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In the United States, preeclampsia affects 3%-5% of all pregnancies and 10%-20% of pregnancies complicated by diabetes. Up to 20% of maternal deaths in the United States – and a much larger percentage of maternal deaths worldwide – occur in women with the condition, as do numerous maternal and fetal comorbidities. These include severe hypertension, pulmonary edema, stroke, and kidney and liver injury in the mother, and stillbirth, placental abruption, growth restriction, and premature delivery of the fetus.
Longer-term complications for the offspring include chronic lung disease, hearing and vision disorders, cerebral palsy and other neurodevelopmental disorders, and – as shown by more recent research – poor cardiovascular and metabolic outcomes.
Preeclampsia predisposes the mother to at least a twofold increased risk of future heart disease, compared with a woman who does not have the condition. In addition, women with preeclampsia who deliver at term are approximately two times more likely to die prematurely from heart disease than women without a history of preeclampsia, and those who deliver before 34 weeks’ gestation have been shown to have a ninefold greater risk of premature death. The American Heart Association, in fact, now includes preeclampsia in its list of heart disease risk factors.
Much attention now is focused on statins (inhibitors of HMG-CoA reductase), which have been used for more than 30 years for the primary and secondary prevention of heart disease. The properties and mechanisms of this class of drugs – and the similarities in the pathophysiology of cardiovascular disease and preeclampsia – make statins a plausible candidate for preeclampsia prevention. Thus far, data from preclinical work and subsequent pilot studies have been encouraging.
The commonalities
Preeclampsia is unique to pregnancy, but its pathophysiology and risk factors largely overlap with those of adult atherosclerotic cardiovascular disease. The exact pathophysiology of preeclampsia is unknown, but it is generally agreed that angiogenic imbalance and endothelial dysfunction play key roles, as do associated inflammation and oxidative stress.
Women with preeclampsia have been shown, for instance, to have had increased levels of antiangiogenic factors (soluble FMS-like tyrosine kinase 1 and soluble endoglin) and decreased levels of angiogenic factors (vascular endothelial growth factor and placental growth factor) prior to developing the condition clinically. Risk factors common to both preeclampsia and heart disease include chronic hypertension, dyslipidemia, diabetes or insulin resistance, obesity, and a family history of the condition.
Statins, meanwhile, have been shown to prevent or reverse angiogenic imbalance by promoting the release of vascular endothelial growth factor and placental growth factor and by suppressing the production of soluble FMS-like tyrosine kinase 1 and soluble endoglin. The drugs also improve vascular relaxation and exhibit anti-inflammatory and antioxidative effects, thereby broadly improving endovascular health. In the cardiovascular arena, notably, men and women who have elevated inflammatory markers even without hypercholesterolemia have been shown to have improved cardiovascular outcomes with statin treatment.
In various mouse models of preeclampsia studied in the past decade, pravastatin, a hydrophilic statin, has had beneficial effects. Mice with the angiogenic imbalance characteristic of preeclampsia that received this statin have shown a reversal of the imbalance, as well as reduced blood pressure, increased levels of nitric oxide synthase production, decreased oxidative stress, improved vascular reactivity, decreased kidney damage and proteinuria, and other positive effects. These effects occurred without detrimental outcomes to the mice or any increase in the rates of anomalies or resorption in offspring (Clin Obstet Gynecol. 2017 Mar;60:161-8).
Moreover, in addition to ameliorating the preeclampsia phenotype, pravastatin use in these animal models has improved pregnancy outcomes and reduced rates of pregnancy losses.
Safety issues
So, can we use statins in pregnancy? When statins were originally marketed in the 1980s, they were labeled pregnancy category X, which means 1) that there is evidence of fetal abnormalities or risk and 2) that these risks clearly outweigh potential benefits.
This designation for statins was based largely on the second half of the definition (no benefit to outweigh any risk). In addition, there were theoretical concerns about the inhibition of cholesterol synthesis during embryologic development and about a small case series of the original lipophilic statins suggesting an increased risk of malformations. While pregnancy category X does not exist anymore, statins are still labeled as contraindicated in pregnancy.
