The role of statins in the prevention of preeclampsia

Abstract

Preeclampsia is a common hypertensive disorder of pregnancy associated with significant neonatal and maternal morbidity and mortality. Though the exact cause of preeclampsia remains unknown, it is generally accepted that abnormal placentation resulting in the release of soluble anti-angiogenic factors, coupled with increased oxidative stress and inflammation, leads to systemic endothelial dysfunction and the clinical manifestations of the disease. Statins have been shown to correct similar pathophysiologic pathways that underlie the development of preeclampsia. Pravastatin, specifically, has been shown 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 demonstrated a favorable safety profile for pravastatin and more recent evidence does not support the prior teratogenic concerns surrounding statins in pregnancy. With reassuring and positive findings from pilot studies and strong biologic plausibility, statins should be investigated in large clinical randomized-controlled trials for the prevention of preeclampsia.

Introduction

Preeclampsia is a morbid multisystem hypertensive disorder that complicates 3–8% of pregnancies. In its severe form, preeclampsia 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.¹ Preeclampsia 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 preeclampsia prevention despite its modest effect and the contradictory results of the majority of the large aspirin prevention trials.² Iatrogenic delivery, often preterm, remains the primary intervention to decrease maternal morbidity and mortality.

Preeclampsia shares many pathophysiologic features, as well as risk factors, with adult cardiovascular disease. Endothelial injury and inflammation underlie both preeclampsia and atherosclerosis. Additionally, preeclampsia has been identified as an independent risk factor for cardiovascular disease later in life. A diagnosis of preeclampsia more than doubles the risk of future hypertension, ischemic heart disease, and stroke.^3–6 When compared to patients who did not develop preeclampsia, the relative risk (RR) of developing cardiovascular disease later in life was 2.0 for patients with mild preeclampsia and 5.4 for patients with severe preeclampsia.⁷ Similarly, the RR of death from cardiovascular disease later in life was 2.1 for patients who had preeclampsia at term and 9.5 for patients who were delivered for preeclampsia prior to 34 weeks.⁸ Whether the association between preeclampsia and cardiovascular morbidity later in life is causal remains controversial. However, this relationship has led many experts to describe preeclampsia as an early manifestation of underlying cardiovascular disease predisposition, unmasked by the demands of pregnancy. Rather than causing future cardiovascular disease, preeclampsia 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 preeclampsia. In this article we review the use of statins and their role in the treatment and prevention of preeclampsia.

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.⁹ Decreased intrahepatic cholesterol levels lead to increased expression of low-density lipoprotein (LDL) receptors and reuptake (and thus lowering) of circulating lipids.^10–12 Decreasing serum lipid levels has been shown 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 and for primary and secondary cardiovascular protection.^13,14

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, like 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.¹⁵ Statins are absorbed rapidly following oral administration and most are highly bound to plasma proteins. Lipophilic statins cross easily into hepatocytes and other cells via passive diffusion whereas hydrophilic statins require active transport and more hepato-selective.¹⁵

Principal Effects

Until recently, statins were touted predominantly for their ability to decrease cholesterol concentrations and the progression of atherosclerosis.¹² 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 atoravastatin 80 mg) leads to > 50% reduction in LDL-C, moderate intensity therapy (rosuvastatin 5–10 mg, atoravatstain 20–40 mg, pravastatin 40 mg, or simvastatin 20–40 mg) leads to 30–50% reduction in LDL-C, whereas low intensity therapy (atoravatstain 10 mg, pravastatin 10–20 mg, or simvastatin 10 mg) leads to <30% reduction in LDL-C.^16,17 Decreased atherosclerosis is supported by angiographic and magnetic resonance imaging studies which demonstrate increase in lumen diameter and slowing of stenosis with years of statin therapy.^18–20 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. Though their lipid-lowering effect is well-documented, the clinical benefits of statin therapy occur prior to and are disproportionately greater than the improvement in atherosclerotic disease burden. Patients often experience clinical improvement in markers of vascular disease as early as six months after initiating therapy.^21,22 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.^{23 24} Evaluation of human carotid plaques removed during endarterectomy showed that statin therapy decreased plaque inflammation (via decreased matrix metalloproteinase-2, macrophage, and T-cell levels) and increased plaque stability (via increases in metalloproteinase-1 inhibition and collagen content).²⁵ Additionally, statin therapy has been shown to decrease platelet reactivity and tissue factor expression by inflammatory cells.²³

