Antihyperlipidemic Agents

The large antihyperlipidemic class of drugs can be subdivided into bile acid sequestrants, HMG-CoA reductase inhibitors, fibric acid derivatives, ezetimibe, and niacin. With the possible exception of familial hypercholesterolemia, there appears to be no maternal benefit for the treatment of hyperlipidemia during gestation. Nearly all reported pregnancy exposures have occurred accidentally. If treatment is required, only bile acid sequestrants are considered compatible in pregnancy and lactation.

Ezetimibe (Zetia) also appears to be low risk in gestation, but not in lactation. Because most drug-induced adverse effects (about two-thirds) in nursing infants have been reported during the first month after birth, delaying treatment of a nursing mother until after this period appears to be the best course.

Cholesterol is the precursor of bile acids that are excreted from the liver and gallbladder into the intestine to aid in the digestion of fat in food. Bile acid sequestrants—cholestyramine (Questran and various other names), colestipol (Colestid), and colesevelam (WelChol)—are anion exchange resins that form insoluble complexes with bile acids in the intestine. The complexes are then excreted in the feces, removing cholesterol from the system.

Cholestyramine has been used as a treatment for intrahepatic cholestasis of pregnancy and as an antidote for some types of diarrhea, chlordecone pesticide poisoning, and digitalis toxicity. Because bile acid sequestrants are not absorbed into the systemic circulation, they do not represent a direct risk to the embryo or fetus and are considered compatible with pregnancy (all are rated risk factor B) and lactation. However, the resins also bind fat-soluble vitamins (vitamins A, D, E, and K) in the gut, and deficiencies of these vitamins may result.

The six HMG-CoA reductase inhibitors (statins) are atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). All are contraindicated in pregnancy (risk factor X). Case reports and surveillance studies have described healthy outcomes from a number of pregnancies inadvertently exposed in the first trimester and later. The largest number of cases (187) were reported with simvastatin, with 86 cases that could be evaluated: 74% had normal outcomes, 15% resulted in spontaneous abortion, 6% of cases demonstrated congenital anomalies, 4% of cases had effects related to prematurity, and 1% resulted in fetal death. Three of the five birth defect cases were not related to simvastatin because of the timing of exposure or the outcome was a known chromosome defect. The remaining two cases involved unilateral cleft lip and a clubfoot, neither of which appear to be attributable to simvastatin.

In contrast, a 2004 reference described 178 cases of first-trimester exposure to statins reported to the Food and Drug Administration. Among the 52 cases suitable for evaluation, there were 20 major malformations, some thought to be consistent with inhibition of cholesterol biosynthesis. All 20 defects involved a lipophilic statin (atorvastatin), cerivastatin (Baycol), lovastatin, or simvastatin. No defects were reported with pravastatin, a hydrophilic agent with low tissue penetration that is not associated with animal developmental toxicity. These results are controversial, and controlled studies are needed to determine if there is a causal relationship. Because all statins are probably excreted into milk, women taking these drugs should not breast-feed.

Among the fibric acid derivatives, only gemfibrozil (Lopid) has some human data. The other agent, fenofibrate (TriCor), has no human data. The animal data (developmental toxicity in two animal species at doses up to 10 times the human dose) for each drug suggest there may be a risk to the human embryo or fetus. Thus, the safest course is to avoid these drugs in pregnancy (both are risk factor C). Although there are no data, the drugs are probably excreted into milk, and women on these agents should not breast-feed because of the potential toxicity, such as tumors, in their infants.

Ezetimibe (risk factor C) selectively inhibits the intestinal absorption of cholesterol and related phytosterols. At doses up to 10 times the human dose, the drug is teratogenic in rats but not in rabbits. Human pregnancy exposures have not been reported. If therapy during pregnancy is mandated, ezetimibe appears to be a better choice than statins. There are no data on use during lactation, but the drug is probably excreted into milk. Toxicity is a potential concern, and nursing infants should be monitored for headache, diarrhea, arthralgia, pharyngitis, sinusitis, and other adverse effects observed in adults.

