Examining the safety of lipid-lowering drugs in pregnancy

 

Lipid-lowering medications are some of the most commonly prescribed drugs in the United States. But while much is known about their general safety, the data are limited when it comes to pregnancy and breastfeeding.

Antilipemic agents are a pharmacologic class that contains 18 drugs. The class is divided into eight subclasses: bile acid sequestrants; fibric acid derivatives, HMG-CoA inhibitors; immunoglobulins; monoclonal antibodies; oligonucleotide inhibitors; vitamins; as well as two miscellaneous drugs, ezetimibe (Zetia) and lomitapide (Juxtapid). Another antilipemic – dextrothyroxine – has been removed from the market by the manufacturer.

Bile acid sequestrants

Bile acid sequestrants include cholestyramine (Prevalite, Questran), colesevelam (Welchol), and colestipol (Colestid). These drugs have the potential to cause fetal toxicity. This assessment is based on their mechanism of action. These agents are not absorbed systemically, or absorption is very poor and they bind bile acids into a nonabsorbable complex. This action can reduce intestinal absorption of fat-soluble vitamins A, D, E, and K.

In one case, the mother was taking cholestyramine beginning at 19 weeks’ gestation for intrahepatic cholestasis. Ten weeks later, reduced fetal movements were noted, and fetal ultrasound scans revealed expanding bilateral subdural hematomas with hydrocephalus, an enlarged liver, and bilateral pleural effusions. The mother’s prothrombin ratio was markedly elevated but responded to intravenous vitamin K. Labor was induced to deliver a 1,660-g infant who died 15 minutes after birth.¹

Reports of fetal harm have not been located for the other two agents in this class, but there is only one case report involving five women for colesevelam and no reports for colestipol. Nevertheless, both of these drugs have the potential to cause fetal hemorrhage if they are taken for prolonged periods in pregnancy.

Fibric acid derivatives

The fibric acid derivatives subclass includes fenofibrate (Tricor, Lofibra) and gemfibrozil (Lopid).

©Jupiterimages/Thinkstock.com

Fenofibrate is indicated as adjunctive therapy to diet for the treatment of primary hypercholesterolemia or mixed dyslipidemia, and for hypertriglyceridemia. The drug was embryotoxic in rats and rabbits at doses less than 10 times the maximum human dose. There are three reports describing the use of the drug in human pregnancy. In one case a woman was treated in the third trimester and, in the second case, during the first 8 weeks’ gestation. Both pregnancies ended in healthy male infants. In a third case, a woman was treated with fenofibrate for acute pancreatitis due to hyperlipidemia and with carbimazole for Graves’ disease. She stopped the drug when her pregnancy was diagnosed (unspecified gestational age). At 18 weeks’ gestation, intrauterine death was confirmed.²

Six reports, involving 13 pregnancies, have described the use of gemfibrozil during all phases of pregnancy. No teratogenic effects were observed in these cases. In one woman, similar concentrations of gemfibrozil and its active metabolite were found in the umbilical vein and artery at levels within the normal reference for adults.

Statins

There are seven HMG-CoA inhibitors, known as statins: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor).

The interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia. Moreover, cholesterol and products synthesized by cholesterol are important during fetal development as shown by the rise in maternal cholesterol levels during pregnancy. Although the potential for embryo-fetal harm has not been clearly documented, and that potential may eventually be confirmed as low, the use of these agents in the first trimester are best classified as contraindicated.

One consideration in estimating the embryo-fetal risk of statins is their classification as either lipophilic or hydrophilic. Three of the seven statins are hydrophilic (fluvastatin, pravastatin, and rosuvastatin); the remaining four agents are lipophilic. In a 2004 review of 70 reports, all adverse birth outcomes were reported following exposure to lipophilic statins (atorvastatin, lovastatin, or simvastatin) and none with the hydrophilic pravastatin. The authors stated that the findings were due to the fact that lipophilic agents equilibrate between maternal and embryonic compartments, whereas pravastatin is minimally present in the embryo.³ If this is indeed the case, and a statin must be used during pregnancy, fluvastatin, pravastatin, or rosuvastatin appears to be best.