Endothelial Protection

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.²⁶ Endothelium-dependent vascular relaxation is predominantly mediated by NO while 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.²⁶ 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.²⁷ 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.²⁶ This is likely due to statin’s ability to upregulate endothelial nitric oxide synthase (eNOS) expression, which increases NO production and promotes vessel relaxation. Statins have also been shown to restore the function of eNOS in pathologic conditions as well as increase the expression of tissue-type plasminogen activator (t-PA) and decrease the expression of potent vasoconstrictor ET-1.²⁶ Additionally, statins have been shown to promote the proliferation, migration, and survival of circulating endothelial progenitor cells, which are important for angiogenesis and endothelial restoration after injury.²⁶

Decreased Inflammation

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 disease.²⁸ Statin therapy has been shown to decrease hs-CRP levels independent of lipid levels, an effect seen within 14 days.²⁹ However, the mechanism behind the decrease in inflammatory markers is not well understood. It has been demonstrated that some (though not all) statins selectively inhibit an important inflammatory cell adhesion protein, α_Lβ₂ integrin (also referred to as lymphocyte function–associated antigen 1, or integrin LFA-1).^30,31 Statin therapy has additionally been shown to effect immune cell signaling. Interferon gamma (INF-γ) 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 INF-γ-mediated induction of MHC-II expression leading to a decrease in T-cell activation.³² 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.²⁶

Statins for Preeclampsia

Pathophysiology of Preeclampsia

The pathogenesis of preeclampsia, while not completely understood, is believed to be a two-stage process, originating early in pregnancy with abnormal cytotrophoblast invasion and remodeling of the spiral arterioles during early placenta development.³³ Though the exact trigger remains unknown, it is generally accepted that a combination of genetic, environmental, and immunologic factors play an important role in the early stage.³⁴ 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 eventually the clinical signs and symptoms of preeclampsia [Figure 1].

Figure 1.

Pathophysiology of preeclampsia and effect of statins

*Original figure

Angiogenesis refers to the physiologic process by which new blood vessels form from pre-existing 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 as well as pseudovasculogenesis, the process by which placental cytotrophoblast cells convert from an epithelial to an endothelial phenotype. Normal placental development depends on a balance between pro- and anti-angiogenic 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 preeclampsia and is thought to be a critical feature to its etiology.³⁵ Soluble Fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), are two anti-angiogenic factors that have both been shown to neutralize and inhibit the effects of circulating pro-angiogenic mediators such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) [Figure 1]. In animal models, overexpression of sFlt-1 results in a preeclampsia-like condition which is reversed by lowering sFlt-1 levels below a critical threshold.³⁴ In humans, both of these anti-angiogenic factors are known to increase dramatically several weeks prior to the onset of clinical manifestiaons.^34,36,37

Exaggeration of the inflammatory cascade is also a feature of preeclampsia and is manifested by reversal of the Th1 and Th2 responses (increase in Th1 pro-inflammatory cytokines, such as TNF-α, IL-1, IL-2, IFN-γ, and decrease in Th2 anti-inflammatory cytokines such as IL-4, IL-10). The increase of pro-inflammatory cytokines, along with a vasoconstrictive imbalance in vasoactive mediators, exacerbate oxidative stress and lead to endothelial injury. Furthermore, preeclampsia is associated with suppression of the heme oxygenase-1 (HO-1) and carbon monoxide pathways which have anti-inflammatory, anti-oxidant, and vaso-protective properties.³⁴ 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 leads to the oxidation of LDL, another finding similar to atherosclerotic cardiovascular disease..³⁸

Statins for Prevention of Preeclampsia: Biological Plausibility

The properties and mechanisms of action of statins make them highly promising candidates for the prevention and/or treatment of preeclampsia. Statins up-regulate eNOS, promoting NO production in the vasculature.^39,40 They also promote VEGF and PlGF release, reduce sflt-1 and sEng concentrations, and up-regulate the transcription and expression of HO-1 in endothelial and vascular smooth muscle.^41–43 Activation of the HO-1/CO pathway by statins has been shown, in some but not all studies, to suppress the production of sFlt-1.⁴⁴ Statins are also known to have anti-inflammatory properties and have been shown to decrease hs-CRP even in patients with normal cholesterol levels.⁴⁵ They are also known to upregulate Th2 anti-inflammatory cytokine production and down regulate Th1 pro-inflammatory cytokine production (Table 1) [Figure 1].⁴⁶ These immunomodulatory and anti-inflammatory 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/or treatment of preeclampsia.