Pravastatin is one of the safest statins to consider in pregnancy for several reasons: It is one of the most hydrophilic statins and is a substrate of the placental efflux transporters, such as P-glycoprotein; both of those properties limit its ability to cross the placenta. It also has a short-elimination half-life, is cleared through both hepatic and renal routes, and is among the most hepatoselective statins available (one of the weakest inhibitors of HMG-CoA reductase). Indeed, in vitro placental transfer studies suggest that pravastatin transfer is limited and slow and that clearance is significantly higher in the fetal-to-maternal direction than in the maternal-to-fetal direction.
Animal studies have demonstrated that pravastatin is not teratogenic and has no effect on placental weight, pup birth weight, and pup adult weight. Moreover, at least six published cohort studies of women with first-trimester exposure to statins (women who had been prescribed the drugs before becoming pregnant and who received the drugs in the first trimester before realizing they were pregnant) showed no patterns or increased rates of congenital anomalies, compared with women without exposure to known teratogens. Additionally, these cohorts did not show any associations with miscarriage or fetal growth restriction (Obstet Gynecol. 2013 Feb;121:349-53).
A more recent cohort study of close to 900,000 women – of which 1,152 women used a statin (pravastatin or other statins) during their first trimester – similarly found no significant increases in any type of congenital malformation, compared with other completed pregnancies in the larger cohort. Notably, the analysis of this cohort was done using propensity score–based methods to control for potential confounders, including prepregnancy conditions that prompted use of a statin (BMJ. 2015;350:h1035).
A drawback to this body of research is that, with the exception of the BMJ study, the cohorts have been generally small; furthermore, in keeping with current recommendations, most of the statin-exposed patients discontinued use of the drugs upon confirmation of their pregnancies, thereby leaving the effects of long-term use unknown.
A promising pilot
Daily pravastatin use in pregnancy, starting in the second trimester, got its first major test of safety and pharmacokinetics in a pilot randomized, controlled trial undertaken by the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s (NICHD’s) Obstetric-Fetal Pharmacology Research Units Network. Women with singleton pregnancies and a history of severe preeclampsia requiring delivery prior to 34 weeks’ gestation were randomized between 12 and 16 weeks’ gestation to receive pravastatin or placebo until delivery.
This pilot is the first of three cohorts of women who were or will be randomized in separate pilot trials to escalating doses of pravastatin: 10 mg, 20 mg, and 40 mg (the last of which is the usual dose for lipid lowering in adults). Results of the first cohort, in which 20 patients were randomized to 10 mg pravastatin or placebo, were reported in 2016, and those from the second cohort will be reported soon. The third pilot is currently enrolling women.
In this first pilot we found no differences in rates of congenital anomalies or other identifiable maternal or fetal/neonatal safety risks, no differences in adverse events, and no maternal, fetal, or neonatal deaths. There were also no reports of myopathy/rhabdomyolysis or liver injury; the most common adverse events were heartburn (reported by four patients in the pravastatin group and three in the placebo group) and musculoskeletal pain (reported by four patients and one patient, respectively).
Although not statistically significant, a 10-mg dose of pravastatin was associated with favorable outcomes. None of the women receiving pravastatin developed preeclampsia, while four in the placebo group developed the disorder (with three of these four having severe preeclampsia).
Women in the pravastatin group also were less likely to have an indicated preterm delivery (one vs. five in the placebo group), and their neonates were less likely to be admitted to intermediate nurseries or the neonatal ICU. In addition, their angiogenic profiles were improved (higher placental growth factor and lower FMS-like tyrosine kinase 1 and soluble endoglin).
Importantly, while pravastatin reduced maternal cholesterol concentrations, there were no differences in birth weight or umbilical cord cholesterol concentrations (total cholesterol or LDL) between the two groups (Am J Obstet Gynecol. 2016;214[6]:720.e1-17).
That cholesterol concentrations were not reduced in fetuses exposed to pravastatin is reassuring and aligns with findings from other studies showing that fetal cholesterol concentrations are largely independent from maternal cholesterol concentrations or diet. For instance, we know from studies of Smith-Lemli-Opitz syndrome, a multiple congenital anomaly/intellectual disability syndrome caused by a defect in cholesterol synthesis, that there is not any significant interaction between cholesterol concentrations of the mother and fetus. Only about 10% of the fetal absolute cholesterol requirement comes from the mother, research has demonstrated.
The future
Infant follow-up in the NICHD study is planned, and a large, randomized clinical trial powered to look at the efficacy of pravastatin for preventing preeclampsia in high-risk women has been approved by the NICHD. Once funded, the study is expected to enroll approximately 1,700 pregnant women who have a history of severe preeclampsia and delivery before 36 weeks’ gestation and who are between 10 and 16 weeks’ gestation.
