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Gout during pregnancy and lactation.

Gout is characterized by recurrent attacks of acute inflammatory arthritis caused by crystals of uric acid deposited in joints, tendons, and surrounding tissues. About half of cases involve the big toe, but it can present as gouty tophi (a deposit of monosodium urate crystals in the joints, cartilage, bone, and throughout the body that may break out through the skin), kidney stones, or urate nephropathy.

Acute gouty arthritis is an uncommon condition in women of reproductive potential, as only about 10%-15% of cases involve women and it typically occurs after menopause (J. Rheumatol. 1994;21:1365-6). A study from Britain described 158 subjects with a dominantly inherited disorder known as familial juvenile hyperuricemic nephropathy (Nucleosides Nucleotides Nucleic Acids 2006;25:1071-5). The disorder - characterized by hyperuricemia, gout, and potentially fatal renal disease - affects children, young women (some pregnant), and men equally. The gout drug allop-urinol is the treatment of choice for this genetic metabolic disease.

The incidence of gout during women's childbearing years is 1.5 cases per 10,000 patient-years. Maternal gout may be associated with an increased risk of pregnancy complications and adverse outcomes. In a study of 473,529 women in Taiwan with singleton live births in 2001-2003, 4,361 (0.9%) had been diagnosed with gout in the 2 years before giving birth. In a subgroup of 3,261 subjects with a reliable diagnosis, gout significantly increased the risk of preeclampsia, preterm birth, cesarean delivery, low birth weight, and small-for-gestational age infants. However, the authors acknowledged that because of the large sample size and the small magnitude of the outcomes, the clinical relevance of their findings may be questionable. (Int. J. Gynaecol. Obstet. 2010;109:157-8). No mention was made of the agents used for gout treatment in their population.

There are currently five drugs that can be used to treat gout: allopurinol (Zyloprim), colchicine (Colcrys), febuxostat (Uloric), pegloticase (Krys-texxa), and probenecid. All have a Food and Drug Administration pregnancy risk category C. A sixth agent, sulfinpyrazone (Anturane), a uricosuric agent, has been withdrawn from the market, but there are no reports describing its use to treat gout in pregnant women.

Allopurinol inhibits xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. The human pregnancy data are limited but have not shown an association with developmental toxicity. But a 2011 case report described multiple structural defects in a newborn whose mother had taken allopurinol throughout pregnancy to prevent kidney stones. The defects were diaphragmatic hernia; unilateral microtia and absence of external auditory canal; micrognathia; microphthalmia; optic nerve hypoplasia; hypoplasia of the corpus callosum; unilateral renal agenesis; pulmonary agenesis; and cleft lip and palate. The authors suggested that the drug caused the defects, but a chromosome microdeletion/ duplication syndrome could not be ruled out (Am. J. Med. Genet. Part A 2011;155:2247-52).

The occurrence of primary gout with gouty nephropathy is a rare complication. In one case, a woman with gout and a markedly decreased creatinine clearance (30-35 mL/min), was treated with allopurinol (300 mg/day) throughout gestation, and gave birth at 35 weeks to a healthy female infant. Although there is a high rate of recurrence immediately post partum, consistent with the increased incidence of gout flares in postmenopausal woman and during menses, the woman had no recurrence of gout during or after pregnancy (Am. J, Obstet. Gynecol. 1979;133:107-8).

Colchicine is an alkaloid used for the prophylaxis and treatment of gout. The drug is thought to prevent the activation, degranulation, and migration of neutrophils that mediate some gout symptoms. The human pregnancy data on this drug for gout treatment are limited, but it is the agent of choice for the treatment of familial Mediterranean fever. Overall, the human pregnancy experience from both indications is reassuring. However, the drug is teratogenic and embryocidal in animals at low doses, and mutagenic in some assays. Except for pregnant women with familial Mediterranean fever, the drug is best avoided in pregnancy.

Febuxostat, which came onto the market in 2009, is a xanthine oxidase inhibitor that acts by decreasing serum uric acid. This action is similar to that of allopurinol. The use of febuxostat in human pregnancy has not been reported, but the animal data suggest low risk.

Pegloticase is a new drug that was released in 2010. There are no reports describing the use of the drug in human pregnancy, but the animal data suggest low risk. It is a uric acid-specific enzyme that catalyzes the oxidation of uric acid to allantoin, an inert water-soluble purine metabolite, thereby lowering serum uric acid. The high molecular weight (about 540 kDa) suggests that the drug does not cross the placenta.

Probenecid has been available for more than 50 years. It is a uricosuric and renal tubular transport-blocking agent. The drug crosses the human placenta, at least at term. The only reports of its use as a uricosuric in human pregnancy involved women with preeclampsia, not gout. In addition, reports have described its use to partially block the urinary excretion of antibiotics in pregnancy. The combined data do not suggest a risk of structural defects or other forms of developmental toxicity. Animal reproduction studies have apparently not been conducted.

Allopurinol, colchicine, and probenecid are excreted into breast milk and are - or probably are - compatible with breastfeeding. Febuxostat is probably excreted, but there is potential toxicity and nursing infants who may be exposed to the drug in milk should be monitored for liver function abnormalities, nausea, arthralgia, and rash. It is unlikely that pegloticase will be excreted into milk because of its very high molecular weight. However, even if it were excreted, the drug most likely would be digested in the infant's gut.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children's Hospital in Long Beach, Calif; a clinical professor of pharmacy at the University of California, San Francisco; and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is a fellow of the American College of Clinical Pharmacy, coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He said he had no relevant financial disclosures.
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Author:Briggs, Gerald G.
Publication:OB GYN News
Article Type:Medical condition overview
Date:Mar 1, 2012
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