Examining the safety of lipid-lowering drugs in pregnancy

December 5, 2016|ObGyn

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).

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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.

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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.