The large antihyperlipidemic class of drugs can be subdivided into bile acid sequestrants, HMG-CoA reductase inhibitors, fibric acid derivatives, ezetimibe, and niacin. With the possible exception of familial hypercholesterolemia, there appears to be no maternal benefit for the treatment of hyperlipidemia during gestation. Nearly all reported pregnancy exposures have occurred accidentally. If treatment is required, only bile acid sequestrants are considered compatible in pregnancy and lactation.

Ezetimibe (Zetia) also appears to be low risk in gestation, but not in lactation. Because most drug-induced adverse effects (about two-thirds) in nursing infants have been reported during the first month after birth, delaying treatment of a nursing mother until after this period appears to be the best course.

Cholesterol is the precursor of bile acids that are excreted from the liver and gallbladder into the intestine to aid in the digestion of fat in food. Bile acid sequestrants—cholestyramine (Questran and various other names), colestipol (Colestid), and colesevelam (WelChol)—are anion exchange resins that form insoluble complexes with bile acids in the intestine. The complexes are then excreted in the feces, removing cholesterol from the system.

Cholestyramine has been used as a treatment for intrahepatic cholestasis of pregnancy and as an antidote for some types of diarrhea, chlordecone pesticide poisoning, and digitalis toxicity. Because bile acid sequestrants are not absorbed into the systemic circulation, they do not represent a direct risk to the embryo or fetus and are considered compatible with pregnancy (all are rated risk factor B) and lactation. However, the resins also bind fat-soluble vitamins (vitamins A, D, E, and K) in the gut, and deficiencies of these vitamins may result.

The six HMG-CoA reductase inhibitors (statins) are atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). All are contraindicated in pregnancy (risk factor X). Case reports and surveillance studies have described healthy outcomes from a number of pregnancies inadvertently exposed in the first trimester and later. The largest number of cases (187) were reported with simvastatin, with 86 cases that could be evaluated: 74% had normal outcomes, 15% resulted in spontaneous abortion, 6% of cases demonstrated congenital anomalies, 4% of cases had effects related to prematurity, and 1% resulted in fetal death. Three of the five birth defect cases were not related to simvastatin because of the timing of exposure or the outcome was a known chromosome defect. The remaining two cases involved unilateral cleft lip and a clubfoot, neither of which appear to be attributable to simvastatin.

In contrast, a 2004 reference described 178 cases of first-trimester exposure to statins reported to the Food and Drug Administration. Among the 52 cases suitable for evaluation, there were 20 major malformations, some thought to be consistent with inhibition of cholesterol biosynthesis. All 20 defects involved a lipophilic statin (atorvastatin), cerivastatin (Baycol), lovastatin, or simvastatin. No defects were reported with pravastatin, a hydrophilic agent with low tissue penetration that is not associated with animal developmental toxicity. These results are controversial, and controlled studies are needed to determine if there is a causal relationship. Because all statins are probably excreted into milk, women taking these drugs should not breast-feed.

Among the fibric acid derivatives, only gemfibrozil (Lopid) has some human data. The other agent, fenofibrate (TriCor), has no human data. The animal data (developmental toxicity in two animal species at doses up to 10 times the human dose) for each drug suggest there may be a risk to the human embryo or fetus. Thus, the safest course is to avoid these drugs in pregnancy (both are risk factor C). Although there are no data, the drugs are probably excreted into milk, and women on these agents should not breast-feed because of the potential toxicity, such as tumors, in their infants.

Ezetimibe (risk factor C) selectively inhibits the intestinal absorption of cholesterol and related phytosterols. At doses up to 10 times the human dose, the drug is teratogenic in rats but not in rabbits. Human pregnancy exposures have not been reported. If therapy during pregnancy is mandated, ezetimibe appears to be a better choice than statins. There are no data on use during lactation, but the drug is probably excreted into milk. Toxicity is a potential concern, and nursing infants should be monitored for headache, diarrhea, arthralgia, pharyngitis, sinusitis, and other adverse effects observed in adults.

