Choosing Medication Alternatives During Breastfeeding,Avoiding Alternative Facts

Methicillin-Resistant Staphylococcus Infections

As methicillin-resistant Staphylococcus aureus (MRSA) infections increase in prevalence, more nursing mothers are likely to need alternatives to typical drugs such as dicloxacillin, floxacillin (available as flucloxacillin outside the United States), and erythromycin, which are not active against MRSA. Options for oral treatment include clindamycin, doxycycline, minocycline, rifampin, trimethoprim–sulfamethoxazole, and linezolid. However, each of these options has some potential drawbacks.

Clindamycin has an elevated risk of severe diarrhea and pseudomembranous colitis. In fact, bloody diarrhea has been reported in one breastfed infant during maternal use. More importantly, MRSA can develop clindamycin resistance rapidly, so it is not a drug of choice. Rifampin has a reasonable amount of infant safety information during breastfeeding, and the Centers for Disease Control and Prevention states that breastfeeding should not be discouraged in women taking rifampin. However, resistance also develops rapidly when rifampin is used alone for Staphylococcus infections, so it should only be used as an add-on to other drugs, such as vancomycin.

Doxycycline and minocycline tend to cause concern because of the well-known ability of tetracyclines to deposit in bone and teeth when they are given during pregnancy or to children. However, bone deposition and tooth discoloration have never been reported with any tetracycline during breastfeeding, so short-term use (<2 to 3 weeks) is considered acceptable. Longer use might result in some accumulation in bone, and black discoloration of breast milk has occurred with minocycline.

Trimethoprim–sulfamethoxazole is a good choice for treating MRSA, but because of the potential to displace bili-rubin from albumin, it should not be used in mothers nursing neonates or preterm infants. Another reasonable alternative is linezolid, which is excreted into breast milk in concentration likely to be effective against staphylococcal strains found in mastitis. Limited data indicate that the maximum amount an infant would receive through breast milk would be much less than the standard infant dosage. However, there is no published experience with linezolid treatment during breastfeeding.

Most importantly, effective treatment of mastitis and other skin infections caused by MRSA requires culture and sensitivity testing. Incision and drainage may be required to clear skin and breast infections.^1–3

Hyperlipidemia

Treatment of hyperlipidemia in nursing mothers can be problematic because the mainstays of therapy, the statins, have not been well studied in nursing mothers and because of concern about their interfering with the infant's developing brain, which requires cholesterol for membrane synthesis. Virtually all expert opinion warns against using statins in nursing mothers. Fibrates (e.g., gemfibrozil) are likewise considered to be contraindicated.

A small amount of breast milk information is available on statins. In one study of 11 women who were lactating, but not breastfeeding, pravastatin 20 mg was given orally twice daily for 2.5 days. Peak milk levels of the drug and its metabolite were low. The infant would receive only about 1 mcg/kg or an estimated maximum of 1.4% of the maternal weight-adjusted dosage, which is usually considered acceptable. Another woman started rosuvastatin 40 mg daily on day 33 postpartum. Several milk levels ranged from 15 to 29 mcg/L over the first few days of therapy and again on days 24 and 80 of therapy. Although she apparently breastfed her infant, no mention was made of any effect on her infant.

Alternatives to the statins are the bile acid sequestrants: cholestyramine, colesevelam, and colestipol. 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 gastrointestinal tract, so they cannot enter breast milk. Cholestyramine is marketed only as a rather unpalatable suspension, but colestipol and colesevelam are available as tablets. The newer drug ezetimibe is orally absorbed and nothing is known about its excretion into breast milk, so it should probably be avoided.

Certainly in the neonatal period, a nonabsorbable resin would be preferred. After the infant is beyond 2 months of age, one might consider adding a small dose of pravastatin for some additional lowering of lipids and for potential pleiotropic effects, such as antiplatelet and antioxidant effects and arterial plaque stabilization. ⁴

An intriguing new possibility is evolocumab (Repatha^®). It is a large protein with a high molecular weight, so the amount in milk is likely to be very low and absorption by older infants is unlikely because of digestion in the infant's gastrointestinal tract. It is given every 2 to 4 weeks by subcutaneous injection. Although it is not contraindicated in nursing mothers, it should be used with caution while nursing a newborn or preterm infant, who might be able to absorb some of the drug from milk. It is quite expensive, but might serve as a bridge in severe hypercholesterolemia until a high-dose statin can be given.

Hyperthyroidism

Hyperthyroidism during breastfeeding poses several potential problems. Diagnosis of the condition is often performed using radioactive iodine. Because iodine is concentrated both in breast milk and the infant's thyroid, radioactivity can pose a risk to the infant. Excessive radiation to the breasts of nursing mothers might also increase her breast cancer risk.

