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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.
Preeclampsia (PE) is a morbid multisystem hypertensive disorder that complicates 3% to 8% of pregnancies. In its severe form, PE may lead to maternal seizure, stroke, intracranial bleeding, coagulopathy, renal failure, pulmonary edema, and death. Fetal consequences may include growth restriction, stillbirth, and complications related to prematurity.
PE has been the focus of incredible efforts to understand, treat, and prevent its development, with limited success. Professional societies currently recommend low-dose aspirin for PE prevention despite its modest effect and the contradictory results of most large aspirin prevention trials.
Iatrogenic delivery, often preterm, remains the primary intervention to decrease maternal morbidity and mortality.
PE shares many pathophysiological features and risk factors with adult cardiovascular disease. Endothelial injury and inflammation underlie both PE and atherosclerosis. In addition, PE has been identified as an independent risk factor for cardiovascular disease later in life. A diagnosis of PE more than doubles the risk of future hypertension, ischemic heart disease, and stroke.
When compared with patients who did not develop PE, the relative risk (RR) of developing cardiovascular disease later in life was 2.0 for patients with mild PE and 5.4 for patients with severe PE.
Similarly, the RR of death from cardiovascular disease later in life was 2.1 for patients who had PE at term and 9.5 for patients who were delivered for PE before 34 weeks of gestation.
Whether the association between PE and cardiovascular morbidity later in life is causal remains controversial. However, this relationship has led many experts to describe PE as an early manifestation of underlying cardiovascular disease predisposition, unmasked by the demands of pregnancy. Rather than causing future cardiovascular disease, PE may represent a failed result of the maternal “stress test” that is pregnancy. As such, interventions known to decrease cardiovascular morbidity, such as statins, have garnered attention and recently shown promise in the prevention of PE. In this article, we review the use of statins and their role in the treatment and prevention of PE.
Statins for cardiovascular disease
Pharmacologic properties
Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase is the enzyme responsible for the conversion of HMG-CoA to mevalonate in the mevalonic acid pathway of cholesterol biosynthesis. HMG-CoA reductase inhibitors, known as statins, competitively inhibit this rate-liming enzyme resulting in decreased downstream production of cholesterol.
Decreased intrahepatic cholesterol levels lead to increased expression of low-density lipoprotein (LDL) receptors and reuptake (and thus lowering) of circulating lipids.
Decreasing serum lipid levels has been found to prevent the development and progression of atherosclerotic cardiovascular disease, and statins remain among the most potent and widely used medications for lowering LDL cholesterol (LDL-C) and for primary and secondary cardiovascular protection.
Cholesterol Treatment Trialists' (CTT) Collaborators The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
First-generation statins, which include lovastatin, pravastatin, and fluvastatin, are the least potent. Second-generation statins include simvastatin and atorvastatin and are currently the most widely used. Third-generation statins, such as rosuvastatin, have the highest potency. Statins are also classified according to their hydrophilicity with pravastatin and rosuvastatin being hydrophilic and simvastatin, atorvastatin, and fluvastatin being lipophilic.
Statins are absorbed rapidly following oral administration, and most are highly bound to plasma proteins. Lipophilic statins cross easily into hepatocytes and other cells through passive diffusion, whereas hydrophilic statins require active transport and are more hepatoselective.
The intensity of LDL-C reduction by statins is dependent on the dose and the individual statin used. High-intensity therapy (rosuvastatin 20–40 mg or atorvastatin 80 mg) leads to >50% reduction in LDL-C, moderate-intensity therapy (rosuvastatin 5–10 mg, atorvastatin 20–40 mg, pravastatin 40 mg, or simvastatin 20–40 mg) leads to 30% to 50% reduction in LDL-C, and low-intensity therapy (atorvastatin 10 mg, pravastatin 10–20 mg, or simvastatin 10 mg) leads to <30% reduction in LDL-C.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines.
Decreased atherosclerosis is supported by angiographic and magnetic resonance imaging studies, which reveal an increase in lumen diameter and slowing of stenosis with years of statin therapy.
Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging.
