Women with Graves' disease who take anti-thyroid medications (ATDs) during the first trimester of their pregnancy may have a higher risk for congenital malformations, especially if they took methimazole (MMI) alone, or took that medication in combination with propylthiouracil (PTU). That's the determination of a new nationwide cohort study conducted in South Korea and released Jan. 22, 2018, in the Annals of Internal Medicine.
The American Thyroid Association says the condition is an autoimmune disease that leads to a generalized over-activity of the entire thyroid gland, or hyperthyroidism, and that Graves' is the most common cause of this in the United States.
"Untreated or insufficiently treated Graves' disease (hyperthyroidism) in pregnancy poses a risk to both mother and their offspring," co-authors Jae Hoon Chung, M.D., Ph.D. and Tae Hyuk Kim, M.D., Ph.D of the Samsung Medical Center, Sungkyunk-wan University School of Medicine in Seoul noted in an email interview with HealthCentral. Gi Hyeon Seo, M.D., is third author on the study.
Both medications "are the treatment mainstay," they say, but that they "cross placenta and have potential to cause a problem during organ formation." They cited a 2013 Danish study that associated both antithyroid drugs with teratogenic potential, meaning they can disturb development of the embryo or fetus.
Largest study of its kind
The three researchers used the National Health Insurance prescription claims database in Korea that includes the entire population. The study looked at nearly 2,886,970 pregnancies which accounted for 90 percent of nationwide live births from 2,210,253 women during the study period between 2008 and 2014.
The number of participants wasn't as much of a challenge as establishing "a linkage between offspring and their mothers," say Drs. Chung and Kim. That required analysis of "multi-layered big data." To their knowledge, they say, theirs is the largest study of its kind thus far.
Additionally, during the first trimester, 12,891 pregnancies were exposed to ATDs. During that time, prenatal exposure to MMI and PTU caused relative increases of 31 percent and 16 percent, respectively, in risk levels for congenital malformations. Perhaps surprisingly, a woman who changed medications from MMI to PTU either a few months before pregnancy or during that first trimester was still at heightened risk for congenital malformations.
"This finding emphasizes the importance of early discussion of family planning and effective contraception for women with untreated or insufficiently treated Graves' disease, as with other maternal medical conditions that produce teratogenic risk such as diabetes and phenylketonuria (a type of inherited amino acid metabolism disorder)," say the two co-authors.
Thyroid levels unknown
"In this study, one limitation is that we don't have data on participants' thyroid levels to assess the reason for their hyperthyroidism and if they had Graves' disease or other causes of hyperthyroidism," said endocrinologist Rachel Pessah-Pollack, M.D., to HealthCentral in a telephone interview.
A specialist and author on the subject of endocrine disorders during pregnancy, Dr. Pessah-Pollack is a clinical assistant professor at the Icahn School of Medicine at Mount Sinai in New York City, and vice chairperson of the reproductive scientific committee for the American Association of Clinical Endocrinologists (AACE).
"Typically, we hold off on treating mild hyperthyroidism during pregnancy and monitor closely with thyroid levels. It would have been helpful to know the thyroid levels of these women in the study prior to treatment as well as on treatment," she says. "Ideally, if we saw women with Graves' disease seeking to become pregnant, we would manage their hyperthyroidism pre-conception with more definitive treatments to avoid use of medications that could cause potential teratogenic and congenital defects as seen in this study."
The Korean cohort study underscores the importance of preconception counseling, she says. "And there's a real opportunity for a mother to be treated by other methods prior to pregnancy than antithyroid drugs during pregnancy."
Women have other options
She cites oral radioactive iodine treatment as one option, "with the goal of going from a hyperthyroid state to a hypothyroid state. Levothyroxine can be used safely during pregnancy. However, thyroid levels should be monitored until at goal preconception. Once they are, it's safe for a woman to proceed with pregnancy."
A thyroidectomy or surgical removal of the thyroid gland is another option, she says. However, any surgery carries risk, and patients must recognize they will be on levothyroxine after surgery.
"Women will still need monitoring of their thyroid levels during pregnancy if treated with either radioactive iodine or surgery," Dr. Pessah-Pollack says. "In addition, they may remain positive for Graves' antibodies. That requires monitoring of both the baby and the mother."
If antithyroid drugs are used during pregnancy, focus should be on using the lowest dose possible for the shortest amount of time to minimize risk, she says. "If we can diagnose and treat our patients with Graves’ disease before pregnancy, we have the opportunity to definitively manage their hyperthyroidism and avoid use of antithyroid medications during pregnancy."
As for what's next in their research, the study's authors say they "are exploring safe management of Graves' disease for women of childbearing age."