Summary Safety Review - Iodinated Contrast Medium - Assessing the Potential Risk of Hypothyroidism in Children Under 3 Years of Age

Iodinated contrast medium (ICM) products

Hypothyroidism, a condition where there is decreased thyroid hormone production, in children under 3 years of age

• Health Canada’s safety review concluded that there is a potential risk of hypothyroidism with the use of ICM products in children under 3 years of age. Younger age, very low birth weight, prematurity, and the presence of cardiac or other conditions, such as admission to intensive care units, are associated with a higher risk of hypothyroidism after exposure to ICM products.

• Health Canada reviewed the potential risk of hypothyroidism with the use of ICM products, also known as medical imaging dyes or contrast agents, authorized for use in X-ray or other imaging tests to make it easier to see blood vessels and organs. The safety review was triggered by a labelling update in the United States (U.S.).

• Health Canada will work with the manufacturers to update the product safety information in the Canadian product monograph (CPM) for all ICM products to provide additional information about the risk of hypothyroidism and monitoring recommendations for children under 3 years of age. Health Canada will also inform healthcare professionals about this update through a Health Product InfoWatch communication.

In 2017, Health Canada reviewed the potential risk of transient (temporary) or permanent hypothyroidism with the use of ICM products in children and adults. The Department concluded that there is a risk of rare cases of hypothyroidism with the use of these products in certain patients, mostly infants (less than 1 year of age). The CPMs of all reviewed ICM products were updated to include this risk.

Since 2017, new studies evaluating this risk have been published. In 2023, Health Canada reviewed these new studies and the earlier ones published in the medical literature that assessed the potential risk of hypothyroidism in children under 3 years of age who were exposed to ICM products. The safety review was triggered by a labelling update in the U.S. for children 3 years of age or younger.

Hypothyroidism in young children may be harmful for neurological (brain) and cognitive (how children think and understand) development.

• Iodinated contrast medium products, also known as medical imaging dyes or contrast agents, are authorized for use in X-ray or other imaging tests to make it easier to see blood vessels and organs.

• Iodinated contrast medium products have been marketed in Canada for over 50 years. There are 8 ICM products currently marketed under the following brand names: Cysto Conray II, Gastrografin, Isovue, Lipiodol Ultra Fluid, Omnipaque, Optiray, Ultravist, and Visipaque.

• Health Canada reviewed information from searches of the Canada Vigilance Database^a, international databases, and the scientific literature.

• At the time of the review, Health Canada had not received any Canadian reports of hypothyroidism related to the use of ICM products in children.

• Health Canada reviewed 18 articles published in the scientific literature^1-18, including 2 studies published since the 2017 review that were conducted in a larger population of children. Overall, the evidence reviewed was limited, but suggested an association between hypothyroidism and ICM exposure in children under 3 years of age. Most cases in these studies reported that hypothyroidism was temporary and did not require treatment.

• The rate of hypothyroidism was found to be higher in children under 3 years of age with the following risk factors: very low birth weight, prematurity, and the presence of cardiac and other conditions, such as admission to intensive care units.

• Health Canada's review of the available information concluded that there is a potential risk of hypothyroidism with the use of ICM products in children under 3 years of age. Younger age, very low birth weight, prematurity, and the presence of cardiac or other conditions, such as admission to intensive care units, are associated with a higher risk of hypothyroidism after exposure to ICM products.

• Despite the limited available evidence, the seriousness and life-long effects on the cognitive and neurological development of children under 3 years of age warrant a precautionary approach.

• Health Canada will work with the manufacturers to update the CPM of all ICM products to provide additional information about the risk of hypothyroidism in children under 3 years of age and recommend monitoring of young children based on their risk factors.

• Health Canada will also inform healthcare professionals about this update through a Health Product InfoWatch communication.

• Health Canada encourages patients and healthcare professionals to report any side effects related to the use of ICM products, and other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving ICM products, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

The analysis that contributed to this safety review included scientific and medical literature, and what is known about the use of these products both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Ares S, et al. thyroid complications, including overt hypothyroidism, related to the use of non-radiopaque silastic catheters for parenteral feeding in prematures requiring injection of small amounts of an iodinated contrast medium. Acta Paediatr. 1995; 84:579-81.

2. Belloni E, et al. Effect of iodinated contrast medium on thyroid function: a study in children undergoing cardiac computed tomography. Pediatric radiol. 2018; 48:1417-1422.

3. Bona G, et al. Effects of iopamidol on neonatal thyroid function. Eur J Radiol. 1992; 14:22-25.

4. Cherella,C.E et al.  Early identification of severe primary hypothyroidism in neonates exposed to intra-lymphatic iodinated contrast: A case series. J.Clin Endocrinol Metab, 2018 103:3583-3588.

5. Cohen et al. Voiding cystography: an unusual route of induced hypothyroidism by iodine overdose in newborn with chronic kidney disease. Pediatric nephrology, 2019, 34:1295-1297.

6. Dechant MJ, et al. thyroidal response following iodine excess for cardiac catheterization and intervention in early infancy. Int J Cardiol. 2016; 223:1014-1018.

7. Dembinski J, et al. thyroid function in very low birthweight infants after intravenous administration of the iodinated contrast medium iopromide. Arch Dis Child Fetal Neonatal Ed. 2000; 82:F215-217.

8. Gilligan et al. Primary thyroid dysfunction after single intravenous iodinated contrast exposure in young children: a propensity score matched analysis. Pediatric radiology 2021, 51(4) 640-648.

9. Jick SS, et al. iodinated contrast agents and risk of hypothyroidism in young children in the United States. Invest Radiol. 2019; 54:296-301.

10. Kayser M and Dinauer C. Prolonged iodine-induced hypothyroidism in a full-term infant with congenital heart disease. Thyroid, 2022 , 32:A69. (POSTER PRESENTATION).

11. Kubicki R, et al. Frequency of thyroid dysfunction in pediatric patients with congenital heart disease exposed to iodinated contrast media – a long term observational study. Journal of Pediatric Endocrinology and Metabolism. 2020; 33 (11):1409.

12. l’Allemand D, et al. Iodine in contrast agents and skin disinfectants as the major cause for hypothyroidism in premature infants during intensive care. Horm Res. 1987; 28:42-49

13. Parravicini E, et al. Iodine, thyroid function, and very low birth weight infants. Pediatrics. 1996; 98:730-734.

14. Piatek,M et al.  Hypothyroidism after percutaneous patent ductus arteriosus device closure in an extremely preterm infant: Possible role of iodinated IV contrast. Neonatology. 2021;117(6):776-779.

15. Rath et al. Does the use of an iodine-containing contrast agent to visualise the PICC tip in preterm babies cause hypothyroidism? A randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2019;104:F212–F214.

16. Rosenberg V, et al. hypothyroidism in young children following exposure to iodinated contrast media: an observational study and a review of the literature. Pediatric Endocrinology Rev. 2018; 16:194-203.

17. Shimura K et al . Two Japanese infants with hypothyroidism following exposure to Iodinated Contrast Medium. JCEM case reports, 2023, 1-4.

18. Thaker VV, et al. Hypothyroidism in infants with congenital heart disease exposed to excess iodine. J Endocr Soc. 2017; 1:1067-78.

1. Canadian reports can be accessed through the Canada Vigilance Online Database.