These findings also translate into improved clinical outcomes and reduced mortality and morbidity from cardiovascular disease. However, the benefits of statin therapy are not solely explained by their lipid-lowering capabilities, and the exact mechanisms of cardiovascular benefit that extend beyond decreased lipoprotein levels are not completely understood. Although their lipid-lowering effect is well documented, the clinical benefits of statin therapy occur before and are disproportionately greater than the improvement in atherosclerotic disease burden. Patients often experience clinical improvement in markers of vascular disease as early as 6 months after initiating therapy.
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
Factors thought to contribute to the benefits of statin therapy include reversal of endothelial dysfunction, decreased inflammation and thrombogenicity, and plaque stabilization, all of which can be seen shortly after beginning therapy.
Plaque stabilization
It is generally accepted that acute coronary events are often caused by disruption of lipid-rich atherosclerotic plaques. Infiltration of the collagen-deficient fibrinous cap of a plaque by inflammatory cells (macrophages, activated lymphocytes) leads to plaque disruption and the formation of a thrombus and potential vessel occlusion.
Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease.
Evaluation of human carotid plaques removed during endarterectomy revealed that statin therapy decreased plaque inflammation (as a result of decreased matrix metalloproteinase-2, macrophage, and T-cell levels) and increased plaque stability (by increase in metalloproteinase-1 inhibition and collagen content).
Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization.
The endothelial layer separates the circulatory compartment from the vascular wall, and as such, it regulates the contractile and hemostatic functions of blood vessels. There is growing evidence to support that endothelial dysfunction, often involving reduced endothelial-derived nitric oxide (NO) production and endothelial activation resulting in the expression of cell surface leukocyte adhesion molecules, is causal in the development of cardiovascular disease.
Endothelium-dependent vascular relaxation is predominantly mediated by nitric oxide (NO), whereas endothelium-dependent vascular constriction is mediated by endothelin-1 (ET-1) and thromboxane-A2. The balance between these endothelium-derived vasoactive substances determines the contractile state of a vessel.
In a study of 30 healthy adults with normal serum cholesterol, a single dose of 0.3 mg cerivastatin resulted in increased flow-mediated dilatation of the brachial artery within 3 hours of administration.
Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects.
There is growing evidence that statin therapy amplifies the effect of other endothelium-dependent medications, increases blood flow, and reduces the density of surface adhesion molecules.
This is likely because of statin’s ability to up-regulate endothelial nitric oxide synthase (eNOS) expression, which increases NO production and promotes vessel relaxation. Statins have also been found to restore the function of eNOS in pathologic conditions and increase the expression of tissue-type plasminogen activator and decrease the expression of potent vasoconstrictor ET-1.
In addition, statins have been found to promote the proliferation, migration, and survival of circulating endothelial progenitor cells, which are important for angiogenesis and endothelial restoration after injury.
Markers of inflammation, most notably high-sensitivity C-reactive protein (hs-CRP), are elevated in patients with atherosclerosis and can help predict the risk of cardiac events and progression of cardiovascular diseases.
Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.
However, the mechanism behind the decrease in inflammatory markers is not well understood. It has been reported that some (though not all) statins selectively inhibit an important inflammatory cell adhesion protein, αLβ2 integrin (also referred to as lymphocyte function–associated antigen 1, or integrin LFA-1).
Statin therapy has in addition been found to affect immune cell signaling. Interferon gamma plays an important role in the immune response by stimulating immune cells to express major histocompatibility complex class II (MHC-II) proteins, which in turn activate T lymphocytes. There is evidence that statins directly inhibit the interferon gamma–mediated induction of MHC-II expression leading to a decrease in T-cell activation.
Through the inhibition of T-cell activation and adhesion molecule expression, statins decrease the presence of inflammatory cytokine-releasing immune cells (monocytes, macrophages, lymphocytes) in the endothelium.
The pathogenesis of PE, although not completely understood, is believed to be a 2-stage process, originating early in pregnancy with abnormal cytotrophoblast invasion and remodeling of the spiral arterioles during early placenta development.
Although the exact trigger remains unknown, it is generally accepted that a combination of genetic, environmental, and immunologic factors plays an important role in the early stage.
Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric–Fetal Pharmacology Research Units Network Pravastatin for the prevention of preeclampsia in high-risk pregnant women.
These changes ultimately culminate in an angiogenic imbalance, coupled with widespread maternal endothelial dysfunction, oxidative stress, and exaggerated inflammation. These promote systemic endothelial dysfunction and result in vasoconstriction, end-organ ischemia, and the clinical signs and symptoms of PE (Figure).
FigurePathophysiology of preeclampsia and effect of statins
Angiogenesis refers to the physiological process by which new blood vessels form from preexisting vessels, whereas vasculogenesis refers to the process by which vessels are formed from angioblast precursor cells. The human placenta undergoes both angiogenesis and vasculogenesis during fetal development and pseudovasculogenesis, the process by which placental cytotrophoblast cells convert from an epithelial phenotype to an endothelial phenotype. Normal placental development depends on a balance between pro- and antiangiogenic factors that promote angiogenesis and normal endothelial function. An imbalance in angiogenic placental mediators, with excessive release of vasoactive factors, has been linked to the development of PE and is thought to be a critical feature to its etiology.
Both soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) are 2 antiangiogenic factors that have been found to neutralize and inhibit the effects of circulating proangiogenic mediators, such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) (Figure). In animal models, overexpression of sFlt-1 results in a PE-like condition, which is reversed by lowering sFlt-1 levels below a critical threshold.
Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric–Fetal Pharmacology Research Units Network Pravastatin for the prevention of preeclampsia in high-risk pregnant women.
Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric–Fetal Pharmacology Research Units Network Pravastatin for the prevention of preeclampsia in high-risk pregnant women.
Exaggeration of the inflammatory cascade is also a feature of PE and is manifested by reversal of the T helper cell 1 (Th1) and T helper cell 2 (Th2) responses (increase in Th1 proinflammatory cytokines, such as tumor necrosis factor alpha [TNF-α], interleukin 1 [IL-1], IL-2, and interferon gamma, and decrease in Th2 antiinflammatory cytokines such as IL-4 and IL-10). The increase of proinflammatory cytokines, along with a vasoconstrictive imbalance in vasoactive mediators, exacerbates oxidative stress and leads to endothelial injury. Furthermore, PE is associated with the suppression of the heme oxygenase-1 (HO-1) and carbon monoxide pathways, which have antiinflammatory, antioxidant, and vasoprotective properties.
Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric–Fetal Pharmacology Research Units Network Pravastatin for the prevention of preeclampsia in high-risk pregnant women.
Endothelial injury can also trigger a cascade of inflammatory and immunogenic processes similar to the endothelial dysfunction seen in atherosclerotic vascular disease. Interestingly, increases in circulating free radicals caused by increased cytokine activity lead to the oxidation of LDL, another finding similar to atherosclerotic cardiovascular disease.
Statins for prevention of PE: biological plausibility
The properties and mechanisms of action of statins make them highly promising candidates for the prevention and/or treatment of PE. Statins up-regulate eNOS, promoting NO production in the vasculature.
They also promote VEGF and PlGF releases, reduce sFlt-1 and sEng concentrations, and up-regulate the transcription and expression of HO-1 in endothelial and vascular smooth muscles.
They are also known to up-regulate Th2 antiinflammatory cytokine production and down-regulate Th1 proinflammatory cytokine production (Table 1, Figure).
These immunomodulatory and antiinflammatory effects, along with other pleiotropic actions on free oxygen radical formation and smooth muscle cell proliferation, make statins highly promising candidates for the prevention and treatment of PE.
Table 1Mechanisms and effects of statins by cell type
The ability of statins to reverse pathophysiological pathways associated with PE and to ameliorate its phenotype was evaluated in several preclinical studies using tissue cultures and different rodent models of PE. Initial studies using preeclamptic villous explants and a mouse model of PE reported that simvastatin therapy increased endothelial HO-1 activity, which, in turn, promoted VEGF and PlGF releases and decreased sFlt-1 levels.
