Graves' Disease in Pregnancy: Choosing the Tx


WASHINGTON — Given growing concerns about propylthiouracil-related liver toxicity, “it may be that we should be weighing the relative risks” of this drug and methimazole for the treatment of Graves' disease during pregnancy, Dr. Susan J. Mandel said.

Propylthiouracil (PTU) has been the preferred therapy for Graves' disease during pregnancy, especially during first-trimester organogenesis, because methimazole (MMI) and carbimazole have been associated with aplasia cutis and rare embryopathy including choanal atresia, esophageal atresia, tracheoesophageal fistula, and athelia.

None of these congenital anomalies has been reported with the use of PTU, Dr. Mandel said at an American Thyroid Association-sponsored meeting. Dr. Mandel is associate chief of the division of endocrinology, diabetes, and metabolism at the University of Pennsylvania, Philadelphia.

Last month, the Food and Drug Administration issued a warning about the risk of severe liver injury associated with the use of PTU with the treatment of Graves' disease. “After analyzing adverse event reports, the FDA has identified an increased risk of liver injury with propylthiouracil, compared with an alternative treatment for Graves' disease, methimazole,” Dr. Amy Egan, deputy director for safety, division of metabolism and endocrinology products, FDA Center for Drug Evaluation and Research, said in a statement.

“Health care professionals should carefully consider which drug to initiate in a patient recently diagnosed with Graves' disease. If PTU therapy is chosen, the patient should be closely monitored for symptoms and signs of liver injury, especially during the first 6 months after initiating therapy.”

The FDA is advising health care professionals to reserve PTU for patients in their first trimester of pregnancy or those who are intolerant of or allergic to methimazole.

The FDA statement, posted on the agency's MedWatch Web site, said that 32 cases of serious liver injury were reported to the FDA from 1969, when the agency's adverse event reporting program was established, through October 2008. Of these cases, 22 were in adults, and included 12 fatalities and 5 liver transplants. Among the 10 pediatric cases, there were 6 reports of liver transplants and 1 fatality, according to the statement.

On the basis of an analysis of these reports, the FDA has determined that the risk of hepatotoxicity is greater with PTU than with MMI. The FDA received only five reports of serious liver injury associated with MMI, which was approved in 1950.

The FDA announced plans to change the prescribing information for PTU to reflect the hepatotoxicity warning

Concerns about PTU's hepatotoxicity have come largely from the pediatric community. Last year, the National Institute of Child Health and Human Development (NICHD) held a conference on “hepatic toxicity following treatment for pediatric Graves' disease.” And most recently, Dr. Scott A. Rivkees of Yale University, New Haven, Conn., and Dr. Donald R. Mattison of NICHD called for an end to the use of PTU in children.

In a letter to the editor published in the April 9 issue of the New England Journal of Medicine (2009;360:1574-5), Dr. Rivkees and Dr. Mattison said that PTU-induced liver failure may occur in 1 in 2,000 to 1 in 4,000 treated children, with nearly 10 times that range developing reversible PTU-induced liver injury.

In the context of Graves' disease in pregnancy, Dr. Mandel said, “it may be that we should be rethinking, what are the relative risks of hepatotoxicity with PTU versus the very rare embryopathy reported with methimazole [and carbimazole].”

Because the changes apparently caused by MMI “all occur by 8-10 weeks' gestation, and some even earlier, there may be a rationale” to using PTU into early pregnancy and then switching to methimazole afterwards,” added Dr. Mandel, also professor of medicine and radiology at the University of Pennsylvania.

The original recommendations to use PTU in pregnancy—before the teratogenic effects of MMI were reported—came from studies suggesting that PTU was less likely to cross the placenta. More recent data acquired through the use of newer measurement techniques have challenged this, demonstrating a similar degree of transplacental passage with both drugs, she noted.

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