC4884459 | biostudies-literature
Project description:BACKGROUND:Non-adherence with medications in pregnancy is increasingly recognized and often results in a higher rate of preventable maternal and fetal morbidity and mortality. Non-adherence with prophylactic aspirin amongst high-risk pregnant women is associated with higher incidence of preeclampsia, preterm delivery and intrauterine growth restriction. Yet, the factors that influences adherence with aspirin in pregnancy, from the women's perspective, remains poorly understood. OBJECTIVE:The study is aimed at understanding the factors, from the women's perspective, that influenced adherence with prophylactic aspirin in their pregnancy. STUDY DESIGN:A sequential-exploratory designed mixed methods quantitative (n = 122) and qualitative (n = 6) survey of women with recent high-risk pregnancy necessitating antenatal prophylactic aspirin was utilized. Women recruited underwent their antenatal care in one of three high-risk pregnancy clinics within the South Western Sydney Local Health District, Australia. The quantitative study was done through an electronic anonymous survey and the qualitative study was conducted through a face-to-face interview. Data obtained was analysed against women's adherence with aspirin utilizing phi correlation (?) with significance set at <0.05. RESULTS:Two key themes, from the women's perspective, that influenced their adherence with aspirin in pregnancy were identified; (1) pill burden and non-intention omission (2) communication and relationship with health care provider (HCP). Pill burden and its associated non-intentional omission, both strongly corelated with reduced adherence (? = 0.8, p = 0.02, ? = 0.8, p<0.01) whilst the use of reminder strategies minimized accidental omission and improved adherence (? = 0.9, p<0.01). Consistent communication between HCPs and a good patient-HCP relationship was strongly associated with improved adherence (? = 0.7, p = 0.04, ? = 0.9, p = <0.01) and more importantly was found to play an important role in alleviating factors that had potentials to negatively influence adherence with aspirin in pregnancy. CONCLUSION:This study identified factors that both positively and negatively influenced adherence with aspirin amongst high-risk pregnant women. Is highlights the importance in recognizing the impact of pill burden in pregnancy and the need to counsel women on the utility of reminder strategies to minimize non-intentional omission. Importantly, it emphasizes on the importance of a positive patient-HCP relationship through effective and consistent communication to achieve the desired maternal and fetal outcomes.
| S-EPMC7046289 | biostudies-literature
Project description:Studies reported that women in a low-risk cohort with stage 1 hypertension defined as 130-139 mmHg/80-89 mmHg, according to the American College of Cardiology/American Heart Association, are more likely to develop into preeclampsia than women with normotensive in the early gestation. In this study, the authors investigated whether preeclampsia was more likely to occur in stage 1 hypertensive women compared to the normotensive pregnant women in a high-risk cohort, which was based on the randomized controlled trial of "Low-dose Aspirin in the Prevention of Preeclampsia in China." Meanwhile, the authors further evaluated the preventive effect of aspirin for preeclampsia in stage 1 hypertension subset. In women enrolled at or before 16 weeks of gestation, in the control group, the preeclampsia occurrence was significantly higher in stage 1 hypertensive woman than in the normotensive women (20.4% vs. 6.2%, aOR 3.960, 95% CI 1.299-12.074, p = .016), while no difference was observed in the aspirin group (4.5% vs. 4.2%, aOR 0.921, 95% CI 0.140-6.070, p = .932). In stage 1 hypertension, the incidences of preeclampsia and preterm birth were significantly lower in the aspirin group as compared to the control group (4.5% vs. 20.4%, aOR 0.139, 95% CI 0.027-0.716, p = .018; 4.5% vs. 18.4%, aOR 0.141, 95% CI 0.025-0.782, p = .025). Compared with the control group, the aspirin group displayed significantly prolonged gestational age at delivery (38.6 ± 1.2 vs. 37.4 ± 3.4, p = .042). This study indicates that the newly classified stage 1 hypertension might be an additional risk factor for preeclampsia in Chinese high-risk pregnant women, and aspirin intervention might be useful.