With continued research, we face the question of whether pravastatin may potentiate the benefit of aspirin in pregnant women. In cardiovascular medicine, there is evidence for additive or synergistic effects of the combined use of aspirin and statins.
Interestingly, a recent prospective cohort study of women with antiphospholipid syndrome and poor outcomes in prior pregnancies showed dramatic improvement in both maternal and fetal/neonatal outcomes when pravastatin was administered after the onset of preeclampsia or intrauterine growth restriction. All 21 women in the cohort were treated with low-dose aspirin and low-molecular-weight heparin; after the development of preeclampsia or intrauterine growth restriction, 10 patients were maintained on aspirin and LMWH, and 11 were started on 20 mg daily pravastatin along with the aspirin and LMWH (J Clin Invest. 2016 Aug;126[8]:2933-40; and J Clin Invest. 2016 Aug;126[8]:2792-4).
Those who received the statin had improved uterine artery Doppler velocimetry, lower systemic blood pressure, and delivered infants with higher birth weights and at a more advanced gestational age (median, 36 weeks’ vs. 26.5 weeks’ gestation). The study did not randomly allocate the women and did not include a placebo arm. Still, it is another impressive proof-of-concept study.
Dr. Costantine is an associate professor of obstetrics and gynecology at the University of Texas Medical Branch in Galveston. He reported that he has no financial disclosures.
In the United States, preeclampsia affects 3%-5% of all pregnancies and 10%-20% of pregnancies complicated by diabetes. Up to 20% of maternal deaths in the United States – and a much larger percentage of maternal deaths worldwide – occur in women with the condition, as do numerous maternal and fetal comorbidities. These include severe hypertension, pulmonary edema, stroke, and kidney and liver injury in the mother, and stillbirth, placental abruption, growth restriction, and premature delivery of the fetus.
Longer-term complications for the offspring include chronic lung disease, hearing and vision disorders, cerebral palsy and other neurodevelopmental disorders, and – as shown by more recent research – poor cardiovascular and metabolic outcomes.
Preeclampsia predisposes the mother to at least a twofold increased risk of future heart disease, compared with a woman who does not have the condition. In addition, women with preeclampsia who deliver at term are approximately two times more likely to die prematurely from heart disease than women without a history of preeclampsia, and those who deliver before 34 weeks’ gestation have been shown to have a ninefold greater risk of premature death. The American Heart Association, in fact, now includes preeclampsia in its list of heart disease risk factors.
Much attention now is focused on statins (inhibitors of HMG-CoA reductase), which have been used for more than 30 years for the primary and secondary prevention of heart disease. The properties and mechanisms of this class of drugs – and the similarities in the pathophysiology of cardiovascular disease and preeclampsia – make statins a plausible candidate for preeclampsia prevention. Thus far, data from preclinical work and subsequent pilot studies have been encouraging.
The commonalities
Preeclampsia is unique to pregnancy, but its pathophysiology and risk factors largely overlap with those of adult atherosclerotic cardiovascular disease. The exact pathophysiology of preeclampsia is unknown, but it is generally agreed that angiogenic imbalance and endothelial dysfunction play key roles, as do associated inflammation and oxidative stress.
Women with preeclampsia have been shown, for instance, to have had increased levels of antiangiogenic factors (soluble FMS-like tyrosine kinase 1 and soluble endoglin) and decreased levels of angiogenic factors (vascular endothelial growth factor and placental growth factor) prior to developing the condition clinically. Risk factors common to both preeclampsia and heart disease include chronic hypertension, dyslipidemia, diabetes or insulin resistance, obesity, and a family history of the condition.
Statins, meanwhile, have been shown to prevent or reverse angiogenic imbalance by promoting the release of vascular endothelial growth factor and placental growth factor and by suppressing the production of soluble FMS-like tyrosine kinase 1 and soluble endoglin. The drugs also improve vascular relaxation and exhibit anti-inflammatory and antioxidative effects, thereby broadly improving endovascular health. In the cardiovascular arena, notably, men and women who have elevated inflammatory markers even without hypercholesterolemia have been shown to have improved cardiovascular outcomes with statin treatment.