Two forms of radioiodine are used for diagnostic thyroid scans, ¹³¹I and ¹²³I. About 31% of administered radioactivity is excreted into breast milk after administration of ¹³¹I. It has a long radioactive half-life of about 8 days. This isotope is contraindicated in nursing mothers and if it is inadvertently given to a nursing mother, breastfeeding of this infant must be stopped permanently. A safer iodine isotope is ¹²³I, with a physical half-life of 13.2 hours, but breastfeeding would still have to be withheld for 3 to 4 days after administration of this isotope. ⁵ An even safer option is the use of ^99mTc-pertechnetate for diagnosis. This compound is also actively taken up by the breast, but the physical half-life of ^99mTc is only about 6 hours. Although breastfeeding would have to be withheld, the abstinence period ranges from 4 to 24 hours, depending on the dose administered. Regardless of the isotope used, the safest course of action may be to have breast milk tested to determine when the radioactivity is at a safe level to resume breastfeeding.

Treatment of hyperthyroidism can involve one of 3 modalities: radioactive ablation of the thyroid with ¹³¹I, surgery, and antithyroid drug therapy. As noted above, use of ¹³¹I, especially in the higher doses used therapeutically, is contraindicated during nursing and would require breastfeeding cessation. Surgery might be appropriate for an individual patient and breastfeeding would usually have to be withheld only during the operation. Anesthetics in current use do not require prolonged breastfeeding abstention beyond the time the mother recovers consciousness. A potential problem with surgery is the abrupt change in thyroid status, which might result in disruption of lactation.

Antithyroid drugs include propylthiouracil (PTU), methimazole, and carbimazole (only available outside the United States). Carbimazole is a prodrug for methimazole, so methimazole data apply equally to carbimazole. PTU was the drug of choice for nursing mothers in the past, because its excretion into breast milk is only about 10% of methimazole's. However, recent findings that the rate of liver injury is higher with PTU than with methimazole has led some experts to recommend that methimazole should be considered the antithyroid drug of choice in nursing mothers. No cases of PTU-induced liver damage have been reported in breastfed infants and it is unknown if the small amounts of the drug in breast milk can cause liver damage, but liver toxicity might be an immunologic reaction and not dose related. Fortunately, follow-up studies have found no evidence of thyroid function alteration or intellectual impairment among infants exposed to methimazole through breast milk with maternal doses up to 20 mg daily. For infants exposed to these drugs through breast milk, the American Thyroid Association recommends infant monitoring only for appropriate growth and development during routine pediatric health and wellness evaluations. Routine assessment of serum thyroid function in the child is not recommended. ⁵ Some mothers might require a beta-adrenergic blocking drug for control of hyperthyroid symptoms such as tachycardia. Although propranolol is the traditional drug used in this setting, other beta blockers that might be appropriate are discussed in the following section.

Beta Blockers

Some large classes of drugs have numerous choices to pick from, and there can be differences among the drugs during breastfeeding. One of these classes is the beta blockers. The passage of beta blockers into breast milk is primarily determined by their protein binding in maternal plasma. The more lipid-soluble beta blockers like propranolol are the most highly protein bound, so they are preferred agents. However, other factors also come into play, such as central nervous system side effects of propranolol in the mother. These include effects that are particularly undesirable in new mothers such as fatigue, insomnia, and depression. The popular drug atenolol is better tolerated by the mother, but it has low protein binding and the highest percentage excreted into milk of all the beta blockers. It is also primarily excreted by the kidney, and can accumulate in neonates because they are less able than older infants to excrete it. Adverse effects have been reported in two infants apparently from atenolol in breast milk. One experienced lethargy and the other experienced cyanosis, bradycardia, and hypothermia. Another issue is that of long-acting active metabolites. Acebutolol has a long-acting metabolite that is excreted in breast milk and acebutolol reportedly caused hypotension, bradycardia, and transient tachypnea in one breastfed infant.

Because of the lack of comparative studies, it is difficult to assess the relative safety of beta blockers during breastfeeding, However, in addition to propranolol, labetalol and metoprolol appear to have the most favorable pharmacokinetic and side effect profiles in the mother and neonate, although caution should be used while nursing preterm infants. As healthy infants mature beyond about 2 months of age, the risk of side effects appears to decrease and the choice of beta blocker can be based more on maternal factors and less on the drugs' excretion into breast milk.

Nonsteroidal Anti-Inflammatory Agents

A somewhat similar situation to beta blockers exists among the nonsteroidal anti-inflammatory agents (NSAIDs). Although all of these drugs have relatively high protein binding and are poorly excreted into breast milk, there are differences in their breast milk excretion and infants' ability to eliminate them. During breastfeeding of newborns, drugs with short half-lives, such as ibuprofen, are preferred over long-acting drugs such as naproxen, which possibly caused gastrointestinal bleeding in one 7-day-old breastfed infant whose mother was taking it. Again, the choice of NSAID is less critical once the infant is over about 2 months of age.