RogerAshford/Thinkstock

Two other indications for statins in pregnancy have been studied. A 2016 study involved 21 patients with obstetric antiphospholipid syndrome that was refractory to low-dose aspirin plus low-molecular-weight heparin. In 11 patients, pravastatin was added to the therapy while in a control group of 10 patients, the standard therapy (aspirin plus heparin) was continued. All the patients had developed preeclampsia and/or intrauterine growth restriction during the standard therapy. The outcomes (live births and gestational age at birth) in the pravastatin group were superior to those in the control group.⁴

Pravastatin also has been used for the prevention and treatment of preeclampsia.^5,6 Although the teratogenic potential of these agents has not been fully determined, the risk for birth defects, if any, appears to be low even when exposure occurs during organogenesis.^7,8,9 Nevertheless, avoiding these products during the first trimester appears to be best.
 

 

Immunoglobulins

The only immunoglobulin in the antilipemic class is evolocumab (Repatha), which has no human pregnancy data. It is an immunoglobulin G2 that is indicated as an adjunct to diet and maximally tolerated statin therapy. It is also indicated as an adjunct to diet and other low-density lipoprotein–lowering therapies in patients with homozygous familial hypercholesterolemia who require additional lowering. No adverse embryo-fetal effects were observed in monkeys. Because statins are contraindicated in the first trimester, the drug, if combined with a statin, can also be classified as contraindicated. However, if the drug is used alone, the embryo-fetal risk appears to be low based on the animal data.

Monoclonal antibodies

The protein alirocumab (Praluent) is a human monoclonal antibody. It is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease. There are no human pregnancy data. The animal data in rats and monkeys suggest low embryo-fetal risk. However, suppression of the humoral immune response to keyhole hemocyanin antigen was observed in infant monkeys at 4-6 months of age. The significance of this in human infants is apparently unknown. Because statins are contraindicated in the first trimester, the drug should not be used with these agents during that period.

Oligonucleotide inhibitors

No reports describing the use of mipomersen (Kynamro), an oligonucleotide inhibitor of apolipoprotein B-100 synthesis, in human pregnancy have been located. The drug is indicated as an adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. It has a very long (1-2 months) elimination half-life. The drug caused fetal toxicity in rats, but not in mice or rabbits.

Vitamins

Niacin is a water-soluble B complex vitamin that is converted in vivo to niacinamide. Niacin has no known embryo-fetal risk.

Miscellaneous agents

The two agents in the miscellaneous category are ezetimibe and lomitapide. Ezetimibe is indicated, either alone or in combination with a statin, as adjunctive therapy to diet for the reduction of cholesterol and triglycerides. Statins are contraindicated in the first trimester, but ezetimibe alone could be used during that period if treatment of the mother was mandated. The drug caused no problems in rabbits, but in rats, a dose 10 times the human exposure increased the incidence of skeletal abnormalities. In one report, a woman with homozygous familial hypercholesterolemia was treated with direct adsorption of lipoprotein apheresis, ezetimibe, and rosuvastatin. When pregnancy was discovered (gestational age not specified), the two drugs were stopped but biweekly apheresis was continued. At 37 weeks’ gestation, the patient gave birth to a healthy 2,400-g male infant.¹⁰

There are no human pregnancy data with lomitapide. It is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including low-density lipoprotein apheresis where available, to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. At doses less than 10 times the human dose, the drug caused congenital malformations and embryo-fetal death in rats, rabbits, and ferrets. The manufacturer classifies the drug as contraindicated in pregnancy because of the animal data.

Breastfeeding

Only niacin, pravastatin, and rosuvastatin have data regarding human milk concentrations. Niacin and its active form – niacinamide – are excreted into breast milk.