| S-EPMC8678830 | biostudies-literature
Project description:ObjectiveThis study aimed to evaluate the utilization of aspirin for preeclampsia prevention before and after implementation of a screening tool during nuchal translucency (NT) ultrasound.Study designOne-year prospective cohort study of patients at high risk for preeclampsia after the implementation of a screening tool (postscreen) administered to all patients at check in for NT (11-13 weeks) ultrasound. Prospective cohort was compared with one-year retrospective cohort (prescreen) the year prior (2017). All patients who presented for NT ultrasound in both cohorts were evaluated for the presence of one or more risk factor for preeclampsia with screening tool collected prospectively and chart review retrospectively. Provider recommendation for aspirin determined by documentation in prenatal record. Primary outcome was rate of provider recommendation for aspirin pre versus post screening tool, compared by Chi-square test and adjusted for potential confounders with multiple regression analysis.ResultsPre- (n = 156) and postscreen (n = 136) cohorts were similar except for race and multifetal gestation. Prescreen, rate of provider recommendation for aspirin was 74%. Of those with prior preeclampsia, 96% were recommended aspirin, compared with 64% of patients with other risk factors (p < 0.001). Postscreen, provider recommendation of aspirin improved to 95% (p < 0.001). Rate of preeclampsia/gestational hypertension were similar between cohorts; however, there was a reduced adjusted risk in overall preterm birth <37 weeks (adjusted odds ratio [aOR] = 0.50 [0.25-0.99]) and preterm birth <34 weeks (aOR = 0.33 [0.13-0.88]) postscreening tool implementation.ConclusionPrior to implementation of a simple screening questionnaire, approximately 25% of high risk patients did not receive the recommendation of aspirin for preeclampsia prevention. High-risk patients who lack a history of preeclampsia were less likely to be advised of aspirin prophylaxis. Use of a simple universal screening tool at time of NT ultrasound significantly improved utilization of aspirin for preeclampsia prevention and may improve patient outcomes.Key points· Despite recommendations, aspirin use for preeclampsia prevention is suboptimal.. · High-risk patients who lack a history preeclampsia were less likely to be advised of aspirin use.. · A simple universal screening tool can significantly improve aspirin utilization..
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Project description:Introduction: Elevated plasma levels of extracellular vesicles have been associated with impaired placentation, angiogenesis imbalance, intravascular inflammation, and endothelial dysfunction in women with preeclampsia, thus suggesting that circulating vesicles may be a good therapeutic target for the treatment of the disease. Recently, statins have been considered a potential treatment for the prevention of preeclampsia because of their pleiotropic effects, including the improvement of endothelial dysfunction and inhibition of inflammatory responses. However, the effects of these drugs on circulating vesicles concentration in women at risk of preeclampsia have not been established. Herein, we aimed to assess the effects of pravastatin on circulating extracellular vesicle generation in women at high risk of term preeclampsia. Methods: In a sample of 68 singleton pregnant women participating in the multicenter, double-blind, placebo-controlled STATIN trial (Nº EducraCT 2016-005206-19 ISRCTN), 35 women received a placebo and 33 women received a 20 mg/day dose of pravastatin for approximately 3 weeks (from 35 to 37 weeks of gestation until delivery). Large extracellular vesicles were characterized and quantified by flow cytometry using annexin V and cell-specific antibodies directed against platelet, endothelial, leukocyte, and syncytiotrophoblast cell surface markers. Results: In women who received the placebo, a significant increase in the plasma levels of large extracellular vesicles from platelets (34%, p < 0.01), leukocytes (33%, p < 0.01), monocytes (60%, p < 0.01), endothelial cells (40%, p < 0.05), and syncytiotrophoblast cells (22%, p < 0.05) were observed. However, treatment with pravastatin significantly reduced the plasma levels of large extracellular vesicles from platelets (42%, p < 0.001), leukocytes (25%, p < 0.001), monocytes (61%, p < 0.001), endothelial cells (69%, p < 0.001), activated endothelial cells (55%, p < 0.001), and syncytiotrophoblast cells (44%, p < 0.001). Discussion: These results indicate that pravastatin reduces the levels of activated cell-derived membrane vesicles from the maternal vasculature, blood, and placental syncytiotrophoblast of women at high risk of term preeclampsia, suggesting that this statin may be beneficial in reducing endothelial dysfunction and pro-inflammatory and pro-coagulatory state characteristics of the disease.
| S-EPMC10323224 | biostudies-literature
Project description:BackgroundAntenatal adherence to aspirin prophylaxis is key to reducing the occurrence of a major pregnancy complication: pre-eclampsia (PE). Up to 75% of pregnant women at increased risk of pre-eclampsia do not take aspirin as prescribed. Little research has been done to understand the psychological determinants of aspirin adherence in pregnancy. This qualitative study aimed to explore barriers and facilitators to aspirin adherence in women at increased risk of PE using version 2 of Theoretical Domains Framework (TDF).MethodsFourteen women from the North-East of England who declared various levels of non-adherence to aspirin (0-5 of 7 prescribed tablets/week) were interviewed 4-18 months after delivery, using the TDF as a guide. Semi-structured interviews were digitally recorded and transcribed verbatim. A thematic framework analysis was used.ResultsWomen exhibited both intentional and unintentional non-adherence and faced multiple barriers at a personal and environmental level. They struggled to initiate, implement and persist in taking medication as prescribed. Women expressed inadequate knowledge about PE and aspirin; they struggled to identify as 'medication takers' and relate to the risk factors for PE as identified by the midwife. Significant barriers within the health-care environment were identified; women had difficulties obtaining medication and perceived conflict amongst health care professionals regarding medication safety.ConclusionA combination of inadequate knowledge, lack of identification with the risk factors and beliefs about consequences of taking medication were interlinked with other domains, such as environmental context and resonate with the Necessity-Concerns Framework.
