Drug Treatment of Rheumatoid Arthritis During Breastfeeding

Conventional Disease-Modifying Agents

Although disease-modifying antirheumatic agents (DMARDs) used to be considered a “last resort,” they are now often used initially in the course of RA to prevent long-term joint damage. Methotrexate is considered the drug of choice by most rheumatologists. Although it has long been used in the treatment of cancer in high doses, the doses used in RA are considerably smaller, usually ≤ 25 mg weekly, either orally or by intramuscular or subcutaneous injection. Although breastfeeding with methotrexate is contraindicated in doses used to treat cancer, the safety of low-dose methotrexate for the nursing mother is unsettled. The first data on breast milk excretion date back to 1972. The amount of drug in the milk of one mother was sufficiently low that the author recommended that breastfeeding could be continued during low-dose methotrexate. Nevertheless, numerous subsequent review articles and professional guidelines cited this article as a reason to not breastfeed during methotrexate use because it was detectable in milk. Since 1972, several other case reports have appeared that confirm the very small amounts of methotrexate in milk after a 25 mg dose, generally at or below the limit of detection of 23 mcg/L. The most recent article appeared in this journal, in which a dose of 92 mg daily for 4 days was given for placenta accretia. Even this dose of almost four times the maximum dose used in RA resulted in only tiny amounts of the drug and its active metabolite in breast milk. Although more data are urgently needed, it appears that a maternal dose of 25 mg weekly does not pose a great risk to the breastfed infant. Various maneuvers have been proposed for protecting the breastfed infant, from doing nothing special to withholding nursing for 24 hours after each dose to avoiding breastfeeding altogether. Continuing breastfeeding with monitoring of the infant's complete blood count and differential is also an option.

Another popular DMARD is hydroxychloroquine. The main concern with this drug is that with a half-life of over 1 month, it accumulates in the body with long-term use and can cause retinal toxicity. As of this writing, 13 women have had hydroxychloroquine levels measured in their milk. Milk levels are dose proportional and the highest recommended dose of 200 mg twice daily produces infant dosages estimated to be 0.1–0.2 mg/kg daily. Although infant serum levels have not been measured, more than 20 infants have been followed long term with no indication of oculotoxicity. Normal flash electroretinograms were found in five of the infants whose mothers took hydroxychloroquine 200 mg daily during pregnancy and breastfeeding, one of whom breastfed for 30 months. Based on these data, most experts and guidelines consider hydroxychloroquine safe to use during breastfeeding.

Sulfasalazine is a combination of the sulfa drug, sulfapyridine, with mesalamine. It is used in RA as well as in inflammatory bowel disease. Sulfasalazine and mesalamine are poorly excreted into breast milk, but are detectable in infant serum and urine. Rather high levels of the mesalamine metabolite N-acetyl-5-aminosalicylate appear in breast milk and its effects on breastfed infants are unknown. Sulfapyridine also appears in milk and infant serum and might cause hemolysis, especially in newborn infants and in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Bloody diarrhea has occurred in an infant whose mother was taking sulfasalazine and a few cases of diarrhea have been reported in infants exposed to mesalamine in breast milk, although the rate is low. Most expert opinion considers sulfasalazine to be acceptable during breastfeeding. If sulfasalazine is used, the infants should be observed for diarrhea and the drug should be avoided in nursing mothers with G6PD-deficient infants.

Other drugs less commonly used in treating RA include azathioprine and cyclosporine. Azathioprine is generally accepted as safe during breastfeeding. Opinion varies as to the safety of cyclosporine during breastfeeding, although recent literature is trending toward considering it safe to use. Another DMARD is leflunomide, a known carcinogen in animals. Apremilast is an oral phosphodiesterase-4 inhibitor used to treat psoriatic arthritis. Both of these drugs are analogs of thalidomide and no information exists on their use in nursing mothers. Accordingly, they are not recommended during breastfeeding.