The average peak milk level in 11 lactating women given pravastatin 20 mg twice daily for 2.5 days was 3.9 mcg/L, whereas the level for the active metabolite was 2.1 mcg/L. Based on these data, a fully breastfed infant would receive daily about 1.4% of the mother’s weight-adjusted dose.¹¹

A 31-year-old woman was treated with rosuvastatin for familial hypercholesterolemia while breastfeeding her infant. The drug was stopped during breastfeeding but was restarted at 33 days post partum. Breast milk concentrations of the drug were 1.2 times serum levels (about 22 ng/mL vs. 18 ng/mL). Unfortunately, no information was provided on the status of the nursing infant.¹²

Three of the above agents have high molecular weights - alirocumab, evolocumab, and mipomersen - and are probably not excreted into mature breast milk. Moreover, colesevelam is not absorbed, and very small amounts of colestipol are absorbed by mothers. Several antilipemic agents have characteristics (for example, low molecular weight or long elimination half-life) that suggest they will be excreted into breast milk: ezetimibe, fenofibric acid (active metabolite of fenofibrate), gemfibrozil, lomitapide, and all the statins.

Taken in sum, all of the antilipemics, with the exception of niacin, have the potential to cause a deficiency of fat-soluble vitamins (A, D, E, K) in mother’s milk and in the nursing infant. Deficiency is a concern for all of these vitamins, but especially for vitamin K, because it could cause bruising, petechiae, hematomas, and bleeding in the nursing infant. In addition, antilipemics could cause low levels in milk of cholesterol and lipids, which are required by a nursing infant. Consequently, they should not be used by mothers who are breastfeeding an infant.
 

 

References

1. Br J Obstet Gynaecol. 1995 Feb;102(2):169-70.

2. J Matern Fetal Neonatal Med. 2015 May;28(8):954-8.

3. Am J Med Genet A. 2004 Dec 15;131(3):287-98.

4. J Clin Invest. 2016 Aug 1;126(8):2933-40.

5. Hypertension. 2015 Sep;66(3):687-97.

6. Am J Obstet Gynecol. 2016 Jun;214(6):720.e1-720.e17.

7. Birth Defects Res A Clin Mol Teratol. 2005 Nov;73(11):888-96.

8. Reprod Toxicol. 2008 Oct;26(2):175-7.

9. Ann Pharmacother. 2012 Oct;46(10):1419-24.

10. Open Cardiovasc Med J. 2015 Dec 29;9:114-7.

11. J Clin Pharmacol. 1988;28:942.

12. Am J Med. 2013 Sep;126(9):e7-e8.
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

 

Lipid-lowering medications are some of the most commonly prescribed drugs in the United States. But while much is known about their general safety, the data are limited when it comes to pregnancy and breastfeeding.

Antilipemic agents are a pharmacologic class that contains 18 drugs. The class is divided into eight subclasses: bile acid sequestrants; fibric acid derivatives, HMG-CoA inhibitors; immunoglobulins; monoclonal antibodies; oligonucleotide inhibitors; vitamins; as well as two miscellaneous drugs, ezetimibe (Zetia) and lomitapide (Juxtapid). Another antilipemic – dextrothyroxine – has been removed from the market by the manufacturer.

Bile acid sequestrants

Bile acid sequestrants include cholestyramine (Prevalite, Questran), colesevelam (Welchol), and colestipol (Colestid). These drugs have the potential to cause fetal toxicity. This assessment is based on their mechanism of action. These agents are not absorbed systemically, or absorption is very poor and they bind bile acids into a nonabsorbable complex. This action can reduce intestinal absorption of fat-soluble vitamins A, D, E, and K.

