Antithyroid Drugs Tied to Risk for Congenital Malformations

Troy Brown, RN

January 22, 2018

Infants born to women who received antithyroid drugs (ATDs) for Graves disease (GD) during the first trimester of pregnancy have an increased risk for congenital malformations, a study has found.

"ATD exposure during the first trimester was associated with significantly increased risk for congenital malformations, particularly for pregnancies in which women received prescriptions for MMI [methimazole] or both ATDs" (MMI or propylthiouracil [PTU]), the researchers write.

Gi Hyeon Seo, MD, from Health Insurance Review and Assessment Service, Wonju-si, Gangwon-do, Korea, and colleagues published their findings online today in Annals of Internal Medicine.   

The authors note, however, that the risk to the fetus must be balanced against the mothers' risks. "Untreated or insufficiently treated GD may result in pregnancy loss and serious fetal and maternal sequelae, providing a compelling indication for timely administration of antithyroid drugs," the researchers explain.

"The available ATDs [PTU, MMI, and carbimazole]…are equally effective for controlling GD in pregnancy. However, they cross the placenta and may cause problems, particularly during first-trimester organogenesis," they add.

The researchers analyzed data from 2,886,970 pregnancies linked to live births among 2,210,253 women in the Korean National Health Insurance database. Of those live births, 12,891 (0.45%) included first-trimester ATD exposure.

Overall, congenital malformations were reported in 937 (7.27%) infants whose mothers received ATDs during the first trimester compared with 170,716 (5.94%) infants whose mothers did not receive ATDs (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.16 - 1.33; P < .001). The increased risk remained significant after adjustment for maternal age, birth year, multiple pregnancies, and infant sex (adjusted OR, 1.19; CI, 1.12 - 1.28; P < .001).

PTU was the most frequently prescribed ATD during the first trimester (PTU alone, 77.0%; MMI alone, 8.7%; PTU and MMI, 14.3%).

"Overall, our results showed that exposure to MMI and PTU during the first trimester resulted in relative increases in the risk for congenital malformations of 31% and 16%, respectively, which corresponded to 17 additional cases per 1000 live births for MMI and 9 per 1000 for PTU," the researchers write.

The absolute risk differences in congenital malformation prevalence per 1000 live births were 8.81 cases for PTU exposure only, 17.05 cases for MMI exposure only, and 16.53 cases for both PTU and MMI exposure, compared with nonexposed infants.

"Specifically, MMI was associated with significantly increased risk for congenital malformations in more varied organ systems, including the nervous, circulatory, and digestive systems. Exposure to both ATDs was associated with significantly increased risk for congenital malformations in the nervous and circulatory systems, cleft lip, and cleft palate," the authors write.

Switching ATDs Not Recommended During First Trimester

The overall risk for congenital malformations, with the exception of MMI embryopathy, remained when women switched between MMI and PTU during the first trimester or the 3 months before pregnancy. "Moreover, switching from PTU to MMI seemed to increase the absolute risk (by 47 cases per 1000 live births) compared with continuing to receive PTU alone. Switching may pose a substantial risk to the embryo through exposure to different teratogens in a sequential manner, rather than minimizing the harmful effect of the prior medication (in our study, MMI)," the researchers explain.

"Taken together, data from our and previous studies suggest that the current guidelines recommending PTU in the first trimester should not be extended as an argument for switching from MMI to PTU after pregnancy detection, because this often occurs during the most critical period of embryonic development," they add.

The authors say that although hyperthyroidism impairs fertility, clinicians should discuss family planning and effective contraception with women who have untreated or insufficiently treated GD. The next best thing would be to change from MMI to PTU before stopping contraception for women who are likely to receive ATD treatment during the first trimester. Clinicians should fully disclose the "residual risk for PTU-associated congenital malformations in the face, neck, genitourinary tract, and musculoskeletal system…as well as the slight chance of hepatic failure."

"However, for women needing a large amount of PTU to control their thyroid disorder, preemptive definite therapy (either by radioactive iodine or surgery) should be considered, because inadequately treated GD may increase the risk for spontaneous abortion and stillbirth," they explain.

"These findings confirm the importance of minimizing MMI use in the first trimester and suggest that the current recommendation of switching from MMI to PTU after pregnancy detection be reconsidered," the researchers conclude.

The authors have disclosed no relevant financial relationships.

Ann Intern Med. Published online January 22, 2018. Abstract

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