| S-EPMC8354178 | biostudies-literature
Project description:Statins (3-hydroxy-3 methyl-glutaryl coenzyme-A reductase inhibitors) are the most commonly prescribed cholesterol-lowering medications due to their efficacy in reducing cardiovascular mortality and morbidities, tolerability, and safety profiles. Based on pathophysiologic similarities between cardiovascular disease and preeclampsia, a common and dangerous complication of pregnancy, there is an increasing interest in studying this class of medications during pregnancy to prevent and/or treat preeclampsia. Undergoing such a study, which entails the use of a pregnancy class X medication for an off-label indication in pregnancy, requires intensive multidisciplinary involvement of a group of experts in basic and clinical pharmacology, research methods, pregnancy physiology and maternal-fetal medicine, as well as U.S. Food and Drug Administration (FDA) regulatory guidelines and practice. Issues of potential fetal risk, altered maternal-fetal pharmacokinetics and pharmacodynamics, and regulatory challenges are real, and must be carefully considered in the process of research in this arena.
| S-EPMC8244660 | biostudies-literature
Project description:BackgroundPreeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin for the prevention of preeclampsia.ObjectiveWe previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here, we report a follow-up, randomized trial of 20 mg pravastatin versus placebo among pregnant women with previous preeclampsia who required delivery before 34+6 weeks' gestation with the objective of evaluating the safety and pharmacokinetic parameters of pravastatin.Study designThis was a pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12+0 and 16+6 weeks of gestation were assigned to receive a daily pravastatin dose of 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy and at 4 to 6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and umbilical cord blood chemistries and maternal and neonatal outcomes, including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight.ResultsOf note, 10 women assigned to receive pravastatin and 10 assigned to receive the placebo completed the trial. No significant differences were observed between the 2 groups in the rates of adverse or serious adverse events, congenital anomalies, or maternal and umbilical cord blood chemistries. Headache followed by heartburn and musculoskeletal pain were the most common side effects. We report the pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life, and others during pregnancy and compare it with those values measured during the postpartum period. In the majority of the umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. The pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than 2-fold higher following a daily 20 mg dose compared with a 10 mg daily pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in nonpregnant subjects.ConclusionThis study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin for the prevention of preeclampsia. Until then, pravastatin use during pregnancy remains investigational.
| S-EPMC8611118 | biostudies-literature
Project description:INTRODUCTION:Low-dose aspirin (LDA) prophylaxis has been shown to reduce women's preeclampsia risk. Evidence regarding LDA adherence rates of pregnant women is based almost exclusively on clinical trials, giving a potentially biased picture. Moreover, these studies do not report on determinants of adherence. Since 2017, obstetric healthcare professionals in a Dutch region have assessed women's preeclampsia risk by means of a prediction tool and counseled those with an above-population average risk on LDA as a prophylactic measure. MATERIAL AND METHODS:From 2017 to 2018, 865 women were recruited in multiple centers and prospectively followed using web-based surveys (Expect Study II). Rates and determinants of LDA usage among women with an increased preeclampsia risk in daily practice were assessed. Results were compared with findings in a similar cohort from a care-as-usual setting lacking risk-based counseling (Expect Study I, n = 2614). Netherlands Trial Register NTR4143. RESULTS:In total, 306 women had a predicted increased preeclampsia risk. LDA usage was higher for women receiving risk-based care than care-as-usual (29.4% vs 1.5%, odds ratio 19.1, 95% confidence interval 11.2-32.5). Daily LDA usage was positively correlated with both predicted risk and women's concerns regarding preeclampsia. Most reported reasons for non- or incomplete use were unawareness of LDA as a preventive intervention, concerns about potential adverse effects and doubts regarding the benefits. CONCLUSIONS:Risk-based counseling was associated with a higher prevalence of LDA usage, but general usage rates were low. Future research regarding potential factors improving the usage of LDA during pregnancy is necessary.
| S-EPMC7317843 | biostudies-literature