In one case, the mother was taking cholestyramine beginning at 19 weeks’ gestation for intrahepatic cholestasis. Ten weeks later, reduced fetal movements were noted, and fetal ultrasound scans revealed expanding bilateral subdural hematomas with hydrocephalus, an enlarged liver, and bilateral pleural effusions. The mother’s prothrombin ratio was markedly elevated but responded to intravenous vitamin K. Labor was induced to deliver a 1,660-g infant who died 15 minutes after birth.¹

Reports of fetal harm have not been located for the other two agents in this class, but there is only one case report involving five women for colesevelam and no reports for colestipol. Nevertheless, both of these drugs have the potential to cause fetal hemorrhage if they are taken for prolonged periods in pregnancy.

Fibric acid derivatives

The fibric acid derivatives subclass includes fenofibrate (Tricor, Lofibra) and gemfibrozil (Lopid).

©Jupiterimages/Thinkstock.com

Fenofibrate is indicated as adjunctive therapy to diet for the treatment of primary hypercholesterolemia or mixed dyslipidemia, and for hypertriglyceridemia. The drug was embryotoxic in rats and rabbits at doses less than 10 times the maximum human dose. There are three reports describing the use of the drug in human pregnancy. In one case a woman was treated in the third trimester and, in the second case, during the first 8 weeks’ gestation. Both pregnancies ended in healthy male infants. In a third case, a woman was treated with fenofibrate for acute pancreatitis due to hyperlipidemia and with carbimazole for Graves’ disease. She stopped the drug when her pregnancy was diagnosed (unspecified gestational age). At 18 weeks’ gestation, intrauterine death was confirmed.²

Six reports, involving 13 pregnancies, have described the use of gemfibrozil during all phases of pregnancy. No teratogenic effects were observed in these cases. In one woman, similar concentrations of gemfibrozil and its active metabolite were found in the umbilical vein and artery at levels within the normal reference for adults.

Statins

There are seven HMG-CoA inhibitors, known as statins: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor).

The interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia. Moreover, cholesterol and products synthesized by cholesterol are important during fetal development as shown by the rise in maternal cholesterol levels during pregnancy. Although the potential for embryo-fetal harm has not been clearly documented, and that potential may eventually be confirmed as low, the use of these agents in the first trimester are best classified as contraindicated.

One consideration in estimating the embryo-fetal risk of statins is their classification as either lipophilic or hydrophilic. Three of the seven statins are hydrophilic (fluvastatin, pravastatin, and rosuvastatin); the remaining four agents are lipophilic. In a 2004 review of 70 reports, all adverse birth outcomes were reported following exposure to lipophilic statins (atorvastatin, lovastatin, or simvastatin) and none with the hydrophilic pravastatin. The authors stated that the findings were due to the fact that lipophilic agents equilibrate between maternal and embryonic compartments, whereas pravastatin is minimally present in the embryo.³ If this is indeed the case, and a statin must be used during pregnancy, fluvastatin, pravastatin, or rosuvastatin appears to be best.

RogerAshford/Thinkstock

Two other indications for statins in pregnancy have been studied. A 2016 study involved 21 patients with obstetric antiphospholipid syndrome that was refractory to low-dose aspirin plus low-molecular-weight heparin. In 11 patients, pravastatin was added to the therapy while in a control group of 10 patients, the standard therapy (aspirin plus heparin) was continued. All the patients had developed preeclampsia and/or intrauterine growth restriction during the standard therapy. The outcomes (live births and gestational age at birth) in the pravastatin group were superior to those in the control group.⁴

Pravastatin also has been used for the prevention and treatment of preeclampsia.^5,6 Although the teratogenic potential of these agents has not been fully determined, the risk for birth defects, if any, appears to be low even when exposure occurs during organogenesis.^7,8,9 Nevertheless, avoiding these products during the first trimester appears to be best.
 