In various mouse models of preeclampsia studied in the past decade, pravastatin, a hydrophilic statin, has had beneficial effects. Mice with the angiogenic imbalance characteristic of preeclampsia that received this statin have shown a reversal of the imbalance, as well as reduced blood pressure, increased levels of nitric oxide synthase production, decreased oxidative stress, improved vascular reactivity, decreased kidney damage and proteinuria, and other positive effects. These effects occurred without detrimental outcomes to the mice or any increase in the rates of anomalies or resorption in offspring (Clin Obstet Gynecol. 2017 Mar;60:161-8).
Moreover, in addition to ameliorating the preeclampsia phenotype, pravastatin use in these animal models has improved pregnancy outcomes and reduced rates of pregnancy losses.
Safety issues
So, can we use statins in pregnancy? When statins were originally marketed in the 1980s, they were labeled pregnancy category X, which means 1) that there is evidence of fetal abnormalities or risk and 2) that these risks clearly outweigh potential benefits.
This designation for statins was based largely on the second half of the definition (no benefit to outweigh any risk). In addition, there were theoretical concerns about the inhibition of cholesterol synthesis during embryologic development and about a small case series of the original lipophilic statins suggesting an increased risk of malformations. While pregnancy category X does not exist anymore, statins are still labeled as contraindicated in pregnancy.
Pravastatin is one of the safest statins to consider in pregnancy for several reasons: It is one of the most hydrophilic statins and is a substrate of the placental efflux transporters, such as P-glycoprotein; both of those properties limit its ability to cross the placenta. It also has a short-elimination half-life, is cleared through both hepatic and renal routes, and is among the most hepatoselective statins available (one of the weakest inhibitors of HMG-CoA reductase). Indeed, in vitro placental transfer studies suggest that pravastatin transfer is limited and slow and that clearance is significantly higher in the fetal-to-maternal direction than in the maternal-to-fetal direction.
Animal studies have demonstrated that pravastatin is not teratogenic and has no effect on placental weight, pup birth weight, and pup adult weight. Moreover, at least six published cohort studies of women with first-trimester exposure to statins (women who had been prescribed the drugs before becoming pregnant and who received the drugs in the first trimester before realizing they were pregnant) showed no patterns or increased rates of congenital anomalies, compared with women without exposure to known teratogens. Additionally, these cohorts did not show any associations with miscarriage or fetal growth restriction (Obstet Gynecol. 2013 Feb;121:349-53).
A more recent cohort study of close to 900,000 women – of which 1,152 women used a statin (pravastatin or other statins) during their first trimester – similarly found no significant increases in any type of congenital malformation, compared with other completed pregnancies in the larger cohort. Notably, the analysis of this cohort was done using propensity score–based methods to control for potential confounders, including prepregnancy conditions that prompted use of a statin (BMJ. 2015;350:h1035).
A drawback to this body of research is that, with the exception of the BMJ study, the cohorts have been generally small; furthermore, in keeping with current recommendations, most of the statin-exposed patients discontinued use of the drugs upon confirmation of their pregnancies, thereby leaving the effects of long-term use unknown.
A promising pilot
Daily pravastatin use in pregnancy, starting in the second trimester, got its first major test of safety and pharmacokinetics in a pilot randomized, controlled trial undertaken by the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s (NICHD’s) Obstetric-Fetal Pharmacology Research Units Network. Women with singleton pregnancies and a history of severe preeclampsia requiring delivery prior to 34 weeks’ gestation were randomized between 12 and 16 weeks’ gestation to receive pravastatin or placebo until delivery.
This pilot is the first of three cohorts of women who were or will be randomized in separate pilot trials to escalating doses of pravastatin: 10 mg, 20 mg, and 40 mg (the last of which is the usual dose for lipid lowering in adults). Results of the first cohort, in which 20 patients were randomized to 10 mg pravastatin or placebo, were reported in 2016, and those from the second cohort will be reported soon. The third pilot is currently enrolling women.
In this first pilot we found no differences in rates of congenital anomalies or other identifiable maternal or fetal/neonatal safety risks, no differences in adverse events, and no maternal, fetal, or neonatal deaths. There were also no reports of myopathy/rhabdomyolysis or liver injury; the most common adverse events were heartburn (reported by four patients in the pravastatin group and three in the placebo group) and musculoskeletal pain (reported by four patients and one patient, respectively).
Although not statistically significant, a 10-mg dose of pravastatin was associated with favorable outcomes. None of the women receiving pravastatin developed preeclampsia, while four in the placebo group developed the disorder (with three of these four having severe preeclampsia).
