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Akankwasa P, Kakooza J, Katongole J, Namutosi E, Lewis C, Okurut E. Antiphospholipid syndrome in pregnancy: A comprehensive review. World J Rheumatol 2025; 12:103837. [DOI: 10.5499/wjr.v12.i2.103837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/17/2025] [Accepted: 01/23/2025] [Indexed: 02/18/2025] Open
Abstract
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by the presence of antiphospholipid antibodies and is associated with thrombotic events and pregnancy complications. The classification and management of APS has evolved over time. The classification criteria for APS include laboratory, macrovascular, microvascular, obstetric, cardiac, and hematologic domains. Management focuses on prevention of thrombotic events and/or anticoagulation as the primary treatment for thrombosis. Postpartum and long-term thromboprophylaxis after delivery are recommended to reduce the risk of thrombotic events. Despite these recommendations, optimal anticoagulation agents and intensity of treatment are still topics of debate. Further research is needed to understand the pathophysiology of APS and improve its management during pregnancy. In this review, we discuss the classification and pathophysiology of APS. Current treatment options and clinical trials are also discussed.
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Affiliation(s)
- Prosper Akankwasa
- Department of Obstetrics and Gynecology, Kampala International University Western Campus, Ishaka Bushenyi, Uganda
| | - Jackson Kakooza
- Department of Surgery, Kampala International University Western Campus, Ishaka Bushenyi, Uganda
| | - John Katongole
- Department of Obstetrics and Gynecology, Kampala International University Western Campus, Ishaka Bushenyi, Uganda
| | - Esther Namutosi
- Department of Obstetrics and Gynecology, Kampala International University Western Campus, Ishaka Bushenyi, Uganda
| | - Catherine Lewis
- Department of Surgery, St. Joseph's Kitovu Hospital, Masaka, Uganda
- Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States
| | - Emmanuel Okurut
- Department of Obstetrics and Gynecology, Kampala International University Western Campus, Ishaka Bushenyi, Uganda
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Pantho AF, Mohamed S, Govande JV, Rane R, Vora N, Kelso KR, Kuehl TJ, Lindheim SR, Uddin MN. Pravastatin Protects Cytotrophoblasts from Hyperglycemia-Induced Preeclampsia Phenotype. Cells 2024; 13:1534. [PMID: 39329718 PMCID: PMC11430553 DOI: 10.3390/cells13181534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/07/2024] [Accepted: 09/10/2024] [Indexed: 09/28/2024] Open
Abstract
There are no effective therapies to prevent preeclampsia (PE). Pravastatin shows promise by attenuating processes associated with PE such as decreased cytotrophoblast (CTB) migration, aberrant angiogenesis, and increased oxidative stress. This study assesses the effects of pravastatin on hyperglycemia-induced CTB dysfunction. METHODS Human CTB cells were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48 h. Some cells were pretreated with pravastatin (1 µg/mL), while others were cotreated with pravastatin and glucose. The expression of urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) mRNA, vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng) were measured. CTB migration was assayed using a CytoSelect migration assay kit. Statistical comparisons were performed using an analysis of variance with Duncan's post hoc test. RESULTS The hyperglycemia-induced downregulation of uPA was attenuated in CTB cells pretreated with pravastatin at glucose levels > 200 mg/dL and cotreated at glucose levels > 300 mg/dL (p < 0.05). Hyperglycemia-induced decreases in VEGF and PlGF and increases in sEng and sFlt-1 were attenuated in both the pretreatment and cotreatment samples regardless of glucose dose (p < 0.05). Pravastatin attenuated hyperglycemia-induced dysfunction of CTB migration. CONCLUSIONS Pravastatin mitigates stress signaling responses in hyperglycemic conditions, weakening processes leading to abnormal CTB migration and invasion associated with PE in pregnancy.
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Affiliation(s)
- Ahmed F. Pantho
- Artemis Biotechnologies LLC, Temple, TX 76504, USA; (A.F.P.); (T.J.K.)
| | - Sara Mohamed
- Baylor Scott & White Health, Temple, TX 76508, USA; (S.M.); (N.V.); (K.R.K.); (S.R.L.)
| | | | - Riddhi Rane
- Texas A&M University College of Medicine, College Station, TX 77807, USA;
| | - Niraj Vora
- Baylor Scott & White Health, Temple, TX 76508, USA; (S.M.); (N.V.); (K.R.K.); (S.R.L.)
| | - Kelsey R. Kelso
- Baylor Scott & White Health, Temple, TX 76508, USA; (S.M.); (N.V.); (K.R.K.); (S.R.L.)
| | - Thomas J. Kuehl
- Artemis Biotechnologies LLC, Temple, TX 76504, USA; (A.F.P.); (T.J.K.)
| | - Steven R. Lindheim
- Baylor Scott & White Health, Temple, TX 76508, USA; (S.M.); (N.V.); (K.R.K.); (S.R.L.)
| | - Mohammad N. Uddin
- Artemis Biotechnologies LLC, Temple, TX 76504, USA; (A.F.P.); (T.J.K.)
- Baylor Scott & White Health, Temple, TX 76508, USA; (S.M.); (N.V.); (K.R.K.); (S.R.L.)
- Texas A&M University College of Medicine, College Station, TX 77807, USA;
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Formisano E, Proietti E, Perrone G, Demarco V, Galoppi P, Stefanutti C, Pisciotta L. Characteristics, Physiopathology and Management of Dyslipidemias in Pregnancy: A Narrative Review. Nutrients 2024; 16:2927. [PMID: 39275243 PMCID: PMC11397408 DOI: 10.3390/nu16172927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/28/2024] [Accepted: 08/30/2024] [Indexed: 09/16/2024] Open
Abstract
Dyslipidemia is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). During pregnancy, physiological changes elevate cholesterol and triglyceride levels to support fetal development, which can exacerbate pre-existing conditions and lead to complications such as pre-eclampsia, gestational diabetes, and increased ASCVD risk for both mother and child. Effective management strategies are necessary, especially for pregnant women with inherited forms of dyslipidemia (i.e., familial hypertriglyceridemia, hyperchylomicronemia), where personalized dietary adjustments are crucial for successful pregnancy outcomes. Pharmacological interventions and lipoprotein apheresis may be necessary for severe cases, though their use is often limited by factors such as cost, availability, and potential fetal risks. Despite the promise of advanced therapies, their widespread application remains constrained by limited studies and high costs. Thus, a personalized, multidisciplinary approach is essential for optimizing outcomes. This review provides a comprehensive overview of current strategies and evidence-based practices for managing dyslipidemia during pregnancy, emphasizing the balance of maternal and fetal health. Additionally, it discusses the physiological changes in lipid metabolism during pregnancy and their implications, particularly for women with inherited forms of dyslipidemia.
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Affiliation(s)
- Elena Formisano
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
- Dietetics and Clinical Nutrition Unit, IRCCS Policlinic Hospital San Martino, 16132 Genoa, Italy
| | - Elisa Proietti
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
| | - Giuseppina Perrone
- Department of Maternal and Child Health and Urological Sciences, Umberto I Hospital, "Sapienza" University of Rome, 00161 Rome, Italy
| | - Valentina Demarco
- Department of Maternal and Child Health and Urological Sciences, Umberto I Hospital, "Sapienza" University of Rome, 00161 Rome, Italy
| | - Paola Galoppi
- Department of Maternal and Child Health and Urological Sciences, Umberto I Hospital, "Sapienza" University of Rome, 00161 Rome, Italy
| | - Claudia Stefanutti
- Department of Molecular Medicine, Extracorporeal Therapeutic Techniques Unit, Lipid Clinic and Atherosclerosis Prevention Centre, Regional Centre for Rare Diseases, Immunohematology and Transfusion Medicine, Umberto I Hospital, "Sapienza" University of Rome, 00161 Rome, Italy
| | - Livia Pisciotta
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
- Dietetics and Clinical Nutrition Unit, IRCCS Policlinic Hospital San Martino, 16132 Genoa, Italy
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Zhao Y, Yang HZ, Li H, Liang S, Wang M, Li CD, Zhuo D, Fan F, Guo M, Lv X, Zhang L, Chen X, Li SS, Jin X. Early statin exposure influences cardiac and skeletal development with implications for ion channel transcriptomes in zebrafish. Comp Biochem Physiol C Toxicol Pharmacol 2024; 280:109905. [PMID: 38522713 DOI: 10.1016/j.cbpc.2024.109905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/26/2024] [Accepted: 03/21/2024] [Indexed: 03/26/2024]
Abstract
Statins, widely prescribed for cholesterol management by inhibiting HMG-CoA reductase in the cholesterol biosynthesis pathway, may also influence vertebrate development. In this study, we investigated the developmental effects of two widely used statins, atorvastatin (ATO) and pravastatin (PRA), on zebrafish offspring. For ATO, we administered doses classified as low (1 μM), medium (5 μM), and high (10 μM), while for PRA, the corresponding concentrations were set at low (18 μM), medium (180 μM), and high (270 μM). Our results showed significant reductions in birth and hatching rates, along with decreased body length in offspring at all ATO concentrations and medium to high PRA concentrations. A notable increase in malformation rates, especially in the spine and heart, was observed across all ATO treatments and in medium and high PRA groups. Additionally, we observed reduced heart contraction rates, decreased heart size, lower bone volumes, and diminished expression of mRNA osteogenic markers. Elevated venous sinus-artery bulb (SV-BA) ratios, increased thoracic area, and abnormal cartilage development were also prominent in all ATO-treated groups. Transcriptome analysis revealed alterations in genes predominantly associated with ion channels. These findings provide insights into the potential impacts of specific concentrations of statins on offspring development and highlight potential gene interactions with statins.
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Affiliation(s)
- Ying Zhao
- School of Medicine, Nankai University, Tianjin, China
| | | | - Huinan Li
- Department of Spinal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Shuang Liang
- Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China
| | - Meng Wang
- Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China
| | - Chun-Di Li
- Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China
| | - Donghai Zhuo
- School of Medicine, Nankai University, Tianjin, China
| | - Feifei Fan
- School of Medicine, Nankai University, Tianjin, China
| | - Miao Guo
- School of Medicine, Nankai University, Tianjin, China
| | - Xinxin Lv
- School of Medicine, Nankai University, Tianjin, China
| | - Lingzhu Zhang
- School of Medicine, Nankai University, Tianjin, China
| | - Xu Chen
- School of Medicine, Nankai University, Tianjin, China; Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China; Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China.
| | - Shan-Shan Li
- School of Medicine, Nankai University, Tianjin, China.
| | - Xin Jin
- School of Medicine, Nankai University, Tianjin, China; Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China; Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin, China.
