August 29, 2019
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Thyroid drug use in early pregnancy may raise risk for birth defects

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Pregnant women with thyroid dysfunction exposed to methimazole therapy during the first trimester are more likely to deliver infants with a birth defect diagnosed before age 2 years than women exposed to propylthiouracil or no therapy, according to a large database analysis published in The Journal of Clinical Endocrinology & Metabolism.

“The present study is an extension of our previous report published in 2013, in which we reported that both [methimazole] and [propylthiouracil] were associated with birth defects diagnosed before the child was [age] 2 years in a nationwide cohort of children born in Denmark from 1996-2008,” Stine Linding Andersen, MD, PhD, of the department of clinical biochemistry at Aalborg University Hospital in Denmark, and colleagues wrote. “The finding of [a methimazole] embryopathy was consistent with case reports and a large observational study from Japan published in 2012, but the finding of a risk [for] birth defects associated with [propylthiouracil] was new and merited further investigation. We now had data to extend the cohort to include children born in Denmark during a 20-year period from 1997-2016.”

Andersen and colleagues analyzed data from Danish pregnant women and their live-born children from the Nationwide Register-Based Cohort (NRBC; n = 1,242,353), a database of all children live-born in Denmark from January 1997 to December 2016, as well as the Danish National Birth Cohort (DNBC; n = 8,803), established from 1997 to 2003, and the North Denmark Region Pregnancy Cohort (NDRPC; n = 14,483), established from 2011 to 2015. In the NRBC, the exposure of main interest was the use of thyroid drugs in early pregnancy, assessed from redeemed prescriptions from 6 months prior to pregnancy up to and including the 10th week of pregnancy. In the DNBC and NDRPC, the exposure of interest was abnormal maternal thyroid function, assessed from measurement of thyroid-stimulating hormone and free thyroxine (FT4) in a stored blood sample collected during early pregnancy (median week 9-10). Researchers assessed information on birth defects from inpatient and outpatient hospital diagnoses in the Danish National Hospital Register. The primary outcome was birth defects diagnosed before age 2 years in offspring. Researchers used Cox proportional hazard models to estimate the association between maternal thyroid function and birth defects in the DNBC and NDRPC.

In the NRBC, 2,718 children (0.2%) were exposed to thyroid drugs in early pregnancy.

The overall frequency of birth defects was 6.7% (95% CI, 6.7-6.8%) in nonexposed children, and higher after exposure to methimazole/carbimazole (9.6%; 95% CI, 8.2-11.2) and propylthiouracil (8.3%; 95% CI, 6.7-10.3). However, researchers found that the frequency of maternal thyroid dysfunction in early pregnancy was similar in the random cohort and in cases of birth defects in the DNBC (12.4 vs. 12.6%) and NDRPC (15.1 vs. 15.4%).

Pregnant woman and doctor (Shutterstock) 
Pregnant women with thyroid dysfunction exposed to methimazole therapy during the first trimester are more likely to deliver infants with a birth defect diagnosed before age 2 years than women exposed to propylthiouracil or no therapy.
Source: Shutterstock

“In a large, extended, nationwide cohort of more than 1 million children live-born in Denmark during a 20-year period, an increased risk of birth defects associated with the use of [thyroid drugs] in early pregnancy was corroborated,” the researchers wrote. “The subtypes of birth defects associated with the use of [methimazole] and [propylthiouracil] differed, and [methimazole] exposure revealed the highest risk and associations with severe birth defects in several organ systems.”

The researchers noted that birth defects observed after early pregnancy exposure to propylthiouracil were located mostly in the urinary system and in the face and neck, whereas exposure to methimazole was associated with birth defects in seven organ systems.

“The role of maternal thyroid function was addressed in independent birth cohorts, and results did not indicate that abnormalities in maternal thyroid function in early pregnancy, per se, is a major risk factor for birth defects,” the researchers wrote.

The researchers concluded that the findings support the use of propylthiouracil in early pregnancy.

“Further and large studies are needed to investigate the risk associated with [propylthiouracil] and to evaluate outcomes of a shift in therapy,” the researchers wrote. “Detailed assessment of the timing of exposure up to and after the start of a pregnancy is crucial to inform this debate.” – by Regina Schaffer

Disclosures: The authors report no relevant financial disclosures.