Anticoagulants and Breastfeeding

Abstract

Occasionally an adverse drug reaction in a nursing infant is reported and becomes an “urban legend” that expands beyond reasonable limits. Such was the case of severe postoperative bleeding in a 4-week-old infant whose mother was taking the oral vitamin K antagonist, phenindione. This was reported in 1970, but led to many years of admonitions that infants could not breastfeed if their mothers were taking an oral anticoagulant, including warfarin. Phenindione is a member of the obsolete indanedione class of anticoagulants and warfarin is a coumarin. Even though both are vitamin K antagonists, they have very different physicochemical properties. Maternal warfarin has since been shown to not affect breastfed infants, even in a mother who inadvertently took five times the prescribed dose (25 mg/day) for a week!¹ Other coumarin anticoagulants used outside the United States, such as acenocoumarol and phenprocoumon, have also been demonstrated to be safe during breastfeeding. This is a result of the extensive binding of coumarin anticoagulants to maternal plasma proteins, which greatly limits their passage into breast milk.

The numerous new anticoagulants that have become available make it an opportune time to review the safety of other classes of anticoagulants during breastfeeding. Additional literature references can be found in the corresponding LactMed records.

Heparins

It is accepted as fact that heparin is not excreted into breast milk because of its highly charged nature and high-molecular weight. Interestingly, no published reports exist of any measurements of heparin in breast milk.

But what about the low-molecular weight (LMW) heparins such as dalteparin (Fragmin^®) and enoxaparin? Might their LMW make them susceptible to excretion into breast milk? Apparently not, because these relatively newer drugs have been used in nursing mothers with no adverse effects reported in their infants. In fact, these drugs have high-molecular weights more than 1,000 daltons and are relatively highly charged like heparin itself. Dalteparin was not detectable in the milk of 2 women, and anti-Xa activity in milk was low in 15 others. Recall that these drugs must be given by injection to be absorbed, so oral administration of a heparin-type anticoagulant to an infant through breast milk presents an additional safety barrier.

In one survey, 15% of mothers expressed concern about taking a LMW heparin while breastfeeding.² So, reassuring nursing mothers that these drugs are safe during breastfeeding is a good idea.

Direct Thrombin Inhibitors

Dabigatran (Pradaxa^®) is the current “poster child” for this class of drugs. It is orally active and may have some therapeutic advantages over vitamin K antagonists. Older drugs in this class of anticoagulants include argatroban, bivalirudin (Angiomax^®), and desirudin (Iprivask^®), which are all given by injection.

None of these drugs has been studied in breast milk and most sources, including the package insert, recommend that they not be used during breastfeeding.^3,4 However, a closer look at the properties of the drugs indicates some important differences among them. Both bivalirudin and desirudin have very high-molecular weights, making it unlikely that they are appreciably excreted into breast milk. Dabigatran and argatroban have LMWs, so they probably can be excreted into breast milk. Commercially available dabigatran comes as the ester, dabigatran etexilate, which improves its oral bioavailability, but only to about 7%. The ester is rapidly converted to dabigatran in the body and would be excreted into breast milk in that form. So, it is unlikely that sufficient dabigatran would be absorbed by the infant to result in bleeding. However, until more data become available, the direct thrombin inhibitors should probably be avoided during breastfeeding.

If a nursing mother experiences bleeding with dabigatran, she might be given the monoclonal antibody reversal agent idarucizumab (Praxbind^®). The amount of idarucizumab in breast milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant's gastrointestinal tract. Idarucizumab is specific for dabigatran and will not reverse other direct thrombin inhibitors, but reversal agents for the other drugs are under development.

Direct Xa Inhibitors

Another class of anticoagulants is the direct factor Xa inhibitors. The first drug in this class was fondaparinux (Arixtra^®), which is administered subcutaneously. Newer oral Xa inhibitors include apixaban (Eliquis^®), edoxaban (Savaysa^®, Lixiana^®), and rivaroxaban (Xarelto^®), which all have relatively good oral bioavailability and are administered by mouth. Rivaroxaban has been measured in the breast milk of one mother who was receiving 15 mg twice daily. The authors calculated that a fully breastfed infant would receive 2.4 μg/kg over the 10-hour period, which would be 1.3% of the maternal weight-adjusted dosage.⁵ A value this low is generally considered to be an indication of relative safety of the drug in breastfeeding, but only this one patient has been studied thus far. No information is available on apixaban or edoxaban in nursing mothers. Like the direct thrombin inhibitors, the package inserts and current expert opinion state that direct Xa inhibitors should not be used during breastfeeding.^3,4

Andexanet alfa is a modified version of recombinant factor Xa that reverses the effects of direct Xa inhibitors. Ciraparantag, also called aripazine, can reverse these antagonists as well as heparin and the LMW heparins. These drugs are not yet FDA approved and no information is available on their use in nursing mothers. Andexanet alfa has a molecular weight of more than 40,000, so it likely will not appear in breast milk.

Antiplatelet Drugs

Many drugs are used for their antiplatelet actions. The most commonly used drugs in the ambulatory setting are clopidogrel (Plavix^®), aspirin, and the aspirin–dipyridamole combination product (Aggrenox^®). Expert opinion and the package insert recommend against the use of clopidogrel or dipyridamole during breastfeeding.³ Dipyridamole is interesting in that it inhibits the active transport of nitrofurantoin into the milk in animal studies.⁶ These early studies have not been replicated in human studies, however.

High-dose aspirin (e.g., for arthritis or fever) should generally be avoided during breastfeeding because of the potential for adverse effects in the breastfed infant. Several case reports indicate that aspirin might cause thrombocytopenia, fever, anorexia, petechiae, or even metabolic acidosis. Hemolysis was reported in a breastfed infant with G-6-PD deficiency whose mother took aspirin. No cases of Reye's syndrome have been reported in infants from aspirin in breast milk.

However, low-dose aspirin (50 to 150 mg daily), which is used as an antiplatelet agent, is considered to be acceptable during breastfeeding.^3,7 A theoretical, but unproven, risk is that low-dose aspirin might cause an antiplatelet effect in the infant if breastfeeding occurs shortly after maternal ingestion. However, once aspirin is converted to salicylate by the mother, this risk is negligible. The conversion takes place with a half-life of 15 to 20 minutes, so after 1 hour, aspirin is absent from breast milk.

In summary, most of the newer oral anticoagulants and antiplatelet drugs have little or no documentation of either their passage into breast milk or their safety for the nursing infant, so they should be avoided during breastfeeding for now, if possible. However, physicochemical factors and clinical data indicate that some of them might prove to be acceptable during nursing after more data become available. Warfarin, heparin, LMW heparins, and low-dose aspirin are currently considered acceptable during breastfeeding.

Footnotes

Disclosure Statement

No competing financial interests exist.

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