POEM: Avoid Methimazole for Graves' Disease in Early Pregnancy

Nancy A Melville

November 04, 2014

SAN DIEGO — New findings out of Japan add to increasing evidence that the use of methimazole to treat the hyperthyroidism of Graves' disease in early pregnancy significantly increases the risk for methimazole embryopathy and indicate that use of this antithyroid drug should be discouraged during pregnancy.

"The continuation of methimazole during the organogenesis period, up to about 12 gestational weeks, confers a definite risk of methimazole embryopathy," said lead author Dr Naoko Arata (National Center for Child Health and Development, Tokyo, Japan).

The findings, presented here at the 2014 Annual Meeting of the American Thyroid Association, are from an interim analysis of the ongoing Pregnancy Outcomes of Exposure to Methimazole (POEM) study.

In a final report from the team, due in 2015, results will clarify whether cessation of methimazole in early pregnancy, at 4 or 5 gestational weeks, is safe, the researchers say.

In the meantime, the American Thyroid Association in fact advises replacing methimazole treatment during the first 3 months of pregnancy with propylthiouracil (PTU) due to the concern of embryopathy. However mounting research, including a new study published in October, demonstrates that PTU also has some important risks of its own (Thyroid. 2014, 24:1533-1540).

Dr Giuseppe Barbesino

The findings therefore underscore the challenges in the treatment of Graves' disease in pregnancy, session comoderator Dr Giuseppe Barbesino (Massachusetts General Hospital, Boston) told Medscape Medical News.

"PTU is currently recommended [as an] alternative to methimazole, but emerging data on potential teratogenic effects of PTU, albeit milder than what [is] seen with methimazole, may soon change this view," said Dr Barbesino.

"Future guidelines may well advise to seek definitive treatment of Graves' hyperthyroidism with surgery or radioiodine when pregnancy is planned. In the case of unplanned pregnancies, however, PTU will still be preferable, in my opinion," he added.

Discourage Methimazole Use in Pregnancy

Dr Arata and the Japanese group compared pregnancy outcomes that were available for three comparison groups: pregnant women with Graves' disease who took any dose of methimazole and/or propylthiouracil (PTU) during the first trimester (n = 93); those who took propylthiouracil (n = 122) during the first trimester; and women with Graves' disease who did not take any dose of either of the drugs during their first trimester (n = 86).

An interim analysis was conducted when the fifth case of methimazole-related anomalies out of 85 live births was reported in the methimazole group (95% confidence interval [CI], 1.9%–13.2%), which is significantly higher than the general incidence rate of just 0.1%.

In all five cases, exposure to methimazole had been throughout the entire pregnancy. The cases specifically involved patent omphalomesenteric ducts (resulting in umbilical discharge of feces or bile) with or without omphalocele (where the intestine or other abdominal organs are outside of the body, covered only by a thin layer of tissue and can be easily seen).

There were meanwhile no cases of methimazole-related embryopathy in the 121 live births in the group of women who had taken propylthiouracil (95% CI, 0.0%–2.4%) or among the 83 live births of women who took no antithyroidal drugs (95% CI, 0.0–3.5%).

"We found in this prospective study, the incidence of methimazole embryopathy was definitely high among women taking methimazole compared with that in the general population," Dr Arata said.

"We should strongly recommend discontinuing methimazole or changing it to other medications, such as propylthiouracil, as early as possible during the organogenesis period in pregnant women with Graves' disease, and preconception counseling is extremely important."

Is Iodine an Alternative Treatment, or Not?

Another study presented at the meeting suggested benefit from a third alternative for Graves' hyperthyroidism during pregnancy — iodine therapy.

Some Graves' disease patients who are treated with methimazole cannot tolerate PTU because of adverse effects, explained the authors, from Ito Hospital Department of Medicine, in Tokyo, Japan.

So in their study of 260 women with Graves' disease, they examined those who were switched from methimazole to inorganic iodide in the first trimester of pregnancy. The incidence of major anomalies was four of 260 (1.53%), significantly lower than the incidence of 47 in a comparison group of 1134 patients treated with methimazole alone (4.14%).

The incidence of methimazole embryopathy in the iodine group was two neonates (0.8%), compared with 18 neonates in the methimazole group (1.6%).

However, there is concern with iodine therapy in pregnancy related to neonatal thyroid dysfunction.

While one neonate in the iodine-alone treatment group had a free T4 level of 0.97 ng/dL and thyroid stimulating hormone (TSH) level of 11.99 mU/L, the infant's thyroid function improved without medication, and there were no signs of goiter development.

"Switching from methimazole to iodine to control hyperthyroidism in Graves' disease patients during the first trimester is a good option to minimize the risk of congenital abnormalities, especially the risk of methimazole embryopathy," say the researchers.

However, Dr Barbesino commented that, despite the findings, iodine treatment has important caveats of its own.

"[The iodine approach] is a thought. However, iodine is effective for a short time only in hyperthyroidism, and it may worsen the hyperthyroidism afterward in some cases," he explained.

"Also, while this report did not observe this, the doses of iodine used to treat hyperthyroidism can cause goiter and hypothyroidism in the fetus after the first trimester."

The authors and Dr Barbesino reported they had no relevant financial relationships.

2014 Annual Meeting of the American Thyroid Association; November 1, 2014; San Diego, CA. Oral abstract 219 and poster 24.

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