 

Immunoglobulins

The only immunoglobulin in the antilipemic class is evolocumab (Repatha), which has no human pregnancy data. It is an immunoglobulin G2 that is indicated as an adjunct to diet and maximally tolerated statin therapy. It is also indicated as an adjunct to diet and other low-density lipoprotein–lowering therapies in patients with homozygous familial hypercholesterolemia who require additional lowering. No adverse embryo-fetal effects were observed in monkeys. Because statins are contraindicated in the first trimester, the drug, if combined with a statin, can also be classified as contraindicated. However, if the drug is used alone, the embryo-fetal risk appears to be low based on the animal data.

Monoclonal antibodies

The protein alirocumab (Praluent) is a human monoclonal antibody. It is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease. There are no human pregnancy data. The animal data in rats and monkeys suggest low embryo-fetal risk. However, suppression of the humoral immune response to keyhole hemocyanin antigen was observed in infant monkeys at 4-6 months of age. The significance of this in human infants is apparently unknown. Because statins are contraindicated in the first trimester, the drug should not be used with these agents during that period.

Oligonucleotide inhibitors

No reports describing the use of mipomersen (Kynamro), an oligonucleotide inhibitor of apolipoprotein B-100 synthesis, in human pregnancy have been located. The drug is indicated as an adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. It has a very long (1-2 months) elimination half-life. The drug caused fetal toxicity in rats, but not in mice or rabbits.

Vitamins

Niacin is a water-soluble B complex vitamin that is converted in vivo to niacinamide. Niacin has no known embryo-fetal risk.

Miscellaneous agents

The two agents in the miscellaneous category are ezetimibe and lomitapide. Ezetimibe is indicated, either alone or in combination with a statin, as adjunctive therapy to diet for the reduction of cholesterol and triglycerides. Statins are contraindicated in the first trimester, but ezetimibe alone could be used during that period if treatment of the mother was mandated. The drug caused no problems in rabbits, but in rats, a dose 10 times the human exposure increased the incidence of skeletal abnormalities. In one report, a woman with homozygous familial hypercholesterolemia was treated with direct adsorption of lipoprotein apheresis, ezetimibe, and rosuvastatin. When pregnancy was discovered (gestational age not specified), the two drugs were stopped but biweekly apheresis was continued. At 37 weeks’ gestation, the patient gave birth to a healthy 2,400-g male infant.¹⁰

There are no human pregnancy data with lomitapide. It is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including low-density lipoprotein apheresis where available, to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. At doses less than 10 times the human dose, the drug caused congenital malformations and embryo-fetal death in rats, rabbits, and ferrets. The manufacturer classifies the drug as contraindicated in pregnancy because of the animal data.

Breastfeeding

Only niacin, pravastatin, and rosuvastatin have data regarding human milk concentrations. Niacin and its active form – niacinamide – are excreted into breast milk.

The average peak milk level in 11 lactating women given pravastatin 20 mg twice daily for 2.5 days was 3.9 mcg/L, whereas the level for the active metabolite was 2.1 mcg/L. Based on these data, a fully breastfed infant would receive daily about 1.4% of the mother’s weight-adjusted dose.¹¹

A 31-year-old woman was treated with rosuvastatin for familial hypercholesterolemia while breastfeeding her infant. The drug was stopped during breastfeeding but was restarted at 33 days post partum. Breast milk concentrations of the drug were 1.2 times serum levels (about 22 ng/mL vs. 18 ng/mL). Unfortunately, no information was provided on the status of the nursing infant.¹²

Three of the above agents have high molecular weights - alirocumab, evolocumab, and mipomersen - and are probably not excreted into mature breast milk. Moreover, colesevelam is not absorbed, and very small amounts of colestipol are absorbed by mothers. Several antilipemic agents have characteristics (for example, low molecular weight or long elimination half-life) that suggest they will be excreted into breast milk: ezetimibe, fenofibric acid (active metabolite of fenofibrate), gemfibrozil, lomitapide, and all the statins.

