Thyroid Drug Tied to Birth Defects Again

Published: Nov 4, 2014 | Updated: Nov 5, 2014

By Kristina Fiore, Staff Writer, MedPage Today

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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Discussant: Bryan Haugen, MD
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Action Points

• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• Another study has linked the Graves' disease treatment methimazole with birth defects.
• Note that most recommendations instruct clinicians to stop methimazole during pregnancy because of earlier associations with birth defects and that these women should instead be treated with propylthiouracil.

SAN DIEGO -- Another study has linked the Graves' disease treatment methimazole with birth defects, Japanese researchers reported here.

In an interim analysis of the prospective POEM study, there was a far higher incidence of methimazole embryopathy in women who took the drug during their first trimester than would be expected in the general population (5.9% versus 0.1%), according to Naoko Arata, PhD, of the National Center for Child Health and Development in Tokyo.

Women shouldn't use the drug in those early stages of pregnancy when the fetus is developing organs, she said at the American Thyroid Association meeting.

Most recommendations instruct clinicians to stop methimazole during pregnancy because of earlier associations with birth defects. These women should instead be treated with propylthiouracil (PTU), the guidelines state.

But PTU has been associated with liver injury to the mother and more recent research suggests that it may also carry risk of birth defects.

Indeed, at last year's ATA meeting, Danish researchers reported that both drugs carried a higher risk of birth defects: 50% higher for PTU and 75% higher for methimazole compared with the general population.

To determine whether the prevalence of methimazole embryopathy increases with methimazole exposure in the first 12 weeks of gestation, Arata and colleagues developed the prospective, multicenter, observational POEM (Pregnancy Outcomes of Exposure to Methimazole) Study.

Methimazole embryopathy included choanal atresia, esophageal atresia, aplasia cutis, umbilical cord defects, or omphalocele, Arata reported.

Since 2008, women with Graves' disease who became pregnant were registered from several thyroid clinics at the Japan Drug Information Institute in Pregnancy.

They were included in the methimazole group if they'd had any dose of methimazole, regardless of PTU use during the first trimester. The PTU group included women who took PTU -- but not methimazole -- during the first trimester.

They also enrolled a group of women who did not take any anti-thyroid drugs during pregnancy.

When the fifth case of methimazole-related anomalies was reported in 2011 -- out of a total of 85 live births -- the researchers decided to conduct an interim analysis.

Arata said these five cases had exposure to methimazole during the whole pregnancy.

She and her colleagues found that the incidence of methimazole embryopathy was far higher than that of the general population, estimating that the odds ratio of embryopathy is expected to be well beyond 20, "which is a public health issue," Arata said.

There were no cases of methimazole-related embryopathy in the 122 PTU patients or in the 86 non-drug-treated patients.

Arata added that patent or remnant of omphalomesenteric duct with or without omphalocele is common with methimazole embryopathy, at least in Japan.

She said she strongly recommends not using methimazole during the organogenesis period in women with Graves' disease, adding that preconception counseling is extremely important.

When asked by an audience member, however, whether she would switch all women on methimazole who are planning to get pregnant to PTU, she said it is difficult to know exactly when a woman would conceive, potentially exposing them to the liver risks of PTU longer than necessary.

"But as soon as they've conceived, we should advise them to change from methimazole to PTU," she said.

Another audience member highlighted the Danish research presented last year, which found additional types of birth defects that weren't mentioned in the current study, including heart, eye, and urinary system defects.

Arata said the final analysis will take those other defects into account. It is expected to be completed in 2015, after having collected outcomes for some 1,000 pregnancies.

Bryan Haugen, MD, head of endocrinology at the University of Colorado in Denver, who was not involved in the study, said it's important to assess the safety of anti-thyroid drugs in women who are pregnant and about to become pregnant.

"The current recommendation is to have patients on PTU in the first trimester, and then to switch them to methimazole in the second and third trimesters because methimazole has some questions around developmental abnormalities in the fetus," Haugen said. "But PTU has potential risks to the liver of the mother."

Haugen added that there's been some newer research that are "much larger and that do show there is a slight increased risk of some of these developmental problems in the fetus, especially with methimazole, but there may even be some with PTU."

"This study ... shows again that we definitely see embryopathy or developmental problems with methimazole, so the recommendation is not to be using it as the fetus is developing organs," Haugen said, noting that this concurs with current recommendations.

However, he added that the ATA's pregnancy guidelines panel will reconvene soon and will "be able to look at new data and probably come out with a slightly changed version [of the guidelines]."