Table 1.

Mechanisms and effects of statins by cell type

	Mechanisms	Effects
Placental trophoblast cells41,42,56	Increased VEGF and PlGF	Decreased inflammation
	Increased HO-1	Improved vascular reactivity
	Decreased sFlt-1 and sEng
Platelets15,26	Inhibition of platelet adhesion	Decreased thrombosis
	Decreased TXA2
Monocytes/ macrophages15,26,31	Inhibition of T-cell adhesion, activation, and release of pro-inflammatory cytokines	Decreased inflammation
Endothelial progenitor cells15,26	Increased mobilization of stem cells	Improved neovascularization and re-endothelialization
Endothelial cells15,39,40	Increased eNOS	Improved endothelial function
	Decreased ET-1	Decreased oxidative stress
	Increased VEGF	Decreased vasoconstriction
	Decreased PAI-1	Decreased inflammation
	Decreased ROS	Improved angiogenesis
Vascular smooth muscle cells49	Decreased AT-1 receptor expression	Decreased vasoconstriction
	Decreased ROS

TXA₂ (thromboxane A2), PAI-1 (plasminogen activator inhibitor-1), ROS (reactive oxygen species), AT-1 (angiotensin II receptor type 1)

Preclinical Studies

The ability of statins to reverse pathophysiological pathways associated with preeclampsia and to ameliorate its phenotype was evaluated in several preclinical studies using tissue cultures and different rodent models of preeclampsia. Initial studies using preeclamptic villous explants and a mouse model of preeclampsia, demonstrated that simvastatin therapy increased endothelial HO-1 activity which, in turn, promoted VEGF and PlGF release and decreased sFlt-1 levels.⁴⁷ Other studies using primary endothelial cells, purified cytotrophoblast cells, and placental explants obtained from women with preterm preeclampsia, demonstrated that pravastatin decreased sFLt-1 and increased endothelial, but not placental, sEng secretion,⁴⁸ and that it was not dependent on upregulation 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 physiologic functions under normoxic conditions.⁴⁹ Lastly, pravastatin was also shown to reduce secretion of endothelin-1 and sFLT-1 in human umbilical vein endothelial and uterine microvascular cells.⁵⁰

Although some studies showed that simvastatin may be a more potent inhibitor of sFlt-1 secretion when compared with pravastatin or rosuvastatin,⁵¹ the majority of studies using murine preeclampsia models evaluated pravastatin, probably due to its more favorable pregnancy profile. Using an adenoviral overexpression of sFlt-1 model, we and others demonstrated that pravastatin improved vascular reactivity by decreasing sFlt-1 and sEng levels and upregulating eNOS in the vasculature.^42,52 In addition, pravastatin up-regulated the expression of VEGF and PlGF and a pro-survival/anti-apoptotic MAPK pathway in the placenta.⁵³ Various other models of preeclampsia including a CBA/J x DBA/2 model of immunologically-mediated preeclampsia,⁵⁴ C1q-deficient (C1q−/−),⁵⁵ and lentiviral vector-mediated placenta-specific sFlt-1 overexpression⁵⁶ reaffirmed that pravastatin restored angiogenic balance, lowered blood pressure, prevented kidney damage (decreased albuminuria, glomerular endotheliosis, and fibrin deposition), improved glomerular and placental blood flow, restored trophoblast invasiveness, and prevented pup growth restriction.^{54 43 55 15}

Human Studies

Earlier reports demonstrated that, when given to women with preterm preeclampsia, pravastatin use was associated with improvement in blood pressure, reduction in sFlt-1 serum concentrations, and improved pregnancy outcomes.⁴⁸ In addition, pravastatin improved angiogenic profiles and prevented fetal demise in a case report of patients with massive perivillous fibrin deposition in the placenta.⁵⁷ A pilot double-blind, placebo-controlled preeclampsia 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 prior preeclampsia that required preterm delivery before 34 weeks to either 10mg 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 two groups. Maternal and neonatal outcomes were overall more favorable in women randomized to pravastatin compared with placebo, with reduced rates of preeclampsia (0 vs. 40%), severe features of preeclampsia, and indicated preterm delivery before 37 weeks (10% vs. 50%). Women receiving pravastatin had increased serum PlGF and decreased sFlt-1 and sEng levels compared with those who received placebo, though the differences did not reach statistical significance. Additionally, 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.⁵⁸ 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 demonstrated similar findings (unpublished data).