Biological Agents

Numerous biological agents have become available and are also DMARDs. Tumor necrosis factor (TNF) inhibitors are monoclonal antibodies that inhibit the proinflammatory cytokine TNF in the synovium of patients with RA. Adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab are approved in the United States for treatment of RA; ustekinumab is approved for use in RA in other countries. These drugs are sometimes used in combination with methotrexate or another DMARD. All of these monoclonal antibodies are high-molecular-weight compounds that pass very poorly into milk. ⁶ Several expert guidelines state that anti-TNF monoclonal antibodies used to treat RA are acceptable to use in mothers who are breastfeeding. These recommendations are based on a variety of evidence, mostly the absence or near absence of the drugs from breast milk in single cases or case series in mothers being treated for RA or inflammatory bowel disease. Some guidelines distinguish among the drugs by how much published data exist in breastfeeding. The most data on excretion into milk are with adalimumab, certolizumab, and infliximab. A few measurements of the drugs in the serum of breastfed infants have mostly found them to be undetectable. Only one infant had small, measurable amounts of infliximab in his serum that was clearly related to breastfeeding. Other infants with measurable serum levels were thought to have obtained the drug transplacentally. In addition to these reports, many other infants have been breastfed during maternal monoclonal antibody use and no adverse reactions in breastfed infants have been reported with the use of any monoclonal antibody in nursing mothers.

The interleukin (IL)-6 inhibitors sarilumab and tocilizumab are also monoclonal antibodies. Sarilumab has no information on use during breastfeeding. A minimal amount of data on tocilizumab indicate that its passage and safety are similar to the better studied TNF-inhibiting monoclonal antibodies.

Other large genetically engineered proteins for RA include abatacept, which interferes with T cell activation; anakinra, which is an IL-1 receptor antagonist; and rituximab, which targets CD20, a B cell-specific surface antigen. Information on these drugs in breastfeeding is limited, but early indications are that they have very low amounts in breast milk like other large proteins.

Janus Kinase Inhibitors

Baricitinib and tofacitinib are small-molecule, oral drugs that inhibit Janus kinase, a signaling mediator in various immune activation pathways. Little information is available on their use during breastfeeding. Because of their likely passage into milk, oral absorption, and toxicity, including possible carcinogenicity, they are currently considered to be contraindicated during breastfeeding by most guidelines. However, a few infants have been safely breastfed during maternal tofacitinib therapy.

Corticosteroids

Oral and intra-articular corticosteroids are sometimes used in treating RA. The oral doses used are low, usually in the range of 5–10 mg per day of prednisone, and usually used for only short periods. Used in this way, there is no concern about breastfeeding and no special precautions need to be taken because amounts in milk are trivial.

Intra-articular injections of corticosteroids have not been studied during breastfeeding, but since small, single doses are used and diffusion out of the joint space occurs slowly, it is unlikely that clinically important amounts enter breast milk. However, there are a few case reports of decreased breast milk production following injection of a corticosteroid into a joint space. Whether these occurrences are drug related or just coincidental is not known.

Nonsteroidal Anti-Inflammatory Drugs

In general, nonsteroidal anti-inflammatory drugs (NSAIDs) are acceptable to use during breastfeeding. They are weak acids that are highly protein bound in maternal plasma, so little reaches the breast milk. Ibuprofen, which has very low levels in breast milk, is a good choice. While nursing a newborn, it is probably best to avoid long-acting drugs such as naproxen, because they might accumulate in the infant. Urticaria occurred in the newborn infant of a mother taking diclofenac. A few case reports of adverse effects with maternal (or wet nurse) aspirin use have been reported, so it is not a preferred agent. One concern with conventional NSAIDs is their antiplatelet effect. One case report of severe gastrointestinal bleeding was reported in a newborn whose mother was taking naproxen. Cyclooxygenase II inhibitors, such as celecoxib, do not have antiplatelet activity and might be preferable to conventional NSAIDs in some situations.

Summary

Drug treatment of RA need not be a barrier to breastfeeding; however, careful drug selection is important. Low-dose methotrexate is a mainstay of therapy, and limited data have found no indication of toxicity in breastfed infants, but more data are needed before it is considered “safe.” The monoclonal antibodies are acceptable to use during breastfeeding, but use of those with the most published data are preferred. The Janus kinase inhibitors are of concern because of their possible toxicity. Although used less frequently, older drugs such as azathioprine, corticosteroids, cyclosporine, hydroxychloroquine, NSAIDs, and sulfasalazine are generally considered acceptable to use during breastfeeding.