Other studies using primary endothelial cells, purified cytotrophoblast cells, and placental explants obtained from women with preterm PE reported that pravastatin decreased sFlt-1 and increased endothelial, but not placental, sEng secretion
and that it was not dependent on up-regulation of HO-1. Moreover, the ability of pravastatin to decrease sFlt-1 concentrations using pravastatin-perfused human placental cotyledons and placental explants was only observed under hypoxic conditions, with no alterations of placental physiological functions under normoxic conditions.
Finally, pravastatin was also found to reduce the secretion of endothelin-1 and sFlt-1 in human umbilical vein endothelial and uterine microvascular cells.
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.
most studies using murine PE models evaluated pravastatin, probably because of its more favorable pregnancy profile. Using an adenoviral overexpression of the sFlt-1 model, we and others reported that pravastatin improved vascular reactivity by decreasing sFlt-1 and sEng levels and up-regulating eNOS in the vasculature.
In addition, pravastatin up-regulated the expression of VEGF and PlGF and a prosurvival or antiapoptotic mitogen-activated protein kinase pathway in the placenta.
Earlier reports found that, when given to women with preterm PE, pravastatin use was associated with improvement in blood pressure, reduction in sFlt-1 serum concentrations, and improved pregnancy outcomes.
In addition, pravastatin improved angiogenic profiles and prevented fetal demise in a case report of patients with massive perivillous fibrin deposition in the placenta.
A pilot double-blind, placebo-controlled PE prevention trial using pravastatin, conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Obstetric-Fetal Pharmacology Research Units Network, randomized women with a history of previous PE that required preterm delivery before 34 weeks of gestation to either 10 mg of oral pravastatin or placebo from 12 to 16 weeks until delivery. Of note, 25% of participants were also taking low-dose aspirin, with no difference between the 2 groups. Maternal and neonatal outcomes were overall more favorable in women randomized to pravastatin than in women randomized to placebo, with reduced rates of PE (0% vs 40%), severe features of PE, and indicated preterm delivery before 37 weeks of gestation (10% vs 50%). Women receiving pravastatin had increased serum PlGF and decreased sFlt-1 and sEng levels compared with those who received placebo, although the differences did not reach statistical significance. In addition, there were no differences in rates of side effects (with myalgia and headache being the most common), congenital anomalies, or adverse events between the groups.
Maternal blood concentrations of liver (alanine and aspartate transaminases) and muscle (creatine kinase) enzymes were not increased with pravastatin therapy. More importantly, birthweight, gestational age at delivery, and neonatal intensive care unit admissions tended to be better in the pravastatin group, although without statistical significance (Table 2). A second cohort of the trial randomized women to 20 mg pravastatin or placebo and revealed similar findings (unpublished data).
Table 2Summary of results of safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women
The use of pravastatin as a therapeutic agent was also evaluated in a prospective study of 21 women with antiphospholipid syndrome (APLS) and poor pregnancy outcomes. All patients received low-dose aspirin and low-molecular-weight heparin per local standard of care, were observed closely throughout pregnancy, and were assigned to pravastatin (20 mg) or standard of care when they developed PE and/or intrauterine growth restriction. Compared with patients in the control cohort, those who received pravastatin had improved uterine artery Doppler velocimetry, had lower blood pressure (130/89 mm Hg [interquartile range (IQR), 125–130/85–90] vs 160/98 mm Hg [IQR, 138–180/90–110]), and delivered infants with higher birthweight (2390 g [IQR, 2065–2770] vs 900 g [IQR, 580–1100]), at a more advanced gestational age (36 weeks [IQR, 35–36] vs 26.5 weeks [IQR, 26–32]).
Moreover, the Statins to Ameliorate Early Onset Pre-Eclampsia (StAmP) trial randomized women with early-onset PE (24–31 weeks of gestation) to pravastatin 40 mg or placebo.
