Treatment of Gout During Breastfeeding

Probenecid

Probenecid is a uricosuric that enhances the elimination of uric acid through the kidney. It also decreases the excretion rate of some drugs, especially some penicillins and cephalosporins, through the kidney. The information that has been generated is based on that use. A nursing mother with mastitis was given 2 g of probenecid daily (twice the dosage used for hyperuricemia) along with cephalexin. After 16 days of therapy at 4.5 weeks postpartum, the average concentration of probenecid in milk was 964 mcg/L, corresponding to an infant dosage of 145 mcg/kg per day or 0.7% of the maternal weight-adjusted dosage, which is considered an acceptably low dosage. Interestingly, her infant developed green liquid stools, severe diarrhea, discomfort, and crying. However, the authors judged the effects to be probably related to the cephalexin in milk rather than the probenecid.

Allopurinol

Allopurinol and its metabolite oxypurinol inhibit xanthine oxidase, reducing the production of uric acid. Both allopurinol and oxypurinol are well absorbed from the gastrointestinal tract, but oxypurinol has a much longer half-life than allopurinol, so it is the predominant active drug. A nursing mother who was 5 weeks postpartum had been taking allopurinol 300 mg/day orally for 4 weeks. From the levels in her milk, the authors calculated that an exclusively breastfed infant would receive between 0.14 and 0.2 mg/kg of allopurinol and between 7.2 and 8 mg/kg per day of oxypurinol. This dose of allopurinol is slightly less than the infant allopurinol dose of 10 mg/kg per day. Allopurinol was undetectable in the plasma of her infant, but the infant had oxypurinol levels that were 33–48% of maternal plasma oxypurinol levels. The infant had no observable side effects and no changes in clinical chemistry or hematology values.

Another article identified 21 infants who were breastfed by mothers taking a combination of allopurinol and a thiopurine (e.g., azathioprine and mercaptopurine) to treat inflammatory bowel disease. All mothers had taken the combination during pregnancy. Two postpartum infant deaths occurred, both at 3 months of age. One infant was a twin who died from complications of preterm birth and the other died from sudden infant death syndrome. No information was provided on the extent of breastfeeding and drug dosages. The authors did not believe the deaths were medication related. No adverse effects were reported in the other 19 infants.

Febuxostat

This drug is a xanthine oxidase inhibitor that is only used in patients who have had an inadequate response to the maximum dose of allopurinol or cannot tolerate allopurinol. A boxed warning on febuxostat labeling states that there is a higher risk of death with febuxostat than with allopurinol. No data are available on breastfeeding, but it is >99% plasma protein bound, so amounts in milk should be low. Febuxostat is not contraindicated during breastfeeding, but it should be used cautiously in nursing mothers until more data become available.

Pegloticase

Pegloticase is an injectable enzyme that breaks down uric acid in the bloodstream. It consists of recombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of Escherichia coli. Uricase is covalently conjugated to polyethylene glycol (PEG). Pegloticase can cause anaphylaxis and it can cause hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The average molecular weight of pegloticase is ∼540 kDa. Although no information is available on its use during breastfeeding, its high molecular weight should inhibit passage into breast milk. Studies with other pegylated drugs indicate that PEG is not excreted into breast milk. Although not contraindicated in breastfeeding, the serious potential side effects of the drug are cause for concern, especially in G6PD-deficient infants.

Rasburicase

Rasburicase is another injectable enzyme that is available specifically for the management of plasma uric acid levels in patients who are receiving anticancer therapy that causes tumor lysis and subsequent hyperuricemia. Similar to pegloticase, rasburicase is a large protein with a molecular weight of ∼34 kDa. It is unlikely to appear in milk in large amounts. However, the drug can cause fatal hypersensitivity reactions, including anaphylaxis. Since small amounts of maternal serum proteins can appear in milk, there might be a risk of sensitization and an allergic reaction in breastfed infants. The manufacturer recommends that breastfeeding be discontinued during rasburicase therapy and for 2 weeks after the final dose.