Women in the pravastatin group also were less likely to have an indicated preterm delivery (one vs. five in the placebo group), and their neonates were less likely to be admitted to intermediate nurseries or the neonatal ICU. In addition, their angiogenic profiles were improved (higher placental growth factor and lower FMS-like tyrosine kinase 1 and soluble endoglin).
Importantly, while pravastatin reduced maternal cholesterol concentrations, there were no differences in birth weight or umbilical cord cholesterol concentrations (total cholesterol or LDL) between the two groups (Am J Obstet Gynecol. 2016;214[6]:720.e1-17).
That cholesterol concentrations were not reduced in fetuses exposed to pravastatin is reassuring and aligns with findings from other studies showing that fetal cholesterol concentrations are largely independent from maternal cholesterol concentrations or diet. For instance, we know from studies of Smith-Lemli-Opitz syndrome, a multiple congenital anomaly/intellectual disability syndrome caused by a defect in cholesterol synthesis, that there is not any significant interaction between cholesterol concentrations of the mother and fetus. Only about 10% of the fetal absolute cholesterol requirement comes from the mother, research has demonstrated.
The future
Infant follow-up in the NICHD study is planned, and a large, randomized clinical trial powered to look at the efficacy of pravastatin for preventing preeclampsia in high-risk women has been approved by the NICHD. Once funded, the study is expected to enroll approximately 1,700 pregnant women who have a history of severe preeclampsia and delivery before 36 weeks’ gestation and who are between 10 and 16 weeks’ gestation.
With continued research, we face the question of whether pravastatin may potentiate the benefit of aspirin in pregnant women. In cardiovascular medicine, there is evidence for additive or synergistic effects of the combined use of aspirin and statins.
Interestingly, a recent prospective cohort study of women with antiphospholipid syndrome and poor outcomes in prior pregnancies showed dramatic improvement in both maternal and fetal/neonatal outcomes when pravastatin was administered after the onset of preeclampsia or intrauterine growth restriction. All 21 women in the cohort were treated with low-dose aspirin and low-molecular-weight heparin; after the development of preeclampsia or intrauterine growth restriction, 10 patients were maintained on aspirin and LMWH, and 11 were started on 20 mg daily pravastatin along with the aspirin and LMWH (J Clin Invest. 2016 Aug;126[8]:2933-40; and J Clin Invest. 2016 Aug;126[8]:2792-4).
Those who received the statin had improved uterine artery Doppler velocimetry, lower systemic blood pressure, and delivered infants with higher birth weights and at a more advanced gestational age (median, 36 weeks’ vs. 26.5 weeks’ gestation). The study did not randomly allocate the women and did not include a placebo arm. Still, it is another impressive proof-of-concept study.
Dr. Costantine is an associate professor of obstetrics and gynecology at the University of Texas Medical Branch in Galveston. He reported that he has no financial disclosures.
In the United States, preeclampsia affects 3%-5% of all pregnancies and 10%-20% of pregnancies complicated by diabetes. Up to 20% of maternal deaths in the United States – and a much larger percentage of maternal deaths worldwide – occur in women with the condition, as do numerous maternal and fetal comorbidities. These include severe hypertension, pulmonary edema, stroke, and kidney and liver injury in the mother, and stillbirth, placental abruption, growth restriction, and premature delivery of the fetus.
Longer-term complications for the offspring include chronic lung disease, hearing and vision disorders, cerebral palsy and other neurodevelopmental disorders, and – as shown by more recent research – poor cardiovascular and metabolic outcomes.
Preeclampsia predisposes the mother to at least a twofold increased risk of future heart disease, compared with a woman who does not have the condition. In addition, women with preeclampsia who deliver at term are approximately two times more likely to die prematurely from heart disease than women without a history of preeclampsia, and those who deliver before 34 weeks’ gestation have been shown to have a ninefold greater risk of premature death. The American Heart Association, in fact, now includes preeclampsia in its list of heart disease risk factors.
Much attention now is focused on statins (inhibitors of HMG-CoA reductase), which have been used for more than 30 years for the primary and secondary prevention of heart disease. The properties and mechanisms of this class of drugs – and the similarities in the pathophysiology of cardiovascular disease and preeclampsia – make statins a plausible candidate for preeclampsia prevention. Thus far, data from preclinical work and subsequent pilot studies have been encouraging.