Taken in sum, all of the antilipemics, with the exception of niacin, have the potential to cause a deficiency of fat-soluble vitamins (A, D, E, K) in mother’s milk and in the nursing infant. Deficiency is a concern for all of these vitamins, but especially for vitamin K, because it could cause bruising, petechiae, hematomas, and bleeding in the nursing infant. In addition, antilipemics could cause low levels in milk of cholesterol and lipids, which are required by a nursing infant. Consequently, they should not be used by mothers who are breastfeeding an infant.
 

 

References

1. Br J Obstet Gynaecol. 1995 Feb;102(2):169-70.

2. J Matern Fetal Neonatal Med. 2015 May;28(8):954-8.

3. Am J Med Genet A. 2004 Dec 15;131(3):287-98.

4. J Clin Invest. 2016 Aug 1;126(8):2933-40.

5. Hypertension. 2015 Sep;66(3):687-97.

6. Am J Obstet Gynecol. 2016 Jun;214(6):720.e1-720.e17.

7. Birth Defects Res A Clin Mol Teratol. 2005 Nov;73(11):888-96.

8. Reprod Toxicol. 2008 Oct;26(2):175-7.

9. Ann Pharmacother. 2012 Oct;46(10):1419-24.

10. Open Cardiovasc Med J. 2015 Dec 29;9:114-7.

11. J Clin Pharmacol. 1988;28:942.

12. Am J Med. 2013 Sep;126(9):e7-e8.
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

 

Lipid-lowering medications are some of the most commonly prescribed drugs in the United States. But while much is known about their general safety, the data are limited when it comes to pregnancy and breastfeeding.

Antilipemic agents are a pharmacologic class that contains 18 drugs. The class is divided into eight subclasses: bile acid sequestrants; fibric acid derivatives, HMG-CoA inhibitors; immunoglobulins; monoclonal antibodies; oligonucleotide inhibitors; vitamins; as well as two miscellaneous drugs, ezetimibe (Zetia) and lomitapide (Juxtapid). Another antilipemic – dextrothyroxine – has been removed from the market by the manufacturer.

Bile acid sequestrants

Bile acid sequestrants include cholestyramine (Prevalite, Questran), colesevelam (Welchol), and colestipol (Colestid). These drugs have the potential to cause fetal toxicity. This assessment is based on their mechanism of action. These agents are not absorbed systemically, or absorption is very poor and they bind bile acids into a nonabsorbable complex. This action can reduce intestinal absorption of fat-soluble vitamins A, D, E, and K.

In one case, the mother was taking cholestyramine beginning at 19 weeks’ gestation for intrahepatic cholestasis. Ten weeks later, reduced fetal movements were noted, and fetal ultrasound scans revealed expanding bilateral subdural hematomas with hydrocephalus, an enlarged liver, and bilateral pleural effusions. The mother’s prothrombin ratio was markedly elevated but responded to intravenous vitamin K. Labor was induced to deliver a 1,660-g infant who died 15 minutes after birth.¹

Reports of fetal harm have not been located for the other two agents in this class, but there is only one case report involving five women for colesevelam and no reports for colestipol. Nevertheless, both of these drugs have the potential to cause fetal hemorrhage if they are taken for prolonged periods in pregnancy.

Fibric acid derivatives

The fibric acid derivatives subclass includes fenofibrate (Tricor, Lofibra) and gemfibrozil (Lopid).

©Jupiterimages/Thinkstock.com

Fenofibrate is indicated as adjunctive therapy to diet for the treatment of primary hypercholesterolemia or mixed dyslipidemia, and for hypertriglyceridemia. The drug was embryotoxic in rats and rabbits at doses less than 10 times the maximum human dose. There are three reports describing the use of the drug in human pregnancy. In one case a woman was treated in the third trimester and, in the second case, during the first 8 weeks’ gestation. Both pregnancies ended in healthy male infants. In a third case, a woman was treated with fenofibrate for acute pancreatitis due to hyperlipidemia and with carbimazole for Graves’ disease. She stopped the drug when her pregnancy was diagnosed (unspecified gestational age). At 18 weeks’ gestation, intrauterine death was confirmed.²

Six reports, involving 13 pregnancies, have described the use of gemfibrozil during all phases of pregnancy. No teratogenic effects were observed in these cases. In one woman, similar concentrations of gemfibrozil and its active metabolite were found in the umbilical vein and artery at levels within the normal reference for adults.