Nonsteroidal anti-inflammatory drugs

Naproxen and ibuprofen have specific indications for the pain of gout while indomethacin and sulindac have specific indications for gouty arthritis. In general, nonsteroidal anti-inflammatory drugs (NSAIDs) can be used by nursing mothers, with short-acting drugs such as ibuprofen preferred during the neonatal period. Naproxen possibly caused prolonged bleeding time, thrombocytopenia, and acute anemia in one 7-day-old infant. In a telephone follow-up study of 20 infants exposed to naproxen during breastfeeding, 2 mothers reported drowsiness and 1 reported vomiting in their infants. None of the reactions required medical attention. Studies on indomethacin indicate that infants receive a dosage of indomethacin smaller than that used to treat patent ductus arteriosus in neonates. No adverse effects were seen in a small number of breastfed infants whose mothers were taking indomethacin. Because no information is available on the use of sulindac during breastfeeding and because of its relatively long half-life, other NSAIDs are preferred, especially while nursing a newborn or preterm infant. Other NSAIDs that have reasonably good documentation of safety during breastfeeding include celecoxib, diclofenac, and flurbiprofen.

Colchicine

Colchicine has long been used both prophylactically and therapeutically in gout. Somewhat surprisingly, a considerable amount of evidence exists for the safety of colchicine use during breastfeeding. Long-term prophylactic maternal doses of colchicine up to 1.5 mg/day for familial Mediterranean fever produce milk levels that result in the infant receiving <10% of the maternal weight-adjusted dosage. The highest milk colchicine levels occur 2–4 hours after a dose, so avoiding breastfeeding during this time can minimize the infant dose. No adverse effects were reported in >50 infants who were breastfed by mothers taking colchicine. Numerous experts and professional guidelines consider colchicine acceptable during breastfeeding in women being treated for familial Mediterranean fever or rheumatic conditions.

Corticosteroids

Prednisone and methylprednisolone are sometimes used systemically to treat gout, and intrabursal or intra-articular betamethasone are used for gouty arthritis. Oral corticosteroids are acceptable to use during breastfeeding. Although some articles recommended a waiting period before resuming nursing, there is no rationale for this maneuver, because milk levels are extremely low. Only very high-dose intravenous corticosteroids (e.g., 1 g of methylprednisolone) might require a short waiting period.

Three cases of decreased milk supply have been reported by nursing mothers after intra-articular injection of a corticosteroid. The cause of this is unclear, but it might be due to the trauma of the injection rather than the drug itself. Nevertheless, with maternal persistence, the milk supply returned in all cases.

Canakinumab

This monoclonal antibody is an interleukin-1 inhibitor that is U.S. Food and Drug Administration (FDA) approved for treatment of systemic juvenile idiopathic arthritis. It is also effective in relieving gout pain and inflammation. Because it is a large protein molecule, only minute amounts, if any, are expected to appear in milk. One patient received canakinumab 150 mg subcutaneously on day 10 postpartum. At birth, a level of 1.33 mg/L was found in cord blood from two maternal doses given during pregnancy. She continued to partially breastfeed her infant, and no detectable canakinumab was found in the infant's serum 10 weeks after the postpartum dose. The child developed normally in the following 2 years, with a normal height and weight at 2 years of age.

In an international multicenter study of mothers exposed to interleukin-1 receptor antagonists (IL-1Ra), four babies were breastfed by mothers who were regularly receiving canakinumab, although it is unclear whether mothers received the drug postpartum or only during pregnancy. There were no reported serious infections and no developmental abnormalities at a mean follow-up of 2.2 years (range, 5 months to 4 years).

Anakinra

Anakinra is the pharmaceutical name for recombinant human IL-1Ra. IL-1Ra is a normal component of human milk where it may play a role as an anti-inflammatory agent. Anakinra is approved for treatment of rheumatoid arthritis, but it is also used off-label to reduce the pain and inflammation of gout. Several infants have been breastfed during maternal anakinra therapy with no obvious adverse effects and normal development. International guidelines indicate that anakinra can be used by nursing mothers.