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Wang R, Zhao J, Li L, Huo Y. Associations between lipid-lowering drugs and pregnancy and perinatal outcomes: a Mendelian randomization study. J Hypertens 2024; 42:727-734. [PMID: 38230624 DOI: 10.1097/hjh.0000000000003664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
INTRODUCTION Mounting evidence has indicated that maternal dyslipidemia is associated with adverse obstetric outcomes, and the actions of lipid-lowering drugs in pregnant women remain controversial. Hence, this study aimed to appraise the causal relationship of lipid-lowering drugs [hydroxymethylglutaryl-coenzyme reductase (HMGCR) inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors] with pregnancy and perinatal outcomes using drug-targeting Mendelian randomization analysis. METHODS As a proxy for lipid-lowering drug exposure, two genetic instruments were used: genetic variants within or near the gene linked to low-density lipoprotein cholesterol (LDL-C) and the expression of quantitative trait loci of the drug target gene. Effect estimates were calculated using the inverse variance weighting (IVW) method and summary data-based Mendelian randomization (SMR) method. Heterogeneity and pleiotropy were assessed by Mendelian randomization-Egger regression, the Cochran Q test, and MR-PRESSO analysis. RESULTS HMGCR inhibitors were ascribed to a reduced risk of preeclampsia in both the IVW-MR method [odds ratio (OR) 0.583; 95% confidence interval (CI) 0.418-0.812; P = 0.001] and SMR analysis (OR 0.816; 95% CI 0.675-0.986; P = 0.036). The causal link between HMGCR inhibitors and offspring birthweight was statistically significant only in the analysis using the IVW method (OR, 0.879; 95% CI, 0.788-0.980; P = 0.020), and the combined results of the OR values supported the potential inhibitory effect of HMGCR inhibitors on offspring birthweight. Causal associations between lipid-lowering drugs and gestational diabetes, preterm birth, and congenital anomalies were not detected in either analysis. CONCLUSION No causal associations were observed between lipid-lowering drugs and gestational diabetes, preterm birth or congenital anomalies, whereas genetically predicted HMGCR inhibition dramatically reduced the risk of preeclampsia but attenuated offspring birthweight.
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Affiliation(s)
- Runfang Wang
- Department of Obstetrics and Gynecology, Hebei General Hospital, Hebei, China
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Brownfoot F, Rolnik DL. Prevention of preeclampsia. Best Pract Res Clin Obstet Gynaecol 2024; 93:102481. [PMID: 38373378 DOI: 10.1016/j.bpobgyn.2024.102481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/19/2023] [Accepted: 02/05/2024] [Indexed: 02/21/2024]
Abstract
Preeclampsia is a relatively common pregnancy complication and constitutes a major cause of morbidity and mortality for mothers and children worldwide. It disproportionally affects low-resource countries. Appropriate identification of individuals at increased risk and prevention of the disease and its complications remain healthcare and research priorities, and the investigation of potential interventions to prevent preeclampsia has driven much of the obstetric research in recent decades. In this article, we review the scientific literature on the topic, highlighting established benefits and remaining questions regarding different non-pharmacological and pharmacological strategies, including exercise, the timing of birth, aspirin and calcium use, among others, as well as potential novel therapies under investigation.
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Affiliation(s)
- Fiona Brownfoot
- Mercy Hospital for Women, Heidelberg, Victoria, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
| | - Daniel Lorber Rolnik
- Women's and Newborn, Monash Health, Clayton, Victoria, Australia; Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
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Bank TC, Kline D, Costantine MM. Challenges in Conducting Clinical Trials for Preeclampsia. Curr Hypertens Rep 2024; 26:59-68. [PMID: 37971596 DOI: 10.1007/s11906-023-01276-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2023] [Indexed: 11/19/2023]
Abstract
PURPOSE OF REVIEW To review recent data describing the challenges and innovations in therapeutic research focused on the prevention and treatment of preeclampsia. RECENT FINDINGS Pregnant individuals have traditionally been excluded from therapeutic research, resulting in a paucity of innovation in therapeutics for pregnancy-specific medical conditions, especially preeclampsia. With the increased awareness of maternal morbidity and mortality, there is significant interest among researchers to expand therapeutic research in pregnancy. Several medications, including aspirin, pravastatin, metformin, and esomeprazole, which are commonly used in non-pregnant populations, are now being investigated for preeclampsia prevention. However, given the historic precedent of exclusion, along with the regulatory, ethical, and feasibility concerns that accompany this population, the study of these and novel medications has been complicated by numerous challenges. While complex, and laden with challenges, there is great ongoing need for therapeutic research to address preeclampsia. Aspirin, pravastatin, metformin, and esomeprazole have all shown promise as potential therapeutic agents; however, their use remains to be optimized, and innovative therapeutics need to be developed.
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Affiliation(s)
- T Caroline Bank
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Diana Kline
- The Ohio State University College of Medicine, Columbus, OH, USA
| | - Maged M Costantine
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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Costantine MM, Clifton RG, Boekhoudt TM, Lawrence K, Gyamfi-Bannerman C, Wisner KL, Grobman W, Caritis SN, Simhan HN, Hebert MF, Longo M, Saade GR. Long-term neurodevelopmental follow-up of children exposed to pravastatin in utero. Am J Obstet Gynecol 2023; 229:153.e1-153.e12. [PMID: 36842489 PMCID: PMC10440254 DOI: 10.1016/j.ajog.2023.02.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 02/16/2023] [Accepted: 02/16/2023] [Indexed: 02/28/2023]
Abstract
BACKGROUND Preeclampsia, especially before term, increases the risk of child neurodevelopmental adverse outcomes. Biological plausibility, preclinical studies, and pilot clinical trials conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Obstetric-Fetal Pharmacology Research Centers Network support the safety and use of pravastatin to prevent preeclampsia. OBJECTIVE This study aimed to determine the effect of antenatal pravastatin treatment in high-risk pregnant individuals on their child's health, growth, and neurodevelopment. STUDY DESIGN This was an ancillary follow-up cohort study of children born to mothers who participated in the Obstetric-Fetal Pharmacology Research Centers Network pilot trials of pravastatin vs placebo in individuals at high risk of preeclampsia (ClinicalTrials.gov; identifier NCT01717586). After obtaining written informed consent (and assent as appropriate), the parent was instructed to complete the Child Behavior Checklist. To assess the child's motor, cognitive, and developmental outcomes, a certified and blinded study psychologist completed child motor, cognitive, emotional, and behavioral assessments using validated tools. Given the small number of individuals in the studies, the 10- and 20-mg pravastatin groups were combined into 1 group, and the results of the pravastatin group were compared with that of the placebo group. RESULTS Of 40 children born to mothers in the original trial, 30 (15 exposed in utero to pravastatin and 15 to placebo) were enrolled in this follow-up study. The time of follow-up, which was 4.7 years (interquartile range, 2.5-6.9), was not different between children in the pravastatin group and children in the placebo group. There was no difference in the child's body mass index percentiles per sex and corrected age, the rates of extremes of body mass index percentiles, or the report of any other medical or developmental complications between the 2 groups. No child born in the pravastatin group had any limitation in motor assessment compared with 2 children (13.3%) who walked with difficulty and 4 children (26.7%) who had reduced manual abilities in the placebo group. Moreover, children born to mothers who received pravastatin had a higher general mean conceptual ability score (98.2±16.7 vs 89.7±11.0; P=.13) and a lower frequency (15.4% vs 35.7%; P=.38) of having a score of <85 (ie, 1 standard deviation lower than the mean) compared with those in the placebo group. Finally, there was no difference in the parents' report on the Child Behavior Checklist between the 2 groups. CONCLUSION This study reported on the long-term neuromotor, cognitive, and behavioral outcomes among children exposed to pravastatin in utero during the second and third trimesters of pregnancy. Although the data were limited by the original trial's sample size, no identifiable long-term neurodevelopmental safety signal was evident with the use of pravastatin during pregnancy. This favorable neonatal risk-benefit analysis justifies continued research using pravastatin in clinical trials.
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Affiliation(s)
- Maged M Costantine
- Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH; Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX.
| | | | | | - Kirsten Lawrence
- Department of Obstetrics and Gynecology, Columbia University, New York, NY
| | | | - Katherine L Wisner
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL
| | - William Grobman
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL
| | - Steve N Caritis
- Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Hyagriv N Simhan
- Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Mary F Hebert
- Department of Pharmacy and Obstetrics and Gynecology, University of Washington, Seattle, WA
| | - Monica Longo
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD
| | - George R Saade
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
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Fruci S, Salvi S, Moresi S, Gallini F, Dell'Aquila M, Arena V, Di Stasio E, Ferrazzani S, De Carolis S, Lanzone A. Pravastatin for severe preeclampsia with growth restriction: Placental findings and infant follow-up. Eur J Obstet Gynecol Reprod Biol 2023; 283:37-42. [PMID: 36764034 DOI: 10.1016/j.ejogrb.2023.01.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 01/18/2023] [Accepted: 01/30/2023] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Preeclampsia (PE) is the major cause of maternal morbidity and mortality and the leading cause of premature delivery worldwide. As well as intrauterine growth restriction (IUGR), PE is associated with pathogenic evidence of placental malperfusion and ischemia. Recent literature has highlighted the potential of pravastatin in the prevention and treatment of these conditions. Aim of this study is to describe perinatal outcomes and placental histopathological findings in a small series of pregnant women with severe PE and IUGR treated with pravastatin on compassionate grounds. Two-year follow up of these babies is provided. STUDY DESIGN Between October 2017 and October 2019 in Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy, women with singleton pregnancy between 19.6 and 27.6 gestational weeks, who presented with severe PE and IUGR were counselled for a compassionate treatment with Pravastatin 40 mg a day. Treated women were compared with controls identified with similar data in terms of gestational age at diagnosis, clinical maternal data, Doppler severity findings. Neonates were followed up for two years. RESULTS The median time from diagnosis to delivery was 39 days (IQR 20) for women in the pravastatin group and 20 days (IQR 20.5) for controls. Looking to maternal blood exams, in the group of women treated with pravastatin, maximum transaminase, creatinine levels were lower than in controls, where the minimum platelet count was higher. Placenta examination did not reveal any significant differences in placental histopathological findings. No significant differences were observed in the investigated perinatal data, as well as in infant follow-up, although an increased prenatal weight gain was found in treated pregnancies in comparison to controls. CONCLUSIONS Our data did not allow us to find significant differences in pregnancy outcome and infant follow-up, as well as in placental histological picture in preeclamptic patients when pravastatin is administered in the late second trimester. However, we suggest its possible role in stabilizing the disease, increasing the prenatal weight gain and prolonging the duration of pregnancy, thus preventing the progression to a more severe maternal disease.
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Affiliation(s)
- Stefano Fruci
- UOC di Patologia Ostetrica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy
| | - Silvia Salvi
- UOC di Patologia Ostetrica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy.
| | - Sascia Moresi
- UOC di Patologia Ostetrica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy
| | - Francesca Gallini
- UOC di Neonatologia, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy; Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Marco Dell'Aquila
- Area of Pathology, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy
| | - Vincenzo Arena
- Area of Pathology and UOS Coordinamento attività di settorato, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy
| | - Enrico Di Stasio
- Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; Dipartimento di scienze laboratoristiche ed infettivologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy
| | - Sergio Ferrazzani
- UOC di Patologia Ostetrica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy; Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Sara De Carolis
- UOC di Patologia Ostetrica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy; Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy.
| | - Antonio Lanzone
- UOC di Patologia Ostetrica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy.