The difference in sFlt-1 levels between the pravastatin (n=27) and placebo (n=29) groups was 292 pg/mL (95% confidence interval [CI], 1175–592; P=.5) 3 days after randomization and 48 pg/mL (95% CI, 1009–913; P=.9) 14 days after randomization. Subjects who received pravastatin had a similar gestational latency after randomization when compared with subjects who received placebo (hazard ratio, 0.84; 95% CI, 0.50–1.40; P=.6) with a median time to delivery of 9 days (IQR, 5–14) in the pravastatin group and 7 days (IQR, 4–11) in the placebo group. Overall, pravastatin use was not associated with a reduction in maternal plasma sFlt-1 levels, prolongation of pregnancy, or other pregnancy outcomes. However, despite its negative results and limitations, the StAmP trial confirmed several findings that support the safety of pravastatin use in high-risk pregnancies.
In addition, the effect of pravastatin in pregnancy with early-onset FGR was evaluated in a nonrandomized controlled study conducted in Spain. Women with early-onset FGR at ≤28 weeks’ gestation were offered a dose of pravastatin 40 mg daily (n=19). A control group (n=19) was matched to the treatment group for gestational age; maternal, obstetrical, and Doppler findings; and angiogenic factors.
Treatment with pravastatin was associated with substantial improvement in angiogenic profile. In addition, latency from diagnosis to delivery was extended by 16.5 days, median newborn birthweight was increased by 260 g, and the rate of PE decreased from 47.4% to 31.6%. However, these clinical findings were not statistically significant.
Although these 4 studies offer insight into the potential role of statins for PE, they are limited by sample size and are conflicting in their design and findings (Table 3). Specifically, the StAmP trial was limited by the timing of the primary outcome, small sample size, slow recruitment, and study medication noncompliance, and neither the StAmP trial nor the NICHD pilot trial was powered for maternal or fetal outcomes. Furthermore, similar to the use of aspirin for PE and progesterone for preterm birth, medications effective in prevention may not necessarily prove effective in treatment. As such, there are other currently active trials that aim to evaluate the utility of pravastatin in preventing PE and other hypertensive disorders in various high-risk groups. Future investigations should include randomized-controlled trials (RCTs) evaluating different statins, doses of pravastatin for both prevention and treatment, and study populations for which statin therapy may be beneficial.
Table 3Summary of human studies evaluating pravastatin for preeclampsia
Study
Author
Year
Country
Design
Sample size
Dose
Primary outcome
Major findings
Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial
Maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy
Pravastatin group found reduced rates of preeclampsia (0% vs 40%), severe features of preeclampsia, and indicated preterm delivery before 37 wk (10% vs 50%)
Pravastatin improves pregnancy outcomes in obstetrical antiphospholipid syndrome refractory to antithrombotic therapy
Uteroplacental blood hemodynamics, progression of preeclampsia features, and fetal or neonatal outcomes
Pravastatin group found improved uterine artery Doppler velocimetry, lower blood pressure (130/89 mm Hg vs 160/98 mm Hg), higher birthweight (2390 g vs 900 g), later delivery (36 wk vs 26.5 wk)
Pravastatin for early-onset preeclampsia: a randomized, blinded, placebo-controlled trial
Proof of principle randomized placebo-controlled trial
56
40 mg
Difference in mean plasma sFlt-1 levels over the first 3 days following randomization
Pravastatin use was not associated with reduction in maternal plasma sFlt-1 levels (difference of 292 pg/mL [95% CI, 1175–592; P=.5]), prolongation of pregnancy, or other pregnancy outcomes
Evaluating the effect of pravastatin in early-onset fetal growth restriction: a nonrandomized and historically controlled pilot study
Doppler progression, sFlt-1 and PlGF values, and pregnancy outcomes
Pravastatin group found improvement in angiogenic profile, greater gestational latency (by 16.5 d), greater birthweight (by 260 g), and decreased rates of preeclampsia (31.6% vs 47.4%)
Cholesterol is an important part of the cell membrane, bile acids, and steroid hormone synthesis. It is essential for normal fetal development. This is evidenced by the congenital malformations that result from genetic aberrations in cholesterol synthesis. Therefore, 6 of 7 known mutations related to cholesterol biosynthesis are extremely rare and often lethal. The seventh, and most common, is the result of a defect in the final step of cholesterol synthesis in which dehydrocholesterol is converted to cholesterol by 7-dehydrocholesterol reductase. This results in a disorder known as Smith-Lemli-Opitz syndrome, which is manifested by derangements in growth, microcephaly, mental retardation, and multiple congenital anomalies, including abnormal facial features, cleft palate, heart defects, fused digits, polydactyly, and underdeveloped external genitalia in males.