Table 2.

Summary of results of 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. (ref)

	10 mg cohort
	Placebo (N= 10)	Pravastatin (N= 10)
Use of low-dose aspirin	3 (30)	2 (20)
Heartburn	3 (30)	4 (40)
Musculoskeletal pain	1 (10)	4 (40)
Maternal, fetal, or infant death	0	0
Rhabdomyolysis	0	0
Liver injury	0	0
Myopathy (weakness without increase in CK)	0	0
Congenital anomalies	2	2
Preeclampsia (any)	4 (40)	0
Preeclampsia with severe features	3 (30)	0
Gestational age at delivery (wks)	36.7± 2.1	37.7± 0.9
Indicated preterm delivery < 37 weeks	5 (50)	1 (10)
Indicated preterm delivery < 34 weeks	1(10)	0 (0)
Total cholesterol at 34– 37 weeks (mg/dl)	252 ± 27	207 ± 31
LDL cholesterol at 34–37 weeks (mg/dl)	130.8 ± 46.7	90.4 ± 21.9
Birth weight (g)	2,877±630	3,018± 260
Highest level of care routine nursery	5 (50)	8 (80)
NICU length of stay ≥ 48 hours	3 (30)	0

The use of pravastatin as a therapeutic agent was also evaluated in a prospective study of 21 women with antiphospholipid syndrome and poor pregnancy outcomes. All patients received low dose aspirin and low molecular weight heparin per local standard of care, were followed closely throughout pregnancy, and were assigned to pravastatin (20 mg) or standard of care when they developed preeclampsia and/or intrauterine growth restriction. Compared with patients in the control cohort, those who received pravastatin had improved uterine artery Doppler velocimetry, lower blood pressure (130/89, IQR [125–130/85–90] vs. 160/98, IQR [138–180/90–110]), and delivered infants with higher birthweight (2390 grams, IQR [2065–2770] vs. 900 grams, IQR [580–1100]), at a more advanced gestational age (36 weeks, IQR [35–36] weeks vs. 26.5 weeks, IQR [26–32]).⁵⁹ Moreover, the StAmP trial randomized women with early-onset preeclampsia (24 to 31 weeks) to pravastatin 40 mg or placebo.⁶⁰ The difference in sFlt-1 levels 3 days after randomization between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95%CI 1175–592; p=0.5) and 14 days after randomization was 48 pg/ml (95% CI 1009–913; p=0.9). Subjects who received pravastatin had a similar gestational latency after randomization when compared to placebo (HR 0.84; 95%CI 0.50–1.40; p=0.6) 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 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.⁶¹ Last, the effect of pravastatin in pregnancy with early-onset fetal growth restriction (FGR) was evaluated in a non-randomized controlled study conducted in Spain. Women with early onset FGR ≤ 28 weeks were offered pravastatin 40 mg daily (n=19). A control group (n=19) was matched to the treatment group for gestational age, maternal, obstetric, Doppler findings, and angiogenic factors.⁸⁴ Treatment with pravastatin was associated with significant improvement in angiogenic profile. In addition, latency from diagnosis to delivery was extended by 16.5 days, median newborn birthweight was increased by 260 grams, and the rate of preeclampsia decreased from 47.4% to 31.6%. However, these clinical findings were not statistically significant

While these 4 studies offer insight into the potential role of statins for preeclampsia, they are limited by sample size and are conflicting in their design and findings. Specifically, the StAmP trial was limited by the timing of the primary outcome, small sample size, slow recruitment, and study medication non-compliance and neither the StAmP trial nor the NICHD pilot trial were powered for maternal or fetal outcomes. Furthermore, similar to the use of aspirin for preeclampsia 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 preeclampsia and other hypertensive disorders in various high-risk groups. Future investigations should include randomized-controlled trials evaluating different statins, doses of pravastatin for both prevention and treatment, and study populations for which statin therapy may be beneficial.