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Al-Ashwal FY, Sulaiman SAS, Sheikh Ghadzi SM, Kubas MA, Halboup A. Physicians and pharmacists' clinical knowledge of statin therapy and monitoring parameters, and the barriers to guideline implementation in clinical practice. PLoS One 2023; 18:e0280432. [PMID: 36662695 PMCID: PMC9858478 DOI: 10.1371/journal.pone.0280432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 01/01/2023] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Millions of individuals worldwide use statins, and their significant impact on cardiovascular disease (CVD) has been well-established. However, a lack of knowledge about the up-to-date guideline recommendations regarding statin therapy is a common barrier to implementation in clinical practice. Therefore, the present study aimed to assess the current clinical knowledge about statin therapy and its monitoring parameters. Also, we evaluated the barriers to cholesterol management guideline implementation in Yemen. METHODS This observational cross-sectional study was conducted over four months, from June/2021 to September/2021, in Sana'a, Yemen. A validated questionnaire was distributed face-to-face to 650 participants (350 physicians and 300 pharmacists). Physicians and pharmacists from governmental and private hospitals and those working in private clinics or community pharmacies were included in the study. RESULTS A total of 496 participants filled out the survey, with 22 being excluded due to incomplete data. So, the study has an overall response rate of 72.9% (474). The majority of pharmacists (81.8%) and physicians (78.7%) could not identify the patient group that needed ASCVD risk assessment before statin therapy initiation. Although a significant proportion of respondents knew of the fact that high-intensity statins are recommended for patients with ASCVD (65.4%) and primary hypercholesterolemia (58.4%), the majority of physicians and pharmacists could not identify the high (61.6% and 66.7.3%, respectively) and moderate statin-intensity doses (72.2% and 68.6%, respectively). Only 21.9% of all respondents knew that atorvastatin and rosuvastatin can be administered at any time of the day. Similarly, a low overall rate of respondents (19.6%) knew that atorvastatin does not need dose adjustment in chronic kidney diseases, with a statistically significant difference in knowledge between physicians and pharmacists (12.5% vs. 25.6%, p <0.001, respectively). Notably, only 39.2% of participants were aware that statins are not safe to use during breastfeeding. Around half of respondents (52.3%) correctly identify the duration (4 to 12 weeks) at which LD-C measuring is recommended after therapy initiation or dose change. The lowest knowledge scores for respondents were related to statin-drug interactions. Age, experience, degree, and previous guideline exposure were all significantly associated with the knowledge scores (p <0.05). The four most perceived barriers to implementing cholesterol management guidelines were no audit on adherence to the guidelines in the workplace (73.4%), insufficient resources to adequately implement and follow up on the guideline's recommendations (73.6%), patient's financial status (75.7%), and lack of familiarity about the guideline's latest recommendations (63.3%). CONCLUSION Physicians and pharmacists had suboptimal clinical knowledge regarding statin therapy, dose intensities, drug-drug interaction, contraindications, and monitoring parameters. Therefore, physicians' and pharmacists' educational interventions regarding the up-to-date recommendation about statins are recommended.
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Affiliation(s)
- Fahmi Y. Al-Ashwal
- Discipline of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, University of Science and Technology, Sana’a, Yemen
| | - Syed Azhar Syed Sulaiman
- Discipline of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia
| | | | - Mohammed Abdullah Kubas
- Clinical Pharmacy Department, University of Science and Technology Hospital (USTH), Sana’a, Yemen
- School of Pharmacy & Medical Sciences, Lebanese International University (LIU), Sana’a, Yemen
| | - Abdulsalam Halboup
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, University of Science and Technology, Sana’a, Yemen
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11
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Hirsch A, Rotem R, Ternovsky N, Hirsh Raccah B. Pravastatin and placental insufficiency associated disorders: A systematic review and meta-analysis. Front Pharmacol 2022; 13:1021548. [PMID: 36438820 PMCID: PMC9682185 DOI: 10.3389/fphar.2022.1021548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 10/19/2022] [Indexed: 11/10/2022] Open
Abstract
Background: Uteroplacental insufficiency associated disorders, such as preeclampsia, fetal growth restriction and obstetrical antiphospholipid syndrome, share pathophysiology and risk factors with cardiovascular diseases treated with statins. Objective: To evaluate pregnancy outcomes among women with uteroplacental insufficiency disorders who were treated with statins. Search Strategy: Electronic databases were searched from inception to January 2022 Selection Criteria: Cohort studies and randomized controlled trials. Data collection and analysis: Pooled odds ratios were calculated using a random-effects model; meta-regression was utilized when applicable. Main Results: The analysis included ten studies describing 1,391 women with uteroplacental insufficiency disorders: 703 treated with pravastatin and 688 not treated with statins. Women treated with pravastatin demonstrated significant prolongation of pregnancy (mean difference 0.44 weeks, 95%CI:0.01-0.87, p = 0.04, I2 = 96%) and less neonatal intensive care unit admissions (OR = 0.42, 95%CI: 0.23-0.75, p = 0.004, I2 = 25%). In subgroup analysis, prolongation of pregnancy from study entry to delivery was statistically significant in cohort studies (mean difference 8.93 weeks, 95%CI:4.22-13.95, p = 0.00) but not in randomized control studies. Trends were observed toward a decrease in preeclampsia diagnoses (OR = 0.54, 95%CI:0.27-1.09, p = 0.09, I = 44%), perinatal death (OR = 0.32, 95%CI:0.09-1.13, p = 0.08, I2 = 54%) and an increase in birth weight (mean difference = 102 g, 95%CI: -14-212, p = 0.08, I2 = 96%). A meta-regression analysis demonstrated an association between earlier gestational age at initiation of treatment and a lower risk of preeclampsia development (R2 = 1). Conclusion: Pravastatin treatment prolonged pregnancy duration and improved associated obstetrical outcomes in pregnancies complicated with uteroplacental insufficiency disorders in cohort studies. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/ identifier CRD42020165804 17/2/2020.
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Affiliation(s)
- Ayala Hirsch
- Department of Obstetrics & Gynecology, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Reut Rotem
- Department of Obstetrics & Gynecology, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Natali Ternovsky
- Division of Clinical Pharmacy, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Bruria Hirsh Raccah
- Division of Clinical Pharmacy, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- Department of Cardiology, Hadassah University Hospital, Jerusalem, Israel
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12
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Considerations for treatment of lipid disorders during pregnancy and breastfeeding. Prog Cardiovasc Dis 2022; 75:33-39. [PMID: 36400231 DOI: 10.1016/j.pcad.2022.11.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 11/06/2022] [Indexed: 11/17/2022]
Abstract
Adequate management of lipid disorders during pregnancy is essential given the association of dyslipidemia with adverse pregnancy outcomes. While there are physiologic changes in lipid levels that occur with normal pregnancy, abnormal alterations in lipids can lead to increased future risk of atherosclerotic cardiovascular disease. There are inherent challenges in the treatment of dyslipidemias during pregnancy and the postpartum period given the lack of adequate data in this population and the contraindication of traditional therapeutic agents. However, it remains of utmost importance to optimize screening and identification of patients at high-risk for atherosclerotic cardiovascular disease so that proper counseling can be provided and the risk for pregnancy complications and downstream cardiovascular complications can be addressed. In this review, we summarize the literature on the association of dyslipidemia in pregnancy with adverse outcomes and discuss considerations for the management of lipid disorders during both pregnancy and breastfeeding.
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13
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Hirsch A, Ternovsky N, Zwas DR, Rotem R, Amir O, Hirsh Raccah B. The effect of statins exposure during pregnancy on congenital anomalies and spontaneous abortions: A systematic review and meta-analysis. Front Pharmacol 2022; 13:1003060. [PMID: 36249743 PMCID: PMC9558136 DOI: 10.3389/fphar.2022.1003060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 08/31/2022] [Indexed: 12/02/2022] Open
Abstract
Objective: To assess the effect of statin exposure during pregnancy on congenital anomalies and spontaneous abortions. Data sources: Electronic databases were searched from inception to January 2022. Study Eligibility Criteria: Cohort studies and randomized controlled trials (RCTs) evaluate the effect of treatment with statins on congenital anomalies in general and cardiac malformations in particular. Studies evaluating spontaneous abortions were included as a secondary outcome. Study appraisal and synthesis methods: Pooled odds ratio was calculated using a random-effects model and meta-regression was utilized when applicable. Results: Twelve cohort studies and RCTs were included in the analysis. Pregnancy outcomes of 2,447 women that received statins during pregnancy were compared to 897,280 pregnant women who did not. Treatment with statins was not associated with a higher risk of overall congenital anomalies (Odd Ratio = 1.1, CI (0.9–1.3), p = 0.33, I2 = 0%). Yet, cardiac malformations were more prevalent among neonates born to statins users (OR = 1.4, CI (1.1–1.8), p = 0.02, I2 = 0%). The risk was higher when exposure occurred during the first trimester. This finding was statistically significant in cohort studies, but not in RCTs. Statin treatment was also associated with a higher rate of spontaneous abortions (OR = 1.5, CI (1.1–2.0), p = 0.005, I2 = 0%). In meta-regression analysis, no significant association between lipophilic statins and the rate of congenital anomalies was found. Conclusion: Overall, treatment with statins during pregnancy was not associated with an increased risk of congenital anomalies. A slight risk elevation for cardiac malformation and spontaneous abortions was seen in cohort studies but not in RCTs. Systematic Review Registration:clinicaltrials.gov, identifier [CRD42020165804 17/2/2020] The meta-analysis was presented online at 42nd annual meeting of SMFM. January 31-5 February 2022.
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Affiliation(s)
- Ayala Hirsch
- Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Natali Ternovsky
- Division of Clinical Pharmacy, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Donna R. Zwas
- Linda Joy Pollin Cardiovascular Wellness Center for Women, Department of Cardiology, Hadassah University Hospital, Jerusalem, Israel
- Department of Cardiology, Hadassah University Hospital, Jerusalem, Israel
| | - Reut Rotem
- Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Offer Amir
- Department of Cardiology, Hadassah University Hospital, Jerusalem, Israel
| | - Bruria Hirsh Raccah
- Division of Clinical Pharmacy, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- Department of Cardiology, Hadassah University Hospital, Jerusalem, Israel
- *Correspondence: Bruria Hirsh Raccah,
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14
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Affiliation(s)
- Marcio Sommer Bittencourt
- Division of Cardiology, Department of Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh - EUA
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15
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Pham A, Polic A, Nguyen L, Thompson JL. Statins in Pregnancy: Can We Justify Early Treatment of Reproductive Aged Women? Curr Atheroscler Rep 2022; 24:663-670. [PMID: 35699821 DOI: 10.1007/s11883-022-01039-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2022] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW Statins are the pillar of secondary prevention in reducing cardiovascular disease in high-risk adults. However, statin discontinuation is the standard recommendation in pregnant and lactating patients. This review evaluates whether we can justify the early treatment of reproductive aged women with statin therapy. RECENT FINDINGS Statins have several potential benefits including its antioxidant, anti-inflammatory, and anti-thrombogenic properties that may prevent the worsening of atherosclerosis in high-risk women. Nevertheless, most studies on statins and teratogenicity have a limited sample size and the effects of long-term statin use on fetal and neonatal health remain unknown. Not all statins may be safe and pravastatin's cholesterol-lowering properties may be too limited to provide much maternal benefit in pregnancy. While emerging evidence supports the use of pravastatin in pregnancy, we need to better assess the risk of early cardiovascular disease and acute progression of atherosclerosis before and during pregnancy to better understand the risks and benefits of statin use.
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Affiliation(s)
- Amelie Pham
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Medical Center North, 1161 21stAvenue, South B-1100, Nashville, TN, 37212, USA
| | - Aleksandra Polic
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Medical Center North, 1161 21stAvenue, South B-1100, Nashville, TN, 37212, USA
| | - Lynsa Nguyen
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Medical Center North, 1161 21stAvenue, South B-1100, Nashville, TN, 37212, USA
| | - Jennifer L Thompson
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Medical Center North, 1161 21stAvenue, South B-1100, Nashville, TN, 37212, USA.