Statins

There are seven HMG-CoA inhibitors, known as statins: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor).

The interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia. Moreover, cholesterol and products synthesized by cholesterol are important during fetal development as shown by the rise in maternal cholesterol levels during pregnancy. Although the potential for embryo-fetal harm has not been clearly documented, and that potential may eventually be confirmed as low, the use of these agents in the first trimester are best classified as contraindicated.

One consideration in estimating the embryo-fetal risk of statins is their classification as either lipophilic or hydrophilic. Three of the seven statins are hydrophilic (fluvastatin, pravastatin, and rosuvastatin); the remaining four agents are lipophilic. In a 2004 review of 70 reports, all adverse birth outcomes were reported following exposure to lipophilic statins (atorvastatin, lovastatin, or simvastatin) and none with the hydrophilic pravastatin. The authors stated that the findings were due to the fact that lipophilic agents equilibrate between maternal and embryonic compartments, whereas pravastatin is minimally present in the embryo.³ If this is indeed the case, and a statin must be used during pregnancy, fluvastatin, pravastatin, or rosuvastatin appears to be best.

RogerAshford/Thinkstock

Two other indications for statins in pregnancy have been studied. A 2016 study involved 21 patients with obstetric antiphospholipid syndrome that was refractory to low-dose aspirin plus low-molecular-weight heparin. In 11 patients, pravastatin was added to the therapy while in a control group of 10 patients, the standard therapy (aspirin plus heparin) was continued. All the patients had developed preeclampsia and/or intrauterine growth restriction during the standard therapy. The outcomes (live births and gestational age at birth) in the pravastatin group were superior to those in the control group.⁴

Pravastatin also has been used for the prevention and treatment of preeclampsia.^5,6 Although the teratogenic potential of these agents has not been fully determined, the risk for birth defects, if any, appears to be low even when exposure occurs during organogenesis.^7,8,9 Nevertheless, avoiding these products during the first trimester appears to be best.
 

 

Immunoglobulins

The only immunoglobulin in the antilipemic class is evolocumab (Repatha), which has no human pregnancy data. It is an immunoglobulin G2 that is indicated as an adjunct to diet and maximally tolerated statin therapy. It is also indicated as an adjunct to diet and other low-density lipoprotein–lowering therapies in patients with homozygous familial hypercholesterolemia who require additional lowering. No adverse embryo-fetal effects were observed in monkeys. Because statins are contraindicated in the first trimester, the drug, if combined with a statin, can also be classified as contraindicated. However, if the drug is used alone, the embryo-fetal risk appears to be low based on the animal data.

Monoclonal antibodies

The protein alirocumab (Praluent) is a human monoclonal antibody. It is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease. There are no human pregnancy data. The animal data in rats and monkeys suggest low embryo-fetal risk. However, suppression of the humoral immune response to keyhole hemocyanin antigen was observed in infant monkeys at 4-6 months of age. The significance of this in human infants is apparently unknown. Because statins are contraindicated in the first trimester, the drug should not be used with these agents during that period.

Oligonucleotide inhibitors

No reports describing the use of mipomersen (Kynamro), an oligonucleotide inhibitor of apolipoprotein B-100 synthesis, in human pregnancy have been located. The drug is indicated as an adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. It has a very long (1-2 months) elimination half-life. The drug caused fetal toxicity in rats, but not in mice or rabbits.

Vitamins

Niacin is a water-soluble B complex vitamin that is converted in vivo to niacinamide. Niacin has no known embryo-fetal risk.