Cholesterol synthesis occurs predominantly in the liver and is mediated by the rate-limiting enzyme HMG-CoA reductase. Lipoproteins carry cholesterol throughout the human body and facilitate cholesterol transport across the syncytiotrophoblast of the placenta, which expresses LDL receptors. Although there is a physiological increase in serum lipid concentrations during normal pregnancy, maternal cholesterol supply is of minimal importance to the developing fetus as 80% of fetal cholesterol is produced endogenously.
This is supported by the fact that fetuses with Smith-Lemli-Opitz syndrome have very low cholesterol concentrations and are not rescued by the normal maternal cholesterol levels. It is also supported by studies reporting that women with abetalipoproteinemia or hypobetalipoproteinemia and those consuming low cholesterol diets have lower maternal serum cholesterol levels yet do not experience increased adverse fetal or pregnancy outcomes.
Given the well-known lipid-lowering effects of statins, there has been historic concern surrounding their use in pregnancy. In 2015, the US Food and Drug Administration implemented the Pregnancy Lactation Labeling Rule, which required that drug manufacturers replace the previous pregnancy letter categorization (ie, A, B, C, D, and X) with a summary of product information discussing the use of the drug in pregnant women, dosing, potential risks, and registry availability. Before this change, statins were assigned to category X because it was felt that there was “no benefit to outweigh the potential risk.” This was also based on the case reports and animal studies from the 1980s, which reported teratogenicity with high doses of statins (namely, lovastatin) in rats.
Mevalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic acid, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase.
Although the teratogenicity of statins, especially pravastatin, has largely been debunked, they remain contraindicated in pregnancy. This is primarily because of theoretical concerns and a lack of data supporting an indication for their use in pregnancy.
Several cohorts (Table 4) of women exposed to statins during pregnancy did not indicate increased teratogenicity or other adverse pregnancy outcomes. However, most of the statin-exposed patients in these cohorts discontinued statin use as soon as pregnancy was confirmed. In an analysis of Medicaid claims from the United States of more than 800,000 pregnant women, including 1152 exposed to statins in the first trimester of pregnancy, and after controlling for confounders (particularly preexisting diabetes) and conducting a propensity score matching, there was no increased risk of congenital malformation (adjusted odds ratio, 1.07; 95% CI, 0.85–1.37) or any pattern of anomalies or propensity for select organ systems with the use of statins.
A 2016 systematic review that included 16 clinical studies (5 case series, 3 cohort series, 3 registry-based studies, 1 RCT, and 4 other systematic reviews) found no relationship between statin use in pregnancy and congenital anomalies.
Moreover, data from the recent pilot human trials, in which pravastatin was used for a much longer duration outside the first trimester of pregnancy, support its safety in pregnancy. In the US pilot trial, there were no increased rate of congenital anomalies and similar concentrations of cord blood markers for neurologic injury, cholesterol, steroidogenic hormones, and liver enzymes between neonates born to women who were assigned to pravastatin and placebo. In addition, all newborns exposed to pravastatin passed either an auditory brain stem response or otoacoustic emission test before being discharged from the hospital after birth.
and the APLS cohort reported improved neonatal outcomes among those born to mothers who received pravastatin compared with those born to mothers who received placebo.
Women with history of previous preeclampsia that required preterm delivery before 34 wk, randomized to 10 mg pravastatin vs placebo between 12 and 16 wk
Pravastatin (10)
Placebo (10)
One fetus in the pravastatin group had hypospadias, and another had coarctation of the aorta (diagnosed postnatally), whereas in the placebo group, 1 fetus had polydactyly, and another had ventriculomegaly
These reassuring findings support the lack of teratogenicity of pravastatin and could be related to its low affinity for lipid environments and reduced permeability to extrahepatic tissues, specifically the embryo, and thus low potential for adverse effect on cholesterol biosynthesis in the developing fetus.