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16
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Karadas B, Uysal N, Erol H, Acar S, Koc M, Kaya-Temiz T, Koren G, Kaplan YC. Pregnancy outcomes following maternal exposure to statins: A systematic review and meta-analysis. Br J Clin Pharmacol 2022; 88:3962-3976. [PMID: 35639354 DOI: 10.1111/bcp.15423] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 05/13/2022] [Accepted: 05/21/2022] [Indexed: 11/29/2022] Open
Abstract
AIM The objective of this meta-analysis was to determine whether maternal exposure to statins is associated with increased rates of major congenital malformations and other adverse pregnancy outcomes. METHODS Pubmed/Medline, Web of Science and Reprotox® databases were searched. Observational cohort and case control studies with prenatal exposure to statins were included. RESULTS Analysis of five cohort studies and one case-control study showed no significant increase in rate of major congenital malformations when exposed group was compared with control ([OR, 1.27; 95% CI 0.80-2.04], [aOR, 1.05; 95% CI 0.84-1.31],). A significant increase in heart defect risk was detected in the statin-exposed group when unadjusted ORs were combined (OR, 2.47; 95% CI 1.36-4.49). Further analysis of the same outcome by using adjusted ORs showed no significant increase in heart defect risk in statin exposed group vs controls (aOR, 1.24; 95% CI 0.93-1.66). A significantly lower live birth rate (OR 0.60, 95% CI 0.49-0.75) and a higher spontaneous abortion rate (OR, 1.36; 95% Cl 1.06-1.75) were detected in the statin-exposed group. CONCLUSIONS Gestational statin exposure was not associated with a significant increase in risk of major congenital malformations, heart defects and other adverse pregnancy outcomes, except spontaneous abortion and live birth rate, which may be associated with maternal comorbidity and other unadjusted risk factors. Further research focusing on particular statins is needed to draw more definitive conclusions.
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Affiliation(s)
- Baris Karadas
- Terafar - Izmir Katip Celebi University Teratology Information, Training and Research Center, Izmir, Turkey.,Department of Pharmacology Izmir, Izmir Katip Celebi University School of Medicine, Turkey
| | - Nusret Uysal
- Terafar - Izmir Katip Celebi University Teratology Information, Training and Research Center, Izmir, Turkey.,Department of Pharmacology Izmir, Izmir Katip Celebi University School of Medicine, Turkey
| | - Hilal Erol
- Department of Pharmacology Izmir, Izmir Ege University School of Medicine, Turkey
| | - Selin Acar
- Terafar - Izmir Katip Celebi University Teratology Information, Training and Research Center, Izmir, Turkey.,Department of Pharmacology Izmir, Izmir Katip Celebi University School of Medicine, Turkey
| | - Meltem Koc
- Department of Family Medicine Izmir, Izmir Katip Celebi University School of Medicine, Turkey
| | - Tijen Kaya-Temiz
- Terafar - Izmir Katip Celebi University Teratology Information, Training and Research Center, Izmir, Turkey.,Department of Pharmacology Izmir, Izmir Katip Celebi University School of Medicine, Turkey
| | - Gideon Koren
- Adelson School of Medicine, Ariel University, Israel.,Motherisk International Program, Shamir Hospital, Israel
| | - Yusuf C Kaplan
- Faculty of Medicine, Izmir University of Economics, Izmir, Turkey
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17
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Affiliation(s)
- Rina Mauricio
- Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
| | - Amit Khera
- Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
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18
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Smith DD, Costantine MM. The role of statins in the prevention of preeclampsia. Am J Obstet Gynecol 2022; 226:S1171-S1181. [PMID: 32818477 PMCID: PMC8237152 DOI: 10.1016/j.ajog.2020.08.040] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/26/2020] [Accepted: 08/14/2020] [Indexed: 02/03/2023]
Abstract
Preeclampsia is a common hypertensive disorder of pregnancy associated with considerable neonatal and maternal morbidities and mortalities. However, the exact cause of preeclampsia remains unknown; it is generally accepted that abnormal placentation resulting in the release of soluble antiangiogenic factors, coupled with increased oxidative stress and inflammation, leads to systemic endothelial dysfunction and the clinical manifestations of the disease. Statins have been found to correct similar pathophysiological pathways that underlie the development of preeclampsia. Pravastatin, specifically, has been reported in various preclinical and clinical studies to reverse the pregnancy-specific angiogenic imbalance associated with preeclampsia, to restore global endothelial health, and to prevent oxidative and inflammatory injury. Human studies have found a favorable safety profile for pravastatin, and more recent evidence does not support the previous teratogenic concerns surrounding statins in pregnancy. With reassuring and positive findings from pilot studies and strong biological plausibility, statins should be investigated in large clinical randomized-controlled trials for the prevention of preeclampsia.
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Affiliation(s)
- Devin D Smith
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH.
| | - Maged M Costantine
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH
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19
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Costantine MM, West H, Wisner KL, Caritis S, Clark S, Venkataramanan R, Stika CS, Rytting E, Wang X, Ahmed MS. A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia. Am J Obstet Gynecol 2021; 225:666.e1-666.e15. [PMID: 34033812 DOI: 10.1016/j.ajog.2021.05.018] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Preeclampsia 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. OBJECTIVE We 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 DESIGN This 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. RESULTS Of 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. CONCLUSION This 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.
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Affiliation(s)
- Maged M Costantine
- Department of Obstetrics and Gynecology, the Ohio State University, Columbus, OH; Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX.
| | - Holly West
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
| | - Katherine L Wisner
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL
| | - Steve Caritis
- Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Shannon Clark
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
| | - Raman Venkataramanan
- Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Catherine S Stika
- Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL
| | - Erik Rytting
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
| | - Xiaoming Wang
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
| | - Mahmoud S Ahmed
- Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
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20
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Management Considerations for Lipid Disorders During Pregnancy. CURRENT TREATMENT OPTIONS IN CARDIOVASCULAR MEDICINE 2021. [DOI: 10.1007/s11936-021-00926-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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21
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Natenzon A, Morris B, Schulman-Marcus J. An Update on Coronary Artery Disease in Pregnancy. CURRENT TREATMENT OPTIONS IN CARDIOVASCULAR MEDICINE 2021. [DOI: 10.1007/s11936-020-00893-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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22
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Mauri M, Calmarza P, Ibarretxe D. Dyslipemias and pregnancy, an update. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2020; 33:41-52. [PMID: 33309071 DOI: 10.1016/j.arteri.2020.10.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 09/25/2020] [Accepted: 10/05/2020] [Indexed: 12/12/2022]
Abstract
During pregnancy there is a physiological increase in total cholesterol (TC) and triglycerides (TG) plasma concentrations, due to increased insulin resistance, oestrogens, progesterone, and placental lactogen, although their reference values are not exactly known, TG levels can increase up to 300mg/dL, and TC can go as high as 350mg/dL. When the cholesterol concentration exceeds the 95th percentile (familial hypercholesterolaemia (FH) and transient maternal hypercholesterolaemia), there is a predisposition to oxidative stress in foetal vessels, exposing the newborn to a greater fatty streaks formation and a higher risk of atherosclerosis. However, the current treatment of pregnant women with hyperlipidaemia consists of a diet and suspension of lipid-lowering drugs. The most prevalent maternal hypertriglyceridaemia (HTG) is due to secondary causes, like diabetes, obesity, drugs, etc. The case of severe HTG due to genetic causes is less prevalent, and can be a higher risk of maternal-foetal complications, such as, acute pancreatitis (AP), pre-eclampsia, preterm labour, and gestational diabetes. Severe HTG-AP is a rare but potentially lethal pregnancy complication, for the mother and the foetus, usually occurs during the third trimester or in the immediate postpartum period, and there are no specific protocols for its diagnosis and treatment. In conclusion, it is crucial that dyslipidaemia during pregnancy must be carefully evaluated, not just because of the acute complications, but also because of the future cardiovascular morbidity and mortality of the newborn child. That is why the establishment of consensus protocols or guidelines is essential for its management.
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Affiliation(s)
- Marta Mauri
- Unidad de Lípidos, Servicio de Medicina Interna, Hospital de Terrassa, Consorci Sanitari de Terrassa, Terrassa, Barcelona, España
| | - Pilar Calmarza
- Servicio de Bioquímica Clínica, Hospital Universitario Miguel Servet, Universidad de Zaragoza, Zaragoza, España.
| | - Daiana Ibarretxe
- Unidad de Medicina Vascular y Metabolismo (UVASMET), Hospital Universitario de Reus, Universidad Rovira y Virgili, IISPV, CIBERDEM, Reus, Tarragona, España
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23
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Itani N, Skeffington KL, Beck C, Niu Y, Katzilieris‐Petras G, Smith N, Giussani DA. Protective effects of pravastatin on the embryonic cardiovascular system during hypoxic development. FASEB J 2020; 34:16504-16515. [DOI: 10.1096/fj.202001743r] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/30/2020] [Accepted: 10/07/2020] [Indexed: 01/23/2023]
Affiliation(s)
- Nozomi Itani
- Department of Physiology, Development & Neuroscience University of Cambridge Cambridge UK
| | - Katie L. Skeffington
- Department of Physiology, Development & Neuroscience University of Cambridge Cambridge UK
| | - Christian Beck
- Department of Physiology, Development & Neuroscience University of Cambridge Cambridge UK
| | - Youguo Niu
- Department of Physiology, Development & Neuroscience University of Cambridge Cambridge UK
| | | | - Nicola Smith
- Department of Physiology, Development & Neuroscience University of Cambridge Cambridge UK
| | - Dino A. Giussani
- Department of Physiology, Development & Neuroscience University of Cambridge Cambridge UK
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Brener A, Lewnard I, Mackinnon J, Jones C, Lohr N, Konda S, McIntosh J, Kulinski J. Missed opportunities to prevent cardiovascular disease in women with prior preeclampsia. BMC Womens Health 2020; 20:217. [PMID: 32998727 PMCID: PMC7528479 DOI: 10.1186/s12905-020-01074-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 09/14/2020] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Cardiovascular disease (CVD) is the leading cause of death in women in every major developed country and in most emerging nations. Complications of pregnancy, including preeclampsia, indicate a subsequent increase in cardiovascular risk. There may be a primary care provider knowledge gap regarding preeclampsia as a risk factor for CVD. The objective of our study is to determine how often internists at an academic institution inquire about a history of preeclampsia, as compared to a history of smoking, hypertension and diabetes, when assessing CVD risk factors at well-woman visits. Additional aims were (1) to educate internal medicine primary care providers on the significance of preeclampsia as a risk factor for CVD disease and (2) to assess the impact of education interventions on obstetric history documentation and screening for CVD in women with prior preeclampsia. METHODS A retrospective chart review was performed to identify women ages 18-48 with at least one prior obstetric delivery. We evaluated the frequency of documentation of preeclampsia compared to traditional risk factors for CVD (smoking, diabetes, and chronic hypertension) by reviewing the well-woman visit notes, past medical history, obstetric history, and the problem list in the electronic medical record. For intervention, educational teaching sessions (presentation with Q&A session) and education slide presentations were given to internal medicine physicians at clinic sites. Changes in documentation were evaluated post-intervention. RESULTS When assessment of relevant pregnancy history was obtained, 23.6% of women were asked about a history preeclampsia while 98.9% were asked about diabetes or smoking and 100% were asked about chronic hypertension (p < 0.001). Education interventions did not significantly change rates of screening documentation (p = 0.36). CONCLUSION Our study adds to the growing body of literature that women with a history of preeclampsia might not be identified as having increased CVD risk in the outpatient primary care setting. Novel educational programming may be required to increase provider documentation of preeclampsia history in screening.