The commonalities
Preeclampsia is unique to pregnancy, but its pathophysiology and risk factors largely overlap with those of adult atherosclerotic cardiovascular disease. The exact pathophysiology of preeclampsia is unknown, but it is generally agreed that angiogenic imbalance and endothelial dysfunction play key roles, as do associated inflammation and oxidative stress.
Women with preeclampsia have been shown, for instance, to have had increased levels of antiangiogenic factors (soluble FMS-like tyrosine kinase 1 and soluble endoglin) and decreased levels of angiogenic factors (vascular endothelial growth factor and placental growth factor) prior to developing the condition clinically. Risk factors common to both preeclampsia and heart disease include chronic hypertension, dyslipidemia, diabetes or insulin resistance, obesity, and a family history of the condition.
Statins, meanwhile, have been shown to prevent or reverse angiogenic imbalance by promoting the release of vascular endothelial growth factor and placental growth factor and by suppressing the production of soluble FMS-like tyrosine kinase 1 and soluble endoglin. The drugs also improve vascular relaxation and exhibit anti-inflammatory and antioxidative effects, thereby broadly improving endovascular health. In the cardiovascular arena, notably, men and women who have elevated inflammatory markers even without hypercholesterolemia have been shown to have improved cardiovascular outcomes with statin treatment.
In various mouse models of preeclampsia studied in the past decade, pravastatin, a hydrophilic statin, has had beneficial effects. Mice with the angiogenic imbalance characteristic of preeclampsia that received this statin have shown a reversal of the imbalance, as well as reduced blood pressure, increased levels of nitric oxide synthase production, decreased oxidative stress, improved vascular reactivity, decreased kidney damage and proteinuria, and other positive effects. These effects occurred without detrimental outcomes to the mice or any increase in the rates of anomalies or resorption in offspring (Clin Obstet Gynecol. 2017 Mar;60:161-8).
Moreover, in addition to ameliorating the preeclampsia phenotype, pravastatin use in these animal models has improved pregnancy outcomes and reduced rates of pregnancy losses.
Safety issues
So, can we use statins in pregnancy? When statins were originally marketed in the 1980s, they were labeled pregnancy category X, which means 1) that there is evidence of fetal abnormalities or risk and 2) that these risks clearly outweigh potential benefits.
This designation for statins was based largely on the second half of the definition (no benefit to outweigh any risk). In addition, there were theoretical concerns about the inhibition of cholesterol synthesis during embryologic development and about a small case series of the original lipophilic statins suggesting an increased risk of malformations. While pregnancy category X does not exist anymore, statins are still labeled as contraindicated in pregnancy.
Pravastatin is one of the safest statins to consider in pregnancy for several reasons: It is one of the most hydrophilic statins and is a substrate of the placental efflux transporters, such as P-glycoprotein; both of those properties limit its ability to cross the placenta. It also has a short-elimination half-life, is cleared through both hepatic and renal routes, and is among the most hepatoselective statins available (one of the weakest inhibitors of HMG-CoA reductase). Indeed, in vitro placental transfer studies suggest that pravastatin transfer is limited and slow and that clearance is significantly higher in the fetal-to-maternal direction than in the maternal-to-fetal direction.
Animal studies have demonstrated that pravastatin is not teratogenic and has no effect on placental weight, pup birth weight, and pup adult weight. Moreover, at least six published cohort studies of women with first-trimester exposure to statins (women who had been prescribed the drugs before becoming pregnant and who received the drugs in the first trimester before realizing they were pregnant) showed no patterns or increased rates of congenital anomalies, compared with women without exposure to known teratogens. Additionally, these cohorts did not show any associations with miscarriage or fetal growth restriction (Obstet Gynecol. 2013 Feb;121:349-53).
A more recent cohort study of close to 900,000 women – of which 1,152 women used a statin (pravastatin or other statins) during their first trimester – similarly found no significant increases in any type of congenital malformation, compared with other completed pregnancies in the larger cohort. Notably, the analysis of this cohort was done using propensity score–based methods to control for potential confounders, including prepregnancy conditions that prompted use of a statin (BMJ. 2015;350:h1035).
A drawback to this body of research is that, with the exception of the BMJ study, the cohorts have been generally small; furthermore, in keeping with current recommendations, most of the statin-exposed patients discontinued use of the drugs upon confirmation of their pregnancies, thereby leaving the effects of long-term use unknown.
