Methimazole Exposure Linked to Higher Pregnancy Complication Rate

Discontinuation of methimazole (MMI) during early pregnancy may be advisable for women with Graves’ disease, according to a Japanese study presented at the 84th Annual Meeting of the American Thyroid Association.

After evaluation of about 1,000 outcomes of pregnancies complicated by Graves’ disease, researchers found that use of the antihyperthyroidism drug during the organogenesis period may increase the risk for embryopathy.

These data are from an interim report on the POEM (Pregnancy Outcomes of Exposure to Methimazole) Study presented at the annual meeting. The researchers said a final report will be available in 2015 to clarify whether cessation of MMI during the first 4 or 5 gestational weeks is safe. 

“The significance of our study is that it is the first prospective study to show high incidence of MMI embryopathy. Its rate may be more than 1.5% to 2%,” said study investigator Naoko Arata, PhD, who is with the National Center for Child Health and Development in Tokyo.  

“We should strongly recommend discontinuing MMI or changing it to other medications as early as possible during the organogenesis period in pregnant women with Graves’ disease.”

The Japanese investigators conducted a prospective study of women with Graves’ disease who became pregnant. Since 2008, they have been comparing pregnancy outcomes among women who took any dose of MMI or propylthiouracil (PTU) during the first 12 weeks of pregnancy.

The primary focus of this ongoing study is to determine whether the prevalence of MMI embryopathy (single or multiple existence of choanal atresia, esophageal atresia, aplasia cutis, umbilical defects or omphalocele) increases with MMI exposure in the first 12 gestational weeks.

For this investigation, the MMI group included women with Graves’ disease who took any dose of MMI and/or PTU during the first 12 weeks of pregnancy. The PTU group included women who took any dose of PTU but not MMI during the first 12 weeks of pregnancy. The non-antithyroidal drug group was composed of women who did not take PTU or MMI during the first trimester.

Once the fifth case of MMI-related anomalies was reported in 2011, the investigators decided an interim analysis of POEM should be performed.  The investigators confirmed that, in the MMI group, there were five cases of MMI-related embryopathy in 85 live births, which was significantly higher than the general incidence of 0.1%. 

Interestingly, there were no cases of MMI-related embryopathy found among 121 live births in the PTU group and 83 in the non-antithyroidal group.

“Of course, this result was very surprising. Preconception care is very important. Disease should be well-controlled before pregnancy and patients should understand about the risks and benefits of medication. The risk of methimazole embryopathy is higher than ever thought, and preconception care and counseling is extremely important,” Dr. Arata told Endocrinology Advisor.

The study showed that among the five cases of MMI embryopathy, the exposure to MMI occurred during the whole pregnancy period.

Henry Bush, MD, who is Chair of the Endocrinology Division at Walter Reed National Military Medical Center in Bethesda, Maryland, said this study confirms previously described birth defects in infants born to mothers exposed to MMI during the first trimester of pregnancy.   

For this reason the 2011 ATA/American Association of Clinical Endocrinologists (AACE) guidelines recommend switching from MMI to PTU as soon as pregnancy is diagnosed, Dr. Bush said.

Dr. Bush noted that this past year a Danish group² also described birth defects in women exposed to PTU in early pregnancy. However, the defects occurred at a lower incidence and affected different regions of the body. 

“The net effect of these types of studies is likely to be a greater push for definitive therapy with thyroid surgery or radioiodine in women with Graves’ disease interested in becoming pregnant in the near future,” Dr. Bush told Endocrinology Advisor. 

References

1. Arata N et al. Oral Abstract 219. Presented at: American Thyroid Association (ATA) 84th Annual Meeting; Oct. 29-Nov. 2, 2014; Coronado, Calif.
2. Andersen SL and Laurberg P. Eur J Endocrinol. 2014;doi: 10.1530/EJE-14-0524.