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Affiliation(s)
- Alina Brener
- Department of Internal Medicine, Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Irene Lewnard
- Department of Obstetrics and Gynecology, Lowell General Hospital, Lowell, MA, USA
| | - Jennifer Mackinnon
- Department of Internal Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Cresta Jones
- Department of Obstetrics, Gynecology and Women's Health, Division of Maternal-Fetal Medicine, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Nicole Lohr
- Department of Internal Medicine, Division of Cardiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Sreenivas Konda
- Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, IL, USA
| | - Jennifer McIntosh
- Department of Obstetrics, Gynecology and Women's Health, Division of Maternal Fetal Medicine, Milwaukee, WI, USA
| | - Jacquelyn Kulinski
- Department of Internal Medicine, Division of Cardiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
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Chowdhary S, Panigrahi P, Kumar R. Five-year experience of anorectal malformation with oesophageal atresia in tertiary care hospital. Afr J Paediatr Surg 2020; 17:49-53. [PMID: 33342833 PMCID: PMC8051628 DOI: 10.4103/ajps.ajps_54_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
AIM We had done this study for TEF with Anorectal malformation and TEF with no Anorectal malformation in terms of age, sex, surgical outcomes and mortality. MATERIALS AND METHODS This was a retrospective review of cases with clinical data (from April 2012 to April 2017). The participants of this study were 236 patients who had been diagnosed and managed for ARM. Among these patients, 25 patients associated with EA were selected as the subject patient group. RESULTS The incidence of tracheoesophageal fistula with ARM was 11.1%. The study has more male preponderance. All cases are of Type c except two cases of Type a. According to the classifications of ARMs, there were two cases with rectourethral fistula and eight cases with rectoperineal fistula and covered anus in the males. In females, there was a varied distribution of seven cases. There was one case (4%) presenting as a part of the Vertebral anorectal malformation cardiac tracheoesophageal renal and limb anomalies (VACTERL) association, which is the representative example of a complex anomaly. Most of the cases died due to cardiac problem and pneumonitis (due to delayed presentation). CONCLUSION The study concludes the experience of EA (±fistulae) with ARM, their distribution, incidence and outcome of the tertiary care centre.
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Affiliation(s)
- Sarita Chowdhary
- Department of Paediatric Surgery, IMS, BHU, Varanasi, Uttar Pradesh, India
| | - Pranay Panigrahi
- Department of Paediatric Surgery, IMS, BHU, Varanasi, Uttar Pradesh, India
| | - Rakesh Kumar
- Department of Paediatric Surgery, IMS, BHU, Varanasi, Uttar Pradesh, India
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McKiever M, Frey H, Costantine MM. Challenges in conducting clinical research studies in pregnant women. J Pharmacokinet Pharmacodyn 2020; 47:287-293. [PMID: 32306165 DOI: 10.1007/s10928-020-09687-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 04/09/2020] [Indexed: 12/30/2022]
Abstract
Maternal mortality and morbidity continue to rise in the United States. Despite these trends there are limited novel interventions to investigate and improve these metrics, partly due to research protocol limitations which restrict participation of pregnant women. Inclusion of pregnant women in research studies is integral to the process of obtaining important information regarding the safety and efficacy of therapeutics or interventions to improve maternal health and pregnancy outcomes. While significant changes in research practices have resulted in an increase of female participants, there remains a paucity of research trials directly targeting pregnant and lactating women. This article provides an overview of issues surrounding inclusion of pregnant or breastfeeding women in research studies, and includes historical perspectives, navigating concerns over safety profile, considerations for appropriate development, and future perspectives.
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Affiliation(s)
- Monique McKiever
- Division of Maternal Fetal Medicine, Department Obstetrics & Gynecology, The Ohio State University Wexner Medical Center, 395 W12th Avenue, Columbus, OH, 43210, USA
| | - Heather Frey
- Division of Maternal Fetal Medicine, Department Obstetrics & Gynecology, The Ohio State University Wexner Medical Center, 395 W12th Avenue, Columbus, OH, 43210, USA
| | - Maged M Costantine
- Division of Maternal Fetal Medicine, Department Obstetrics & Gynecology, The Ohio State University Wexner Medical Center, 395 W12th Avenue, Columbus, OH, 43210, USA.
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Ahmed A, Williams DJ, Cheed V, Middleton LJ, Ahmad S, Wang K, Vince AT, Hewett P, Spencer K, Khan KS, Daniels JP. Pravastatin for early-onset pre-eclampsia: a randomised, blinded, placebo-controlled trial. BJOG 2019; 127:478-488. [PMID: 31715077 PMCID: PMC7063986 DOI: 10.1111/1471-0528.16013] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/04/2019] [Indexed: 01/20/2023]
Abstract
Objective Women with pre‐eclampsia have elevated circulating levels of soluble fms‐like tyrosine kinase‐1 (sFlt‐1). Statins can reduce sFlt‐1 from cultured cells and improve pregnancy outcome in animals with a pre‐eclampsia‐like syndrome. We investigated the effect of pravastatin on plasma sFlt‐1 levels during pre‐eclampsia. Design Blinded (clinician and participant), proof of principle, placebo‐controlled trial. Setting Fifteen UK maternity units. Population We used a minimisation algorithm to assign 62 women with early‐onset pre‐eclampsia (24+0–31+6 weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth. Primary outcome Difference in mean plasma sFlt‐1 levels over the first 3 days following randomisation. Results The difference in the mean maternal plasma sFlt‐1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95% CI −1175 to 592; P = 0.5), and over days 1–14 was 48 pg/ml (95% CI −1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50–1.40; P = 0.6). The median time from randomisation to childbirth was 9 days (interquartile range [IQR] 5–14 days) for the pravastatin group and 7 days (IQR 4–11 days) for the placebo group. There were three perinatal deaths in the placebo‐treated group and no deaths or serious adverse events attributable to pravastatin. Conclusions We found no evidence that pravastatin lowered maternal plasma sFlt‐1 levels once early‐onset pre‐eclampsia had developed. Pravastatin appears to have no adverse perinatal effects. Tweetable abstract Pravastatin does not improve maternal plasma sFlt‐1 or placental growth factor levels following a diagnosis of early preterm pre‐eclampsia #clinicaltrial finds. Pravastatin does not improve maternal plasma sFlt‐1 or placental growth factor levels following a diagnosis of early preterm pre‐eclampsia #clinicaltrial finds.
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Affiliation(s)
- A Ahmed
- Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, UK.,King Fahad Centre for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - D J Williams
- UCL EGA Institute for Women's Health, University College London Hospitals NHS Foundation Trust, London, UK
| | - V Cheed
- Birmingham Clinical Trials Unit, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - L J Middleton
- Birmingham Clinical Trials Unit, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - S Ahmad
- Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, UK
| | - K Wang
- Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, UK
| | - A T Vince
- Birmingham Clinical Trials Unit, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - P Hewett
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - K Spencer
- Barking, Havering & Redbridge University Hospitals NHS Trust, Romford, UK
| | - K S Khan
- Queen Mary University of London, London, UK
| | - J P Daniels
- Nottingham Clinical Trials Unit, School of Medicine, University of Nottingham, Nottingham, UK
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Varghese T, Wenger NK. Non-ST elevation acute coronary syndrome in women and the elderly: recent updates and stones still left unturned. F1000Res 2018; 7:F1000 Faculty Rev-1865. [PMID: 30631426 PMCID: PMC6281006 DOI: 10.12688/f1000research.16492.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/19/2018] [Indexed: 12/17/2022] Open
Abstract
Despite the growing awareness of adverse events with acute coronary syndrome and vigilance to refine pharmacological and interventional therapies, the understanding of how these events present in and affect women and the elderly remains limited. Pathophysiological differences in these subgroups and under-representation in large trials create a medical gap in sex- and age-related outcomes and in our knowledge of how best to detect, diagnose, and treat acute coronary syndrome. This review provides a general overview of recent advances in non-ST elevation myocardial infarction management in women and the elderly and elucidates areas where further exploration is needed.
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Affiliation(s)
- Tina Varghese
- Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
| | - Nanette K. Wenger
- Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
- Emory Heart and Vascular Center, Emory Women's Heart Center, Atlanta, GA, USA
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Boyle AK, Rinaldi SF, Rossi AG, Saunders PTK, Norman JE. Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models. FASEB J 2018; 33:2743-2758. [PMID: 30312114 PMCID: PMC6338657 DOI: 10.1096/fj.201801104r] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Preterm birth (PTB), the leading cause of neonatal morbidity and mortality, urgently requires novel therapeutic agents. Spontaneous PTB, resulting from preterm labor, is commonly caused by intrauterine infection/inflammation. Statins are well-established, cholesterol-lowering drugs that can reduce inflammation and inhibit vascular smooth muscle contraction. We show that simvastatin reduced the incidence of PTB in a validated intrauterine LPS-induced PTB mouse model, decreased uterine proinflammatory mRNA concentrations (IL-6, Cxcl1, and Ccl2), and reduced serum IL-6 concentration. In human myometrial cells, simvastatin reduced proinflammatory mediator mRNA and protein expression (IL-6 and IL-8) and increased anti-inflammatory cytokine mRNA expression (IL-10 and IL-13). Critically, simvastatin inhibited myometrial cell contraction, basally and during inflammation, and reduced phosphorylated myosin light chain concentration. Supplementation with mevalonate and geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, abolished these anticontractile effects, indicating that the Rho/Rho-associated protein kinase pathway is critically involved. Thus, simvastatin reduces PTB incidence in mice, inhibits myometrial contractions, and exhibits key anti-inflammatory effects, providing a rationale for investigation into the repurposing of statins to treat preterm labor in women.—Boyle, A. K., Rinaldi, S. F., Rossi, A. G., Saunders, P. T. K., Norman, J. E. Repurposing simvastatin as a therapy for preterm labor: evidence from preclinical models.