Statin Use in Pregnancy

Fetal Effects

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. Six of the seven 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 last step of cholesterol synthesis in which is dehydrocholesterol is converted to cholesterol by 7-dehydrocholesterol reductase. This results in a disorder known as known as Smith-Lemli-Optiz 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 syncitiotrophoblast of the placenta, which expresses LDL receptors. Though there is a physiologic 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.^62,63 This is supported by the fact that fetuses with Smith-Lemli-Optiz syndrome have very low cholesterol concentrations and are not rescued by the normal maternal cholesterol levels. It is also supported by studies showing 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.^64,65 In the presence of normal fetal sterol synthesis, maternal cholesterol supply is of minimal importance.⁶²

Given the well-known lipid-lowering effects of statins, there has been historic concern surrounding their use in pregnancy. In 2015 the U.S. Food and Drug Administration (FDA) implemented the Pregnancy Lactation Labeling Rule (PLLR) which required that drug manufacturers replace the previous pregnancy letter categorization (i.e., 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. Prior to 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 case reports and animal studies from the 1980s which demonstrated teratogenicity with high doses of statins (namely lovastatin) in rats.⁶⁶ Though the teratogenicity of statins, especially pravastatin, has largely been debunked, they remain contraindicated in pregnancy. This is primarily due to theoretical concerns and a lack of data supporting an indication for their use in pregnancy.⁶⁷ Several cohorts (Table 3) of women exposed to statins during pregnancy did not demonstrate 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 US of more than 800,000 pregnant women, including 1,152 exposed to statins in the first trimester, and after controlling for confounders (particularly pre-existing diabetes) and conducting a propensity score matching, there was no increased risk of congenital malformation (aOR 1.07; 95% CI 0.85–1.37) or any pattern of anomalies or propensity for select organ systems with the use of statins.⁶⁸ A 2016 systematic review that included 16 clinical studies (5 case series, 3 cohort series, 3 registry-based studies, 1 randomized-controlled trial, and 4 other systematic reviews) found no relationship between statin use in pregnancy and congenital anomalies.⁶⁷ Similarly, the more recent cohort and registry-based studies, which controlled for risk factors did not find statins to be teratogenic.⁶⁷ Therefore, it is prudent to interpret the early case series with caution as they did not adjust for confounders and were limited by selection bias.⁶⁷ Moreover, data from the recent pilot human trials, in which pravastatin was used for a much longer duration outside the first trimester, support its safety in pregnancy. In the US pilot trial, there was 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. Additionally, all newborns exposed to pravastatin passed either an Auditory Brain Stem Response (ABR) or Otoacoustic Emissions (OAE) test before discharge from the hospital after birth.⁵⁸ Similarly, the StAmP trial reported no detectable adverse effects on the short-term health of offspring,⁶⁰ and the APLS cohort reported improved neonatal outcomes among those born to mothers who received pravastatin compared with placebo.⁵⁹

Table 3.

Summary of major studies assessing the risk of congenital anomalies with the use of statins in pregnancy