Miscellaneous agents

The two agents in the miscellaneous category are ezetimibe and lomitapide. Ezetimibe is indicated, either alone or in combination with a statin, as adjunctive therapy to diet for the reduction of cholesterol and triglycerides. Statins are contraindicated in the first trimester, but ezetimibe alone could be used during that period if treatment of the mother was mandated. The drug caused no problems in rabbits, but in rats, a dose 10 times the human exposure increased the incidence of skeletal abnormalities. In one report, a woman with homozygous familial hypercholesterolemia was treated with direct adsorption of lipoprotein apheresis, ezetimibe, and rosuvastatin. When pregnancy was discovered (gestational age not specified), the two drugs were stopped but biweekly apheresis was continued. At 37 weeks’ gestation, the patient gave birth to a healthy 2,400-g male infant.¹⁰

There are no human pregnancy data with lomitapide. It is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including low-density lipoprotein apheresis where available, to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. At doses less than 10 times the human dose, the drug caused congenital malformations and embryo-fetal death in rats, rabbits, and ferrets. The manufacturer classifies the drug as contraindicated in pregnancy because of the animal data.

Breastfeeding

Only niacin, pravastatin, and rosuvastatin have data regarding human milk concentrations. Niacin and its active form – niacinamide – are excreted into breast milk.

The average peak milk level in 11 lactating women given pravastatin 20 mg twice daily for 2.5 days was 3.9 mcg/L, whereas the level for the active metabolite was 2.1 mcg/L. Based on these data, a fully breastfed infant would receive daily about 1.4% of the mother’s weight-adjusted dose.¹¹

A 31-year-old woman was treated with rosuvastatin for familial hypercholesterolemia while breastfeeding her infant. The drug was stopped during breastfeeding but was restarted at 33 days post partum. Breast milk concentrations of the drug were 1.2 times serum levels (about 22 ng/mL vs. 18 ng/mL). Unfortunately, no information was provided on the status of the nursing infant.¹²

Three of the above agents have high molecular weights - alirocumab, evolocumab, and mipomersen - and are probably not excreted into mature breast milk. Moreover, colesevelam is not absorbed, and very small amounts of colestipol are absorbed by mothers. Several antilipemic agents have characteristics (for example, low molecular weight or long elimination half-life) that suggest they will be excreted into breast milk: ezetimibe, fenofibric acid (active metabolite of fenofibrate), gemfibrozil, lomitapide, and all the statins.

Taken in sum, all of the antilipemics, with the exception of niacin, have the potential to cause a deficiency of fat-soluble vitamins (A, D, E, K) in mother’s milk and in the nursing infant. Deficiency is a concern for all of these vitamins, but especially for vitamin K, because it could cause bruising, petechiae, hematomas, and bleeding in the nursing infant. In addition, antilipemics could cause low levels in milk of cholesterol and lipids, which are required by a nursing infant. Consequently, they should not be used by mothers who are breastfeeding an infant.
 

 

References

1. Br J Obstet Gynaecol. 1995 Feb;102(2):169-70.

2. J Matern Fetal Neonatal Med. 2015 May;28(8):954-8.

3. Am J Med Genet A. 2004 Dec 15;131(3):287-98.

4. J Clin Invest. 2016 Aug 1;126(8):2933-40.

5. Hypertension. 2015 Sep;66(3):687-97.

6. Am J Obstet Gynecol. 2016 Jun;214(6):720.e1-720.e17.

7. Birth Defects Res A Clin Mol Teratol. 2005 Nov;73(11):888-96.

8. Reprod Toxicol. 2008 Oct;26(2):175-7.

9. Ann Pharmacother. 2012 Oct;46(10):1419-24.

10. Open Cardiovasc Med J. 2015 Dec 29;9:114-7.

11. J Clin Pharmacol. 1988;28:942.

12. Am J Med. 2013 Sep;126(9):e7-e8.
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.