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Affiliation(s)
- Ashley K Boyle
- Tommy's Centre for Maternal and Fetal Health, Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; and
| | - Sara F Rinaldi
- Tommy's Centre for Maternal and Fetal Health, Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; and
| | - Adriano G Rossi
- Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Philippa T K Saunders
- Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Jane E Norman
- Tommy's Centre for Maternal and Fetal Health, Medical Research Council (MRC) Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; and
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30
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Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: A retrospective review of 39 pregnancies. Atherosclerosis 2018; 277:502-507. [DOI: 10.1016/j.atherosclerosis.2018.05.038] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/06/2018] [Accepted: 05/22/2018] [Indexed: 11/22/2022]
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31
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Huai J, Yang Z, Yi YH, Wang GJ. Different Effects of Pravastatin on Preeclampsia-like Symptoms in Different Mouse Models. Chin Med J (Engl) 2018; 131:461-470. [PMID: 29451152 PMCID: PMC5830832 DOI: 10.4103/0366-6999.225058] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Pravastatin (Pra) exerts protective effects on preeclampsia. Preeclampsia is a multifactorial and pathogenic pathway syndrome. The present study compared the effects of Pra on clinical manifestations of preeclampsia in different pathogenic pathways. Methods Two different preeclampsia-like mouse models used in this study were generated with Nω-nitro-L-arginine methyl ester (L-NAME) and used lipopolysaccharide (LPS) from day 7 of gestation, respectively. Pra treatment was administered on day 2 after the models were established in each group (L-NAME + Pra, LPS + Pra, and Control + Pra, n = 8) or normal saline (NS) for the control group (L-NAME + NS, LPS + NS, and Control + NS, n = 8). Maternal weight, serum lipids, the histopathological changes, and lipid deposition in the liver and placenta were observed. The pregnancy outcomes were compared. The blood pressure analysis was carried out on repeated measurements of variance. Student's t-test was used for comparing the two groups. The enumeration data were compared by Chi-square test. Results The mean arterial pressure (MAP) and 24-h urinary protein in the L-NAME + NS and LPS + NS groups were significantly higher than the Control + NS group (F = 211.05 and 309.92 for MAP, t = 6.63 and 8.63 for 24-h urinary protein; all P < 0.05) and reduced in the L-NAME + Pra group as compared to the L-NAME + NS group (F = 208.60 for MAP, t = 6.77 for urinary protein; both P < 0.05). Urinary protein was decreased in the LPS + Pra group as compared to the LPS + NS group (t = 5.33; P < 0.05), whereas MAP had no statistical significance (F = 3.37; P > 0.05). Compared to the Control + NS group, the placental efficiency in the L-NAME + NS and LPS + NS groups decreased significantly (t = 3.09 and 2.89, respectively; both P < 0.05); however, no significant difference was observed in L-NAME + Pra and LPS + Pra groups (t = 1.37 and 0.58, respectively; both P > 0.05). Free fatty acid was elevated in the L-NAME + NS group as compared to the Control + NS group (t = 3.99; P < 0.05) at day 18 of pregnancy and decreased in the L-NAME + Pra group as compared to the L-NAME + NS group (t = 3.28; P < 0.05); however, no significant change was observed in the LPS model (F = 0.32; P > 0.05). Conclusion This study suggested that Pra affected the clinical manifestations differently in preeclampsia-like mouse models generated in various pathogenic pathways.
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Affiliation(s)
- Jing Huai
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China, china
| | - Zi Yang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China, china
| | - Yan-Hong Yi
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China, china
| | - Guang-Jiao Wang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China, china
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Taylor HS, Alderman Iii M, D'Hooghe TM, Fazleabas AT, Duleba AJ. Effect of simvastatin on baboon endometriosis. Biol Reprod 2018. [PMID: 28637327 DOI: 10.1093/biolre/iox058] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Endometriosis, a common disorder affecting women of reproductive age, is characterized by ectopic growth of the endometrial tissues, altered steroid hormone response, and inflammation. Previous studies revealed that statins, selective inhibitors of the key step of mevalonate pathway, inhibit growth of endometrial stromal cells in vitro and reduce endometriotic lesions in murine models of endometriosis. This study evaluated the effects of simvastatin on the development of endometriosis in a baboon model of this disease. Sixteen baboons were randomly assigned to the treatment group (simvastatin, 20 mg daily) or to the control group. Endometriotic lesions were evaluated by laparoscopy after 3 months. The volume of red, orange-red, and white endometriotic lesions was significantly reduced by 78% in animals treated with simvastatin. The expression of a marker of proliferation, proliferating cell nuclear antigen (PCNA), was significantly reduced in animals receiving simvastatin in red lesions, white lesions, black lesions, and in adhesions. Simvastatin was also associated with an increase in the expression of estrogen receptor alpha in red lesions, and a decrease in the expression of estrogen receptor beta in black lesions, in adhesions, and in eutopic endometrium. Furthermore, simvastatin significantly reduced the expression of neopterin, a marker of inflammation, oxidative stress, and immune system activation. Collectively, the present findings indicate that the inhibition of the mevalonate pathway by simvastatin reduces the risk of developing endometriosis in the primate model of this disease by decreasing the growth of endometrial lesions, by modulating the expression of genes encoding for estrogen receptors, and by reducing inflammation.
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Affiliation(s)
- Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Myles Alderman Iii
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Thomas M D'Hooghe
- Research Group Reproductive Medicine and Biology, Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium.,Division of Reproductive Health and Reproductive Biology, Institute of Primate Research, Karen, Nairobi, Kenya
| | - Asgerally T Fazleabas
- Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, Michigan, USA
| | - Antoni J Duleba
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA.,Division of Reproductive Endocrinology and Infertility, Department of Reproductive Medicine, University of California, San Diego, La Jolla, California, USA
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Carson RA, Rudine AC, Tally SJ, Franks AL, Frahm KA, Waldman JK, Silswal N, Burale S, Phan JV, Chandran UR, Monaghan AP, DeFranco DB. Statins impact primary embryonic mouse neural stem cell survival, cell death, and fate through distinct mechanisms. PLoS One 2018; 13:e0196387. [PMID: 29738536 PMCID: PMC5940229 DOI: 10.1371/journal.pone.0196387] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 04/12/2018] [Indexed: 12/11/2022] Open
Abstract
Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway (CBP), and are used for the prevention of cardiovascular disease. The anti-inflammatory effects of statins may also provide therapeutic benefits and have led to their use in clinical trials for preeclampsia, a pregnancy-associated inflammatory condition, despite their current classification as category X (i.e. contraindicated during pregnancy). In the developing neocortex, products of the CBP play essential roles in proliferation and differentiation of neural stem-progenitor cells (NSPCs). To understand how statins could impact the developing brain, we studied effects of pravastatin and simvastatin on primary embryonic NSPC survival, proliferation, global transcription, and cell fate in vitro. We found that statins dose dependently decrease NSPC expansion by promoting cell death and autophagy of NSPCs progressing through the G1 phase of the cell cycle. Genome-wide transcriptome analysis demonstrates an increase in expression of CBP genes following pravastatin treatment, through activation of the SREBP2 transcription factor. Co-treatment with farnesyl pyrophosphate (FPP), a CBP metabolite downstream of HMG-CoA reductase, reduces SREBP2 activation and pravastatin-induced PARP cleavage. Finally, pravastatin and simvastatin differentially alter NSPC cell fate and mRNA expression during differentiation, through a non-CBP dependent pathway.
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Affiliation(s)
- Ross A. Carson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Anthony C. Rudine
- Department of Pediatrics, Division of Newborn Medicine, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Serena J. Tally
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Alexis L. Franks
- Department of Pediatrics, Division of Child Neurology, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Krystle A. Frahm
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Jacob K. Waldman
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Neerupma Silswal
- Department of Biomedical Sciences, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, United States of America
| | - Suban Burale
- Department of Biomedical Sciences, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, United States of America
| | - James V. Phan
- Department of Biomedical Sciences, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, United States of America
| | - Uma R. Chandran
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - A. Paula Monaghan
- Department of Biomedical Sciences, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, United States of America
| | - Donald B. DeFranco
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
- * E-mail:
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Bioconversion of mevastatin to pravastatin by various microorganisms and its applications – A review. BIOCATALYSIS AND AGRICULTURAL BIOTECHNOLOGY 2018. [DOI: 10.1016/j.bcab.2017.11.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Marrs CC, Costantine MM. Should We Add Pravastatin to Aspirin for Preeclampsia Prevention in High-risk Women? Clin Obstet Gynecol 2017; 60:161-168. [PMID: 27906745 PMCID: PMC5250542 DOI: 10.1097/grf.0000000000000248] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
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 proposed for preventing preeclampsia. However, before statin administration becomes part of routine clinical practice, a large, well-designed, and adequately powered randomized-controlled trial is needed.
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Affiliation(s)
- Caroline C. Marrs
- Fellow, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, the University of Texas Medical Branch, Galveston Texas
| | - Maged M. Costantine
- Associate Professor, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, the University of Texas Medical Branch, Galveston Texas
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Berry C, Atta MG. Hypertensive disorders in pregnancy. World J Nephrol 2016; 5:418-28. [PMID: 27648405 PMCID: PMC5011248 DOI: 10.5527/wjn.v5.i5.418] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 05/31/2016] [Accepted: 06/27/2016] [Indexed: 02/06/2023] Open
Abstract
Renal injury or failure may occur in the context of pregnancy requiring special considerations with regard to fetal and maternal health. The condition of pregnancy itself may be a major factor in such injuries. In addition, for many young women previously known to be healthy, pregnancy may be the first presentation for routine urine and blood testing which may yield previously subclinical renal disease. As such, pregnancy may add complexity to considerations in the management of renal disease presenting coincidentally requiring knowledge of the physiologic changes and potential renal disorders that may be encountered during pregnancy.
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Karalis DG, Hill AN, Clifton S, Wild RA. The risks of statin use in pregnancy: A systematic review. J Clin Lipidol 2016; 10:1081-90. [DOI: 10.1016/j.jacl.2016.07.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 07/11/2016] [Indexed: 10/21/2022]
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Campos LM, Rios EA, Guapyassu L, Midlej V, Atella GC, Herculano-Houzel S, Benchimol M, Mermelstein C, Costa ML. Alterations in zebrafish development induced by simvastatin: Comprehensive morphological and physiological study, focusing on muscle. Exp Biol Med (Maywood) 2016; 241:1950-1960. [PMID: 27444151 DOI: 10.1177/1535370216659944] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 06/24/2016] [Indexed: 11/15/2022] Open
Abstract
The cholesterol synthesis inhibitor simvastatin, which is used to treat cardiovascular diseases, has severe collateral effects. We decided to comprehensively study the effects of simvastatin in zebrafish development and in myogenesis, because zebrafish has been used as a model to human diseases, due to its handling easiness, the optical clarity of its embryos, and the availability of physiological and structural methodologies. Furthermore, muscle is an important target of the drug. We used several simvastatin concentrations at different zebrafish developmental stages and studied survival rate, morphology, and physiology of the embryos. Our results show that high levels of simvastatin induce structural damage whereas low doses induce minor structural changes, impaired movements, and reduced heart beating. Morphological alterations include changes in embryo and somite size and septa shape. Physiological changes include movement reduction and slower heartbeat. These effects could be reversed by the addition of exogenous cholesterol. Moreover, we quantified the total cell number during zebrafish development and demonstrated a large reduction in cell number after statin treatment. Since we could classify the alterations induced by simvastatin in three distinct phenotypes, we speculate that simvastatin acts through more than one mechanism and could affect both cell replication and/or cell death and muscle function. Our data can contribute to the understanding of the molecular and cellular basis of the mechanisms of action of simvastatin.