Study	Year	Study type	Population/ exposure	Statin (n)	Control (n)	Congenital anomalies
Edison et al80	2004	case series	Ascertained reports of exposure to statin reported to the FDA (1987 to 2001)	n=70; pravastatin n=20	None	22 reports of congenital anomalies, none with pravastatin
Ofori et al63	2007	Population based registry	Statin use within one year before and during pregnancy (1997–2003)	n=64; pravastatin n=12	Use of statins only before conception (1 year – 1 month) (n=67)	Exposed vs non-exposed: 4.7% vs.10.5% aOR 0.36 (95% CI 0.06–2.18) No anomalies with pravastatin
Taguchi et al81	2008	Prospective observational cohort	Pregnant women exposed to statins and contacting the motherisk teratology information service (1998 to 2005)	n=64; pravastatin n=6	No exposure to known teratogens (n=64)	Exposed vs non-exposed: 2.2% vs 1.9%; p = 0.93
Winterfeldet al82	2013	Multicenter observational prospective	Pregnant women exposed to statins and contacting the European teratology information services (1990–2009)	(n=249; pravastatin n=32)	Exposure to agents known to be non-teratogenic (n=249)	Exposed vs non-exposed.: 4.1% vs. 2.7%, OR 1.5 (95% CI 0.5 – 4.5)
Bateman et al68	2015	cohort	Women with live birth, from US Medicaid data (2000–2007)	n=1152; pravastatin n=75	No statin use in the first trimester (propensity score matched group)	Exposed vs non-exposed: 6.3% vs. 3.6%, aOR 1.04 (95% CI 0.85–1.37)
Costantine et al58	2016	Randomized trial	Women with history of prior preeclampsia that required preterm delivery before 34 weeks, randomized to 10mg pravastatin vs placebo between 12–16 weeks.	Pravastatin (10)	Placebo (n=10)	One fetus in the pravastatin group had hypospadias and another had coarctation of the aorta (diagnosed postnatally), whereas in the placebo group, one fetus had polydactyly and another had ventriculomegaly.
Lefkou et al59	2016	Prospective cohort	Women with antiphospholipid syndrome and poor obstetric history.	Pravastatin (n=11)	Patients receiving standard of care (n=10)	n/a (No reports of congenital anomalies)
McGrogan et al83	2017	cohort	Women using statins before or during the 1st trimester (1992 – 2009)	n = 281, pravastatin n=8	No statin use (n = 2,643)	Exposed vs non-exposed: 3.2% vs. 2.8%, OR* 1.6 (95% CI 0.72–3.64)
Ahmed et al60	2020	Randomized trial	Women with early-onset preeclampsia, randomized to 40mg pravastatin vs placebo	Pravastatin (30)	Placebo (n=32)	n/a (no detectable adverse effects on the short-term health of offspring)

^*Unadjusted OR calculated from data in report.

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.⁶³ Pravastatin remains one of the least potent statins with high hepato-selectivity and limited transfer across the placenta.^69–71 The limited transplacental transfer of pravastatin is supported by its hydrophilicity and its action as a substrate to placental efflux transporters.⁷² 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.^58,60,73

Maternal Effects

The safety and side effects profile of statins have been studied extensively in the non-obstetric population. In general, statins are considered safe and well-tolerated, especially pravastatin. Pooled data from large randomized-controlled trials in non-pregnant patients have reassured clinicians that serious side effects of pravastatin, most notably liver injury and rhabdomyolysis, are extremely rare. Three 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 pravastatin 40 mg daily or placebo and accumulated more than 112,000 person-years of exposure. During five years of exposure, the rates of marked elevations of aminotransferases were low and similar between the two groups (<1.2%).^21,74,75 In an indirect comparison meta-analysis which included 159,458 patients, Alberton et al assessed 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 less than 2%.⁷⁶ This finding is consistent with other large, long-term studies. In these trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal side effects. Myalgia is also a common symptom associated with pravastatin use and ranges in incidence from 0.6 to 10.9%.⁷⁷ 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.⁷⁸ An additional benefit of pravastatin compared with other statins, is that it is the least diabetogenic.⁷⁹

Data regarding maternal safety of pravastatin use in pregnancy are limited to the more recent trials and cohorts, which showed similar rates of adverse and serious adverse events between pravastatin and placebo groups with the most common side 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.^{58 60}

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. The majority of pravastatin following hepatic uptake is excreted into bile and eventually re-enters 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.⁷¹ As such, pravastatin was not found in adult cerebrospinal fluid and is thought to have limited ability to cross the blood-brain barrier.⁷¹ Moreover, the pharmacokinetics of pravastatin are not significantly changed by renal or hepatic dysfunction, making it appealing for use with preeclampsia.⁷¹

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 2–3 hours in pregnancy and not different from postpartum values. Similarly, pravastatin C_max, T_max, and fraction of the drug excreted unchanged in the urine are consistent with those previously reported in non-pregnant subjects. However, it appears that there is an increase in apparent oral clearance (CL/F) and a decrease in pravastatin area under the curve (AUC) in pregnancy compared with postpartum, predominantly related to the increased in renal clearance during pregnancy.

Conclusion

Preeclampsia is a common hypertensive disorder of pregnancy associated with significant maternal and fetal morbidity. 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 preeclampsia. Though promising, these preventive benefits, along with the potential role of statin therapy in the treatment of preeclampsia, must be investigated in larger randomized-controlled trials.