The large antihyperlipidemic class of drugs can be subdivided into bile acid sequestrants, HMG-CoA reductase inhibitors, fibric acid derivatives, ezetimibe, and niacin. With the possible exception of familial hypercholesterolemia, there appears to be no maternal benefit for the treatment of hyperlipidemia during gestation. Nearly all reported pregnancy exposures have occurred accidentally. If treatment is required, only bile acid sequestrants are considered compatible in pregnancy and lactation.

Ezetimibe (Zetia) also appears to be low risk in gestation, but not in lactation. Because most drug-induced adverse effects (about two-thirds) in nursing infants have been reported during the first month after birth, delaying treatment of a nursing mother until after this period appears to be the best course.

Cholesterol is the precursor of bile acids that are excreted from the liver and gallbladder into the intestine to aid in the digestion of fat in food. Bile acid sequestrants—cholestyramine (Questran and various other names), colestipol (Colestid), and colesevelam (WelChol)—are anion exchange resins that form insoluble complexes with bile acids in the intestine. The complexes are then excreted in the feces, removing cholesterol from the system.

Cholestyramine has been used as a treatment for intrahepatic cholestasis of pregnancy and as an antidote for some types of diarrhea, chlordecone pesticide poisoning, and digitalis toxicity. Because bile acid sequestrants are not absorbed into the systemic circulation, they do not represent a direct risk to the embryo or fetus and are considered compatible with pregnancy (all are rated risk factor B) and lactation. However, the resins also bind fat-soluble vitamins (vitamins A, D, E, and K) in the gut, and deficiencies of these vitamins may result.

The six HMG-CoA reductase inhibitors (statins) are atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). All are contraindicated in pregnancy (risk factor X). Case reports and surveillance studies have described healthy outcomes from a number of pregnancies inadvertently exposed in the first trimester and later. The largest number of cases (187) were reported with simvastatin, with 86 cases that could be evaluated: 74% had normal outcomes, 15% resulted in spontaneous abortion, 6% of cases demonstrated congenital anomalies, 4% of cases had effects related to prematurity, and 1% resulted in fetal death. Three of the five birth defect cases were not related to simvastatin because of the timing of exposure or the outcome was a known chromosome defect. The remaining two cases involved unilateral cleft lip and a clubfoot, neither of which appear to be attributable to simvastatin.

In contrast, a 2004 reference described 178 cases of first-trimester exposure to statins reported to the Food and Drug Administration. Among the 52 cases suitable for evaluation, there were 20 major malformations, some thought to be consistent with inhibition of cholesterol biosynthesis. All 20 defects involved a lipophilic statin (atorvastatin), cerivastatin (Baycol), lovastatin, or simvastatin. No defects were reported with pravastatin, a hydrophilic agent with low tissue penetration that is not associated with animal developmental toxicity. These results are controversial, and controlled studies are needed to determine if there is a causal relationship. Because all statins are probably excreted into milk, women taking these drugs should not breast-feed.

Among the fibric acid derivatives, only gemfibrozil (Lopid) has some human data. The other agent, fenofibrate (TriCor), has no human data. The animal data (developmental toxicity in two animal species at doses up to 10 times the human dose) for each drug suggest there may be a risk to the human embryo or fetus. Thus, the safest course is to avoid these drugs in pregnancy (both are risk factor C). Although there are no data, the drugs are probably excreted into milk, and women on these agents should not breast-feed because of the potential toxicity, such as tumors, in their infants.

Ezetimibe (risk factor C) selectively inhibits the intestinal absorption of cholesterol and related phytosterols. At doses up to 10 times the human dose, the drug is teratogenic in rats but not in rabbits. Human pregnancy exposures have not been reported. If therapy during pregnancy is mandated, ezetimibe appears to be a better choice than statins. There are no data on use during lactation, but the drug is probably excreted into milk. Toxicity is a potential concern, and nursing infants should be monitored for headache, diarrhea, arthralgia, pharyngitis, sinusitis, and other adverse effects observed in adults.