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Affiliation(s)
- Laise M Campos
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil
| | - Eduardo A Rios
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil
| | - Livia Guapyassu
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil
| | - Victor Midlej
- Laboratório de Ultraestrutura Celular, Universidade Santa Úrsula, RJ 22231-010, Brazil
| | - Georgia C Atella
- Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil
| | - Suzana Herculano-Houzel
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil
| | - Marlene Benchimol
- Laboratório de Ultraestrutura Celular, Universidade Santa Úrsula, RJ 22231-010, Brazil
| | - Claudia Mermelstein
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil
| | - Manoel L Costa
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21949-590, Brazil
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Boland MR, Tatonetti NP. Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review. THE PHARMACOGENOMICS JOURNAL 2016; 16:411-29. [PMID: 27401223 PMCID: PMC5028238 DOI: 10.1038/tpj.2016.48] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 04/15/2016] [Accepted: 05/02/2016] [Indexed: 12/18/2022]
Abstract
Mendelian diseases contain important biological information regarding developmental effects of gene mutations that can guide drug discovery and toxicity efforts. In this review, we focus on Smith–Lemli–Opitz syndrome (SLOS), a rare Mendelian disease characterized by compound heterozygous mutations in 7-dehydrocholesterol reductase (DHCR7) resulting in severe fetal deformities. We present a compilation of SLOS-inducing DHCR7 mutations and the geographic distribution of those mutations in healthy and diseased populations. We observed that several mutations thought to be disease causing occur in healthy populations, indicating an incomplete understanding of the condition and highlighting new research opportunities. We describe the functional environment around DHCR7, including pharmacological DHCR7 inhibitors and cholesterol and vitamin D synthesis. Using PubMed, we investigated the fetal outcomes following prenatal exposure to DHCR7 modulators. First-trimester exposure to DHCR7 inhibitors resulted in outcomes similar to those of known teratogens (50 vs 48% born-healthy). DHCR7 activity should be considered during drug development and prenatal toxicity assessment.
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Affiliation(s)
- M R Boland
- Department of Biomedical Informatics, Columbia University, New York, NY, USA.,Observational Health Data Sciences and Informatics, Columbia University, New York, NY, USA
| | - N P Tatonetti
- Department of Biomedical Informatics, Columbia University, New York, NY, USA.,Observational Health Data Sciences and Informatics, Columbia University, New York, NY, USA.,Department of Systems Biology, Columbia University, New York, NY, USA.,Department of Medicine, Columbia University, New York, NY, USA
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Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, Easterling TR, Haas DM, Haneline LS, Caritis SN, Venkataramanan R, West H, D'Alton M, Hankins G. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol 2016; 214:720.e1-720.e17. [PMID: 26723196 DOI: 10.1016/j.ajog.2015.12.038] [Citation(s) in RCA: 175] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 12/09/2015] [Accepted: 12/17/2015] [Indexed: 11/28/2022]
Abstract
BACKGROUND Preeclampsia 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. OBJECTIVE As 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 DESIGN We 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). RESULTS Ten 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. CONCLUSION This 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.
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Affiliation(s)
- Maged M Costantine
- Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
| | | | - Mary F Hebert
- Department of Pharmacy and Obstetrics and Gynecology, University of Washington, Seattle, WA
| | - Mahmoud S Ahmed
- Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX
| | - Linda M Brown
- Department of Obstetrics and Gynecology and Pediatrics, RTI International, Rockville, MD
| | - Zhaoxia Ren
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
| | - Thomas R Easterling
- Department of Pharmacy and Obstetrics and Gynecology, University of Washington, Seattle, WA
| | - David M Haas
- Department of Obstetrics and Gynecology and Pediatrics, Indiana University, Indianapolis, IN
| | - Laura S Haneline
- Department of Obstetrics and Gynecology and Pediatrics, Indiana University, Indianapolis, IN
| | - Steve N Caritis
- Department of Pharmacy and Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Raman Venkataramanan
- Department of Pharmacy and Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA
| | - Holly West
- Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX
| | | | - Gary Hankins
- Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX
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Brownfoot FC, Tong S, Hannan NJ, Hastie R, Cannon P, Kaitu'u-Lino TJ. Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta. BMC Pregnancy Childbirth 2016; 16:117. [PMID: 27207105 PMCID: PMC4874016 DOI: 10.1186/s12884-016-0902-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 05/13/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Preeclampsia is associated with the placental release of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG). These anti-angiogenic factors cause hypertension and multi-organ injury. Pravastatin decreases placental secretion of sFlt-1 in vitro and is currently being examined in clinical trials as a potential treatment for preeclampsia. However, it is possible that different classes of statins may be more potent at decreasing sFlt-1 secretion. We compared the relative potency of three different generations of statins on sFlt-1 and sENG secretion from human endothelial cells, trophoblast cells, and placenta explants. METHODS We performed functional experiments using primary human umbilical vein endothelial cells, trophoblast cells and preterm preeclamptic placental explants to assess the affect of simvastatin, rosuvastatin and pravastatin on sFlt-1 and sENG secretion and compared the relative potency of each statin at reducing these factors (Inhibitory Concentration 50). Furthermore we assessed the effect of each statin on the antioxidant and cytoprotective enzyme, heme-oxygenase 1. RESULTS All statins reduced sFlt-1 secretion from endothelial cells, trophoblasts and preterm preeclamptic placental explants. Simvastatin was the most potent inhibitor of sFlt-1 secretion from endothelial cells (IC 50 3.2 μM), trophoblast cells (IC 50 61.4 μM) and placental explants. Simvastatin was 28 times and 3 times more potent at reducing sFlt-1 secretion from endothelial cells and 85 times and 33 times more potent at reducing sFlt-1 secretion from trophoblast cells than pravastatin or rosuvastatin respectively. All statins increased sENG secretion from endothelial cells however did not change secretion from placental explants. While all statins up-regulated heme-oxygenase 1 in endothelial cells, only simvastatin up-regulated its expression in placenta from patients with preterm preeclampsia. CONCLUSION Simvastatin may be a more potent inhibitor of sFlt-1 secretion from endothelial cells, trophoblast cells and placenta from women with preterm preeclampsia than either pravastatin or rosuvastatin.
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Affiliation(s)
- Fiona C Brownfoot
- Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia.
| | - Stephen Tong
- Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia
| | - Natalie J Hannan
- Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia
| | - Roxanne Hastie
- Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia
| | - Ping Cannon
- Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia
| | - Tu'uhevaha J Kaitu'u-Lino
- Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, Victoria, Australia
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Chen Y, Liu Z, Chen J, Zuo Y, Liu S, Chen W, Liu G, Qiu G, Giampietro PF, Wu N, Wu Z. The genetic landscape and clinical implications of vertebral anomalies in VACTERL association. J Med Genet 2016; 53:431-7. [PMID: 27084730 PMCID: PMC4941148 DOI: 10.1136/jmedgenet-2015-103554] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 03/17/2016] [Indexed: 01/22/2023]
Abstract
VACTERL association is a condition comprising multisystem congenital malformations, causing severe physical disability in affected individuals. It is typically defined by the concurrence of at least three of the following component features: vertebral anomalies (V), anal atresia (A), cardiac malformations (C), tracheo-oesophageal fistula (TE), renal dysplasia (R) and limb abnormalities (L). Vertebral anomaly is one of the most important and common defects that has been reported in approximately 60–95% of all VACTERL patients. Recent breakthroughs have suggested that genetic factors play an important role in VACTERL association, especially in those with vertebral phenotypes. In this review, we summarised the genetic studies of the VACTERL association, especially focusing on the genetic aetiology of patients with vertebral anomalies. Furthermore, genetic reports of other syndromes with vertebral phenotypes overlapping with VACTERL association are also included. We aim to provide a further understanding of the genetic aetiology and a better evidence for genetic diagnosis of the association and vertebral anomalies.
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Affiliation(s)
- Yixin Chen
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Zhenlei Liu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jia Chen
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yuzhi Zuo
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Sen Liu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Weisheng Chen
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Gang Liu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Guixing Qiu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Philip F Giampietro
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Nan Wu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Zhihong Wu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Alarcon VB, Marikawa Y. Statins inhibit blastocyst formation by preventing geranylgeranylation. Mol Hum Reprod 2016; 22:350-63. [PMID: 26908642 DOI: 10.1093/molehr/gaw011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 01/29/2016] [Indexed: 12/14/2022] Open
Abstract
STUDY HYPOTHESIS Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the mevalonate pathway and prescription drugs that treat hypercholesterolemia, compromise preimplantation mouse development via modulation of HIPPO signaling. STUDY FINDING HMG-CoA reductase activity is required for trophectoderm specification, namely blastocyst cavity formation and Yes-associated protein (YAP) nuclear localization, through the production of isoprenoid geranylgeranyl pyrophosphate (GGPP) and the action of geranylgeranyl transferase. WHAT IS KNOWN ALREADY Previous studies have shown that treatment of mouse embryos with mevastatin prevents blastocyst formation, but how HMG-CoA reductase is involved in preimplantation development is unknown. HIPPO signaling regulates specification of the trophectoderm lineage of the mouse blastocyst by controlling the nuclear localization of YAP. In human cell lines, the mevalonate pathway regulates YAP to mediate self-renewal and survival through geranylgeranylation of RHO proteins. These studies suggest that in preimplantation development, statins may act through HIPPO pathway to interfere with trophectoderm specification and thereby inhibit blastocyst formation. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Eight-cell stage (E2.5) mouse embryos were treated in hanging drop culture with chemical agents, namely statins (lovastatin, atorvastatin, cerivastatin and pravastatin), mevalonic acid (MVA), cholesterol, squalene, farnesyl pyrophosphate (FPP), geranylgeranyl pyrophosphate (GGPP), geranylgeranyltransferase inhibitor GGTI-298, RHO inhibitor I, and squalene synthase inhibitor YM-53601, up to the late blastocyst stage (E4.5). Efficiency of blastocyst formation was assessed based on gross morphology and the measurement of the cavity size using an image analysis software. Effects on cell lineages and HIPPO signaling were analyzed using immunohistochemistry with confocal microscopy based on the expression patterns of the lineage-specific markers and the nuclear accumulation of YAP. Effects on cell lineages were also examined by quantitative RT-PCR based on the transcript levels of the lineage-specific marker genes. Data were analyzed using one-way ANOVA and two-sample t-test. MAIN RESULTS AND THE ROLE OF CHANCE All four statins examined inhibited blastocyst formation. The adverse impact of statins was rescued by supplementation of MVA (P < 0.01) or GGPP (P < 0.01) but not squalene nor cholesterol. Blastocyst formation was also prevented by GGTI-298 (P < 0.01). These results indicate that HMG-CoA reductase activity is required for blastocyst formation mainly through the production of GGPP but not cholesterol. Inhibition of RHO proteins, known targets of geranylgeranylation, impaired blastocyst formation, which was not reversed by GGPP supplementation. Nuclear localization of YAP was diminished by statin treatment but fully restored by supplementation of MVA (P < 0.01) or GGPP (P < 0.01). This suggests that HIPPO signaling is regulated by GGPP-dependent mechanisms, possibly geranylgeranylation of RHO, to enable trophectoderm formation. YM-53601 prevented blastocyst formation (P < 0.01), but its adverse impact was not rescued by supplementation of squalene or cholesterol, suggesting that squalene synthesis inhibition was not the cause of blastocyst defects. LIMITATIONS, REASONS FOR CAUTION Analyses were conducted on embryos cultured ex vivo, but they enable the determination of specific concentrations that impair embryo development which can be compared with drug concentrations in the reproductive tract when testing in vivo impact of statins through animal experimentations. Also, analyses were conducted in only one species, the mouse. Epidemiological studies on the effects of various types of statins on the fertility of women are necessary. WIDER IMPLICATIONS OF THE FINDINGS Our study reveals how the mevalonate pathway is required for blastocyst formation and intersects with HIPPO pathway to provide a mechanistic basis for the embryotoxic effect of statins. This bears relevance for women who are taking statins while trying to conceive, since statins have potential to prevent the conceptus from reaching the blastocyst stage and to cause early conceptus demise. LARGE SCALE DATA Not applicable. STUDY FUNDING AND COMPETING INTERESTS This study was supported by grants from the George F. Straub Trust of the Hawaii Community Foundation (13ADVC-60315 to V.B.A.) and the National Institutes of Health, USA (P20GM103457 to V.B.A.). The authors have no conflict of interest to declare.