A promising pilot
Daily pravastatin use in pregnancy, starting in the second trimester, got its first major test of safety and pharmacokinetics in a pilot randomized, controlled trial undertaken by the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s (NICHD’s) Obstetric-Fetal Pharmacology Research Units Network. Women with singleton pregnancies and a history of severe preeclampsia requiring delivery prior to 34 weeks’ gestation were randomized between 12 and 16 weeks’ gestation to receive pravastatin or placebo until delivery.
This pilot is the first of three cohorts of women who were or will be randomized in separate pilot trials to escalating doses of pravastatin: 10 mg, 20 mg, and 40 mg (the last of which is the usual dose for lipid lowering in adults). Results of the first cohort, in which 20 patients were randomized to 10 mg pravastatin or placebo, were reported in 2016, and those from the second cohort will be reported soon. The third pilot is currently enrolling women.
In this first pilot we found no differences in rates of congenital anomalies or other identifiable maternal or fetal/neonatal safety risks, no differences in adverse events, and no maternal, fetal, or neonatal deaths. There were also no reports of myopathy/rhabdomyolysis or liver injury; the most common adverse events were heartburn (reported by four patients in the pravastatin group and three in the placebo group) and musculoskeletal pain (reported by four patients and one patient, respectively).
Although not statistically significant, a 10-mg dose of pravastatin was associated with favorable outcomes. None of the women receiving pravastatin developed preeclampsia, while four in the placebo group developed the disorder (with three of these four having severe preeclampsia).
Women in the pravastatin group also were less likely to have an indicated preterm delivery (one vs. five in the placebo group), and their neonates were less likely to be admitted to intermediate nurseries or the neonatal ICU. In addition, their angiogenic profiles were improved (higher placental growth factor and lower FMS-like tyrosine kinase 1 and soluble endoglin).
Importantly, while pravastatin reduced maternal cholesterol concentrations, there were no differences in birth weight or umbilical cord cholesterol concentrations (total cholesterol or LDL) between the two groups (Am J Obstet Gynecol. 2016;214[6]:720.e1-17).
That cholesterol concentrations were not reduced in fetuses exposed to pravastatin is reassuring and aligns with findings from other studies showing that fetal cholesterol concentrations are largely independent from maternal cholesterol concentrations or diet. For instance, we know from studies of Smith-Lemli-Opitz syndrome, a multiple congenital anomaly/intellectual disability syndrome caused by a defect in cholesterol synthesis, that there is not any significant interaction between cholesterol concentrations of the mother and fetus. Only about 10% of the fetal absolute cholesterol requirement comes from the mother, research has demonstrated.
The future
Infant follow-up in the NICHD study is planned, and a large, randomized clinical trial powered to look at the efficacy of pravastatin for preventing preeclampsia in high-risk women has been approved by the NICHD. Once funded, the study is expected to enroll approximately 1,700 pregnant women who have a history of severe preeclampsia and delivery before 36 weeks’ gestation and who are between 10 and 16 weeks’ gestation.
With continued research, we face the question of whether pravastatin may potentiate the benefit of aspirin in pregnant women. In cardiovascular medicine, there is evidence for additive or synergistic effects of the combined use of aspirin and statins.
Interestingly, a recent prospective cohort study of women with antiphospholipid syndrome and poor outcomes in prior pregnancies showed dramatic improvement in both maternal and fetal/neonatal outcomes when pravastatin was administered after the onset of preeclampsia or intrauterine growth restriction. All 21 women in the cohort were treated with low-dose aspirin and low-molecular-weight heparin; after the development of preeclampsia or intrauterine growth restriction, 10 patients were maintained on aspirin and LMWH, and 11 were started on 20 mg daily pravastatin along with the aspirin and LMWH (J Clin Invest. 2016 Aug;126[8]:2933-40; and J Clin Invest. 2016 Aug;126[8]:2792-4).
Those who received the statin had improved uterine artery Doppler velocimetry, lower systemic blood pressure, and delivered infants with higher birth weights and at a more advanced gestational age (median, 36 weeks’ vs. 26.5 weeks’ gestation). The study did not randomly allocate the women and did not include a placebo arm. Still, it is another impressive proof-of-concept study.
Dr. Costantine is an associate professor of obstetrics and gynecology at the University of Texas Medical Branch in Galveston. He reported that he has no financial disclosures.