Treating Hyperlipidemia During Breastfeeding

Statins

Statins (hydroxy methylglutaryl coenzyme A reductase inhibitors) are the most widely used lipid-lowering drugs. Little information is available on their use during breastfeeding, but all drugs in this class are labeled as contraindicated during breastfeeding and most expert opinion warns against using statins in nursing mothers. Pharmacokinetics of statins are somewhat variable by drug. All have rather poor oral bioavailability in the range of 20–30%, which provides a measure of safety for the infant, especially with pravastatin and rosuvastatin. Protein binding of atorvastatin and rosuvastatin is high, also providing some degree of safety, although actual measurement of the drugs in breast milk is more important. Half-life determines how long the infant will be exposed to any drug that is absorbed. The half-lives of atorvastatin and rosuvastatin are rather long at 20–30 hours, whereas the half-life of pravastatin is shorter at about 2 hours. No statin is unequivocally safer based on physicochemical and pharmacokinetic parameters.

Measurements of statins in breast milk are scanty. Milk levels of rosuvastatin in two mothers taking 20 and 40 mg daily were up to 29 mcg/L in one mother and a maximum of 59 mcg/L in the other. Pravastatin was measured in the milk of 11 women. Peak milk levels averaged 3.9 mcg/L for pravastatin and 2.1 mcg/L for its metabolite. These correspond to relative infant dosages of about 0.13%. No measurements of any other statins in milk have been reported.

Some clinical data are available from mothers who breastfed their infants. In a case series of patients with homozygous familial hypercholesterolemia, 6 patients breastfed 11 infants after restarting statin therapy postpartum. Most of the women were using atorvastatin, either 40 or 80 mg/day. Normal early childhood development was reported for all the infants. No infant outcome information is available for the other marketed statins.

Niacin

Niacin (nicotinic acid) is a normal component of human milk and supplementation with vitamin doses increases niacin levels in milk. However, no studies have been performed with high-dose niacin used to lower cholesterol levels. Nevertheless, high-dose niacin is considered to be a contraindication to breastfeeding because of concerns similar to the statins.

Absorption Inhibitors

Cholestyramine, colesevelam, and colestipol are nonabsorbable resins that bind bile acids in the gastrointestinal (GI) tract. Cholesterol is the major precursor of bile acids, so the removal of bile acids from the enterohepatic circulation increases the use of cholesterol to synthesize bile acids. These drugs are not very potent and can be unpleasant to take, but they remain commercially available. Although these drugs have not been studied in nursing mothers, they are not absorbed from the mother's GI tract, so they cannot enter breast milk. Cholestyramine is marketed only as a rather unpalatable suspension, but colestipol and colesevelam are available as tablets.

Ezetimibe is another oral cholesterol-lowering agent that works by inhibiting cholesterol absorption from the GI tract. Similar to the resins, it has not been studied in nursing mothers. Unlike the resins, it is absorbed and can be found in the plasma of the person taking it. Rat studies found blood levels in pups up to half of the mother's. Although it is not contraindicated in nursing mothers, it is probably best avoided in nursing mothers in favor of the nonabsorbable resins until more human lactation information is available.

Monoclonal Antibodies

Alirocumab and evolocumab are monoclonal antibodies that target proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes to promote LDLR degradation within the liver. Inhibition of the binding increases LDLRs, which in turn increases clearance of low-density lipoprotein (LDL) from the bloodstream. These drugs are the most potent cholesterol-lowering drugs available, with decreases in LDL of 40–50% used alone and up to 60% when used with a statin. They are usually added on to statin therapy when LDL reduction is insufficient. They have also been shown to reduce cardiovascular events. The downside to these drugs is their high cost and need for injections every 2–4 weeks.

No information is available on the clinical use of alirocumab or evolocumab during breastfeeding. Because they are large protein molecules with molecular weights of >140,000, the amount in milk is likely to be very low and absorption is unlikely because they are probably destroyed in the infant's GI tract. Many monoclonal antibodies have been studied in nursing mothers, such as those used to treat inflammatory bowel disease and rheumatoid arthritis. They are usually undetectable in breast milk and in the serum of breastfed infants. Because of the likelihood that the PCSK9 inhibitors do not reach the breastfed infant, they are not contraindicated in the product labeling and can be used in nursing mothers.

Triglyceride-Lowering Drugs

Fenofibric acid (fenofibrate) and gemfibrozil are fibric acid derivatives used primarily in the treatment of elevated triglycerides, although they do have a beneficial effect on LDL levels, but less than the statins. No information is available on the use of these drugs during breastfeeding or on their excretion into human milk. Because of the lack of information, these drugs are discouraged in nursing mothers.

Fish oil is mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid. In addition to over-the-counter products, several commercial products are Food and Drug Administration approved for decreasing triglycerides in patients with severe hypertriglyceridemia. Icosapent ethyl is an EPA ethyl ester that is marketed specifically to reduce triglycerides either alone or with a statin. Extrapolation from studies on fish oil supplementation to nursing mothers indicates that these products should not cause harm to the breastfed infant.

Conclusion

Treatment of hyperlipidemia in the nursing mother is somewhat complicated and requires clinical judgment that will not be guided by good clinical data. A major issue is the widespread admonition that statins are contraindicated during breastfeeding. A contrary view has been expressed by Norwegian experts who feel that the risks of statins are low and mothers should continue breastfeeding during statin therapy, with rosuvastatin being the preferred agent. ¹

One approach might be the following. If a mother nursing a newborn requires lowering of serum cholesterol, the therapy should take into account the severity of her hyperlipidemia. Modest elevations might be treated with diet alone or with diet plus a nonabsorbable resin. If these measures are not adequate after a month or two, one could consider adding a statin that has some published information on breastfeeding, such as rosuvastatin, pravastatin, or atorvastatin. The dosage can be started low and increased as the infant matures. The statin might also provide the mother some beneficial pleiotropic effects, such as antiplatelet and antioxidant effects, and arterial plaque stabilization. A fish oil product could be added if triglycerides are also elevated. For severe elevations of cholesterol, a PCSK9 inhibitor monoclonal antibody could be used until high-dose statins are considered acceptable, perhaps after weaning. The risks of these antibodies appear to be low and they are not contraindicated by their labeling.