Sharp Decline in Antithyroid-Drug Embryopathy Seen After Alert

Nancy A Melville

October 03, 2016

DENVER — New data shed more light on the specific risks of congenital birth defects associated with the Graves' disease drug methimazole (MMI) and the timing of the teratogenic effects.

The results indicate that there were significant declines in MMI-related embryopathy following a national alert in Japan about the risk of birth complications with the drug and importantly identify a critical 6-week gestation point beyond which the damage seems to occur.

"For patients receiving continuous administration of methimazole after conception, the incidence of methimazole embryopathy was zero if methimazole administration was terminated before 6 gestational weeks, but increased by 5% to 8% if methimazole was terminated after 6 weeks," explained Naoko Arata, PhD, of the National Center for Child Health and Development, in Tokyo, Japan, in presenting the findings here at the American Thyroid Association (ATA) 2016 Annual Meeting.

The results represent the final report of the prospective Pregnancy Outcomes of Exposure to Methimazole (POEM) study, which evaluated pregnancy outcomes in Japan from 2008 to 2015, providing a unique look at pregnancy outcomes in women treated with antithyroid medications before and after the 2011 issuance of an alert from the Japanese Thyroid Association (JTA) warning against the use of methimazole in the first trimester of pregnancy.

The alert was issued after an interim analysis from the POEM study showed an increase of 5.9% of embryopathy among infants of mothers treated with MMI, compared with those not treated.

The final report from POEM included findings on three groups of women with Graves' disease — those treated with methimazole in the first trimester, regardless of whether they switched to an alternative antithyroid drug propylthiouracil (PTU; n = 277); those treated with PTU but no methimazole; n = 327); and those with Graves' disease who were not treated with antithyroid medications (n = 279), as well as 2010 healthy controls.

The results showed an overall incidence of MMI embryopathy of 2.7% (95% CI, 1.1–5.4%) of 263 live births, compared with one case among 1837 live births in the healthy control group and zero cases in either the PTU or no-antithyroid-medication group.

In looking at the incidence rates before and after the JTA alert, the incidence of MMI embryopathy in the MMI-treated group declined from 4.3% (95% CI, 1.4–9.7) beforehand to 1.4% (0.2–4.9) afterward, when women were switched from methimazole, with no statistically significant declines in any of the other groups.

Time of Discontinuation of MMI Is Key

"We found the incidence of methimazole-associated malformations was extremely high in the MMI group compared with the other two groups of Graves' disease and control," Dr Arata emphasized.

But the period of gestation during which MMI exposure occurred was key, she noted.

The highest incidence of embryopathy occurred when MMI was discontinued after 8 weeks' gestation (7.6%), while no cases were observed when MMI was discontinued before 6 weeks' gestation.

"We recommend avoiding exposure of MMI during the organogenesis period in women with Graves' disease," she stressed.

The study showed no evidence of a dose response regarding the MMI embryopathy risk, she added.

"Cessation of MMI or changing it to other medications (ie, PTU) before [pregnancy] or in [very] early pregnancy may be recommended. Preconception counseling is extremely important."

A look at rates of general malformation in the four groups showed an incidence of 5.7% in the MMI-treated group, compared with 3.1% in the PTU group, 1.4% in the no-antithyroid-medication group, and 2.2% in the control group.

Six of 14 anomalies seen in the MMI-treated group were related to MMI embryopathy, compared with none among the 13 anomalies reported in the PTU group. Five cases of general malformation occurred in the no-antithyroid-drug group.

MMI embryopathy includes single or multiple existence of choanal atresia, esophageal atresia, aplasia cutis, umbilical defects, and/or omphalocele. In the general population, the incidence of such defects is estimated at approximately one in 1000 newborns.

An increased risk of congenital abnormalities associated with MMI as well as PTU in early pregnancy has been demonstrated in other research, including a large Danish nationwide register-based cohort study published in 2013 (J Clin Endocrinol Metab. 2013;98: 4373-4381), showing a higher incidence of overall congenital defects during early pregnancy with both of the drugs, although the types of malformations differed between the two medications.

And a meta-analysis of eight studies published in 2015 also showed an increased relative risk of congenital abnormalities associated with PTU and MMI/carbimazole (PLoS One. 2015;10:e0126610).

Additional Data Needed on Antithyroid Medications in Pregnancy

The collective findings underscore the fact that "additional data are needed to add to the understanding of the pregnancy-associated risks of the use of antithyroid medications, particularly during early pregnancy," Angela M Leung, MD, an assistant professor of medicine at the division of endocrinology, University of California, Los Angeles David Geffen School of Medicine, and moderator of the session, told Medscape Medical News.

The most recent ATA guidelines recommend that women with Graves' disease being treated with MMI switch to PTU in the first trimester of pregnancy, while methimazole is preferred during the second and third trimester, Dr Leung noted.

While the risk of fetal anomalies has been well documented, these newest data from POEM importantly examined the decline in embryopathy after discontinuation of MMI, underscoring the drug's effect, said Tim Korevaar, MD, Erasmus University Medical Center in Rotterdam, Netherlands, in commenting on the study.

"This study is important because it is a replication of the earlier seminal studies that indicated these important problems," he told Medscape Medical News.

Furthermore, it adds to the evidence base with regard to the importance of the timing at which methimazole is stopped — which fits with the physiology of early fetal organogenesis — and it also informs on the effects of changes in the Japanese national recommendations.

And it further underscores the effectiveness of prescribing alerts, he added.

"This indicates that by making physicians aware of the potential harms associated with early pregnancy use of methimazole, it is possible to change prescribing behavior and overcome methimazole-induced fetal anomalies."

Drs Arata, Leung, and Korevaar had no relevant financial relationships.

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American Thyroid Association (ATA) 2016 Annual Meeting; September 23, 2016; Denver, Colorado. Abstract 1.

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