In utero exposure to thionamide antithyroid drugs linked to Congenital abnormalities

The risk of congenital abnormalities associated with antithyroid drug (ATD) therapy is higher for carbimazole or methimazole (CMZ/MMI) than for propylthiouracil (PTU) but does not appear to be lowered by switching ATDs during pregnancy, says an article published in Clinical Endocrinology.

The danger of congenital abnormalities following in utero thionamide antithyroid medication exposure remains uncertain. Existing meta-analyses precede and exclude more recent trials, and observational studies are conflicting. As a result, Medha Agrawal and colleagues conducted an updated meta-analysis assessing the risk of congenital abnormality in women being exposed to carbimazole or methimazole, propylthiouracil, or uncontrolled hyperthyroidism during pregnancy.

For this investigation, articles published up to August 2021 were searched in Medline, Embase, and the Cochrane database. To account for heterogeneity, separate crude and adjusted risk estimates were combined using random effects models and subgroup analyses.

The key findings of this study were as follow:

1. There were 16 cohort studies with 5957, 15,785, and 15,666 exposures to CMZ/MMI, PTU, and untreated hyperthyroidism, respectively.

2. CMZ/MMI and PTU had higher adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for congenital abnormalities when compared to nondisease controls.

3. The crude risk for CMZ/MMI was elevated in comparison to PTU.

4. Exposure to both CMZ/MMI and PTU, i.e., women who switched ATDs during pregnancy, was also associated with an increased risk.

5. However, the timing of the ATD switch was highly variable, and some investigations included pre-pregnancy switches.

6. The extra number of abnormalities per 1000 live births was 17.2 in patients exposed to CMZ/MMI, 9.8 in patients exposed to PTU, and 31.4 in patients exposed to both CMZ/MMI and PTU.

7. The risk in the untreated group was the same as in the control or ATD groups. In terms of thyroid status, the untreated group was significantly varied.

8. Subgroup analysis revealed stronger favorable relationships in studies with more than 500 exposures and up to a year of follow-up.

In conclusion, this meta-analysis found that ATD therapy during pregnancy has a low incidence of congenital abnormalities. The magnitude of risk is slightly higher for CMZ/MMI than for PTU, and switching ATDs post conception does not appear to diminish this risk, while more accurate exposure timing studies are needed to determine the impact of switching ATDs during pregnancy. More research is needed to determine the danger associated with moderate thyroid dysfunction and the ideal thyroid function threshold at which ATDs can be safely stopped during pregnancy.

Reference:

Agrawal, M., Lewis, S., Premawardhana, L., Dayan, C. M., Taylor, P. N., & Okosieme, O. E. (2021). Antithyroid drug therapy in pregnancy and risk of congenital anomalies: Systematic review and meta‐analysis. In Clinical Endocrinology (Vol. 96, Issue 6, pp. 857–868). Wiley. https://doi.org/10.1111/cen.14646