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Affiliation(s)
- Vernadeth B Alarcon
- Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
| | - Yusuke Marikawa
- Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
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Zecchini C, Chanoine S, Chapuis C, Claustre J, Schir E, Allenet B, Saint Raymond C, Bedouch P. [Therapeutic Drug Management for Transplanted Women with a Planned Pregnancy: About Two Cases of Lung and Heart-lung Transplantation]. Therapie 2015; 70:493-9. [PMID: 26223163 DOI: 10.2515/therapie/2015033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 04/17/2015] [Indexed: 11/20/2022]
Abstract
Advances in lung transplantation allow the women of childbearing age to consider becoming mothers. When planning to become pregnant, a therapeutic drug management of immunosuppressive drugs and associated therapies is required. It must take into account teratogenic and fetotoxic drugs, as well as pharmacokinetic changes encountered during pregnancy. Increasingly data are currently available on the management of immunosuppressive drugs and associated therapies during pregnancy. We report the case management of drug therapy before and during pregnancy in two patients after a lung or heart-lung transplantation. To prevent the emergence of complications for mother and child, a literature review has been necessary to manage drug therapies of each patient.
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Affiliation(s)
- Céline Zecchini
- Pôle Pharmacie, Centre Hospitalier Universitaire de Grenoble, France
| | - Sébastien Chanoine
- Pôle Pharmacie, Centre Hospitalier Universitaire de Grenoble, France - Université Grenoble Alpes, CNRS/ThEMAS TIMC UMR 5525, Grenoble, France
| | - Claire Chapuis
- Pôle Pharmacie, Centre Hospitalier Universitaire de Grenoble, France
| | - Johanna Claustre
- Clinique Universitaire de Pneumologie, Centre Hospitalier Universitaire de Grenoble, France
| | - Edith Schir
- Centre Régional de Pharmacovigilance, Grenoble, France
| | - Benoît Allenet
- Pôle Pharmacie, Centre Hospitalier Universitaire de Grenoble, France - Université Grenoble Alpes, CNRS/ThEMAS TIMC UMR 5525, Grenoble, France
| | - Christel Saint Raymond
- Clinique Universitaire de Pneumologie, Centre Hospitalier Universitaire de Grenoble, France
| | - Pierrick Bedouch
- Pôle Pharmacie, Centre Hospitalier Universitaire de Grenoble, France - Université Grenoble Alpes, CNRS/ThEMAS TIMC UMR 5525, Grenoble, France
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Heart disease in pregnancy. Best Pract Res Clin Obstet Gynaecol 2015; 29:579-97. [DOI: 10.1016/j.bpobgyn.2015.04.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 04/03/2015] [Accepted: 04/05/2015] [Indexed: 12/29/2022]
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Chaiworapongsa T, Romero R, Korzeniewski SJ, Chaemsaithong P, Hernandez-Andrade E, Segars JH, DeCherney AH, McCoy MC, Kim CJ, Yeo L, Hassan SS. Pravastatin to prevent recurrent fetal death in massive perivillous fibrin deposition of the placenta (MPFD). J Matern Fetal Neonatal Med 2015; 29:855-62. [PMID: 25893545 DOI: 10.3109/14767058.2015.1022864] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Massive perivillous fibrin deposition of the placenta (MPFD) or maternal floor infarction (MFI) is a serious condition associated with recurrent complications including fetal death and severe fetal growth restriction. There is no method to evaluate the risk of adverse outcome in subsequent pregnancies, or effective prevention. Recent observations suggest that MFI is characterized by an imbalance in angiogenic/anti-angiogenic factors in early pregnancy; therefore, determination of these biomarkers may identify the patient at risk for recurrence. We report the case of a pregnant woman with a history of four consecutive pregnancy losses, the last of which was affected by MFI. Abnormalities of the anti-angiogenic factor, sVEGFR-1, and soluble endoglin (sEng) were detected early in the index pregnancy, and treatment with pravastatin corrected the abnormalities. Treatment resulted in a live birth infant at 34 weeks of gestation who had normal biometric parameters and developmental milestones at the age of 2. This is the first reported successful use of pravastatin to reverse an angiogenic/anti-angiogenic imbalance and prevent fetal death.
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Affiliation(s)
- Tinnakorn Chaiworapongsa
- a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .,b Department of Obstetrics and Gynecology , Wayne State University , Detroit , MI , USA
| | - Roberto Romero
- a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .,c Department of Obstetrics and Gynecology , University of Michigan , Ann Arbor , MI , USA .,d Department of Epidemiology and Biostatistics , Michigan State University , East Lansing , MI , USA .,e Department of Molecular Obstetrics and Genetics , Wayne State University , Detroit , MI , USA
| | - Steven J Korzeniewski
- a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .,b Department of Obstetrics and Gynecology , Wayne State University , Detroit , MI , USA .,d Department of Epidemiology and Biostatistics , Michigan State University , East Lansing , MI , USA
| | - Piya Chaemsaithong
- a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .,b Department of Obstetrics and Gynecology , Wayne State University , Detroit , MI , USA
| | - Edgar Hernandez-Andrade
- a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .,b Department of Obstetrics and Gynecology , Wayne State University , Detroit , MI , USA
| | - James H Segars
- f Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda , MD , USA
| | - Alan H DeCherney
- f Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda , MD , USA
| | - M Cathleen McCoy
- g Perinatal Unit , Winchester Obstetrics and Gynecology, Winchester Medical Center , Winchester , VA , USA , and
| | - Chong Jai Kim
- a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .,h Department of Pathology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Lami Yeo
- a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .,b Department of Obstetrics and Gynecology , Wayne State University , Detroit , MI , USA
| | - Sonia S Hassan
- a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .,b Department of Obstetrics and Gynecology , Wayne State University , Detroit , MI , USA
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Sharma A, Jaiswal S, Shukla M, Ravindrachary K, Lal J. Coadministration of HMG-CoA reductase inhibitors, atorvastatin and rosuvastatin, does not affect contraceptive efficacy of centchroman. EUR J CONTRACEP REPR 2015; 20:231-5. [PMID: 25798535 DOI: 10.3109/13625187.2015.1017756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE The study aimed to investigate the effect of concomitant use of atorvastatin or rosuvastatin on the pharmacokinetic and pharmacodynamic profile of centchroman, a non-steroidal female oral contraceptive. METHODS A rat model was used to predict pharmacokinetic drug-drug interactions between centchroman and atorvastatin or rosuvastatin. A dried blood spot sampling technique followed by liquid chromatography-tandem mass spectrometry detection was employed for analysis of the pharmacokinetic interaction study samples. Sperm-positive female rats were investigated for postcoital contraceptive activity of centchroman with or without coadministration of atorvastatin or rosuvastatin. RESULTS Coadministration of atorvastatin or rosuvastatin may increase the systemic availability of centchroman in blood, but it does not affect the pharmacodynamic profile of centchroman. CONCLUSION Atorvastatin or rosuvastatin may be prescribed with centchroman without compromising the contraceptive efficacy of centchroman.
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Affiliation(s)
- Abhisheak Sharma
- * Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute , Lucknow , India
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Bateman BT, Hernandez-Diaz S, Fischer MA, Seely EW, Ecker JL, Franklin JM, Desai RJ, Allen-Coleman C, Mogun H, Avorn J, Huybrechts KF. Statins and congenital malformations: cohort study. BMJ 2015; 350:h1035. [PMID: 25784688 PMCID: PMC4362473 DOI: 10.1136/bmj.h1035] [Citation(s) in RCA: 157] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To examine the teratogenic potential of statins. DESIGN Cohort study. SETTING United States. PARTICIPANTS A cohort of 886,996 completed pregnancies linked to liveborn infants of women enrolled in Medicaid from 2000 to 2007. METHODS We examined the risk of major congenital malformations and organ specific malformations in offspring associated with maternal use of a statin in the first trimester. Propensity score based methods were used to control for potential confounders, including maternal demographic characteristics, obstetric and medical conditions, and use of other drugs. RESULTS 1152 (0.13%) women used a statin during the first trimester. In unadjusted analyses, the prevalence of malformations in the offspring of these women was 6.34% compared with 3.55% in those of women who did not use a statin in the first trimester (relative risk 1.79, 95% confidence interval 1.43 to 2.23). Controlling for confounders, particularly pre-existing diabetes, accounted for this increase in risk (1.07, 0.85 to 1.37). There were also no statistically significant increases in any of the organ specific malformations assessed after accounting for confounders. Results were similar across a range of sensitivity analyses. CONCLUSIONS Our analysis did not find a significant teratogenic effect from maternal use of statins in the first trimester. However, these findings need to be replicated in other large studies, and the long term effects of in utero exposure to statins needs to be assessed, before use of statins in pregnancy can be considered safe.
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Affiliation(s)
- Brian T Bateman
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA Division of Obstetric Anesthesia, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Michael A Fischer
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ellen W Seely
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jeffrey L Ecker
- Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jessica M Franklin
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Rishi J Desai
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Cora Allen-Coleman
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Helen Mogun
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Jerry Avorn
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Krista F Huybrechts
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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Jyoti S, Tandon S. Genetic basis for developmental toxicity due to statin intake using embryonic stem cell differentiation model. Hum Exp Toxicol 2015; 34:965-84. [PMID: 25712412 DOI: 10.1177/0960327114564795] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The in utero environment is a key factor controlling the fate of the growing embryo. The deleterious effects of statins during the fetal development are still not very well understood. Data from animal studies and retrospective studies performed in pregnant women give conflicting reports. In this study, using in vitro differentiation model of embryonic stem cells, which mimic the differentiation process of the embryo, we have systematically exposed the cells to lipophilic statins, simvastatin, and atorvastatin at various doses and at critical times during differentiation. The analysis of key genes controlling the differentiation into ecto-, meso- and endodermal lineages was assessed by quantitative polymerase chain reaction. Our results show that genes of the mesodermal lineage were most sensitive to statins, leading to changes in the transcript levels of brachyury, Flk-1, Nkx2.5, and α/β-myosin heavy chain. In addition, changes to endodermal marker α-fetoprotein, along with ectodermal Nes and Neurofilament 200 kDa, imply that during early differentiation exposure to these drugs leads to altered signaling, which could translate to the congenital abnormalities seen in the heart and limbs.
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Affiliation(s)
- S Jyoti
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Biotechnology & Bioinformatics, Solan, India
| | - S Tandon
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Biotechnology & Bioinformatics, Solan, India
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Abstract
New guidelines from the American Academy of Pediatrics now recommend the consideration of statin therapy as a first-line pharmacological measure in children as young as 8 years old with marked hypercholesterolemia. Thus, it is important to review both the safety and efficacy of initiating statin therapy prior to adulthood. Statins interfere with cholesterol synthesis, thereby lowering serum cholesterol levels. However, there are special considerations that need to be made when initiating medications such as statins in the pediatric population. Cholesterol is crucial for various biologic processes including neurological development. Cholesterol also serves as a biochemical precursor to many hormones including those critical in sexual development. This article examines the current evidence for the safety and efficacy of statin use in the pediatric population and identifies areas for future research.
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