This was confirmed in the US pilot study and the StAmP trial in which most neonates exposed to pravastatin in utero had pravastatin concentrations below the lowest level of quantification of the assay.
The safety and side effects profiles of statins have been studied extensively in the nonobstetrical population. In general, statins are considered safe and well tolerated, especially pravastatin. Pooled data from large RCTs in nonpregnant patients have reassured clinicians that serious adverse effects of pravastatin, most notably liver injury and rhabdomyolysis, are extremely rare. Of note, 3 long-term placebo-controlled trials of pravastatin (the West of Scotland Coronary Prevention Study, the Cholesterol and Recurrent Events Study, and the Long-term Intervention with Pravastatin in Ischemic Disease Study) collectively included 19,592 patients randomized to a dose of pravastatin 40 mg daily or placebo and accumulated more than 112,000 person-years of exposure. During 5 years of exposure, the rates of marked elevations of aminotransferases were low and similar between the 2 groups (<1.2%).
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
assessed the adverse events associated with multiple different statins. They found that in pravastatin-exposed patients, the rate of adverse events (rhabdomyolysis, increased aminotransferases, and asymptomatic 10-fold increase in creatine kinase) was <2%. This finding is consistent with other large, long-term studies. In these trials, the most common reasons for discontinuation were mild, nonspecific gastrointestinal adverse effects. Myalgia is also a common symptom associated with pravastatin use and ranges in incidence from 0.6% to 10.9%.
Studies regarding the interaction of pravastatin with other medications did not include pregnant women, and the effects of pregnancy on such interactions are unknown. Outside of pregnancy, statins are known to interact with erythromycin, niacin, cyclosporine, fibrates, bile acid resins, clarithromycin, and cimetidine.
Data regarding maternal safety of pravastatin use in pregnancy are limited to the more recent trials and cohorts, which revealed similar rates of adverse and serious adverse events between the pravastatin and placebo groups with the most common adverse effect among patients who received pravastatin in the US pilot study being heartburn and musculoskeletal pain. Of note, there were no reports of rhabdomyolysis or liver injury.
After oral administration, pravastatin is chemically degraded in the stomach, and a fraction of the intact drug is then rapidly absorbed in the small intestine, delivered to the liver via the portal vein, and then actively transported into hepatocytes. Most of the pravastatin following hepatic uptake is excreted into bile and eventually reenters the enterohepatic circulation, leading to relatively low systemic availability. Active pravastatin that survives first-pass metabolism is then distributed systemically and, outside of the liver and kidneys, is largely confined to the extracellular space.
Data on the effects of pregnancy on pravastatin pharmacokinetics are limited to the US pilot trial. The apparent half-life of pravastatin was estimated to be 2 to 3 hours in pregnancy and not different from postpartum values. Similarly, pravastatin Cmax, pravastatin Tmax, and fraction of the drug excreted unchanged in urine are consistent with those previously reported in nonpregnant subjects. However, it appears that there is an increase in apparent oral clearance and a decrease in pravastatin area under the curve in pregnancy compared with after birth, predominantly related to the increase in renal clearance during pregnancy.
Conclusion
PE is a common hypertensive disorder of pregnancy associated with considerable maternal and fetal morbidities. With suboptimal preventive and limited therapeutic strategies and in view of its biological plausibility and the reassuring pilot studies, pravastatin poses as a potential agent for the prevention of PE. Although promising, these preventive benefits, along with the potential role of statin therapy in the treatment of PE, must be investigated in larger RCTs.
References
Wang A.
Rana S.
Karumanchi S.A.
Preeclampsia: the role of angiogenic factors in its pathogenesis.
The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines.
Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging.
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease.
Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization.
Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects.
Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.
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.
Mevalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic acid, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase.
The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
M.M.C. is supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number 5 UG1 HD027915–29) and the National Heart, Lung, and Blood Institute (grant number 1UG3HL140131–01).
The contents of this article are solely the responsibility of the authors do not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung, and Blood Institute, or the National Institutes of Health.
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