Published: 2 March 2017
Revised: 5 December 2017

Safety Information

Early Warning System - Monitoring Communication

Medsafe emphasises that patients should NOT stop using any medicine or medical device subject to a monitoring communication. If you have any concerns with a medicine or medical device you are using, please contact your health professional. A monitoring communication does not mean that the medicine or medical device causes an adverse event.

Possible risk of hypothyroidism in infants exposed to iodine-containing contrast agents

2 March 2017

Monitoring finishes 30 September 2017.

Medsafe is highlighting a possible association between exposure to iodine-containing contrast agents (ICAs) and the development of hypothyroidism in infants (aged less than 12 months).

This follows an FDA review of ten cases of hypothyroidism in infants exposed to ICAs - six in full term infants with major cardiac abnormalities and four in premature infants (¹). In these reports hypothyroidism was diagnosed 7 to 30 days after receiving an ICA. Improvement was documented in eight cases – four of which required treatment with thyroxine. No reports of hypothyroidism associated with ICAs have been reported to the Centre for Adverse Reactions Monitoring (CARM) in New Zealand.

 ICAs are known to increase the risk of hyperthyroidism, particularly in those with a history of thyroid disease(²). Most New Zealand data sheets include advice regarding this risk. Observational studies have demonstrated that adults and children exposed to ICAs are at increased risk of developing hypothyroidism(^3-5). However, studies in infants and neonates are limited by small numbers, a lack of control group and possible confounding by the use of topical iodine products. Therefore, little is known about this risk in infants and neonates. 

Products Affected

ICAs are medicines used to enhance the ability of blood vessels and organs to be seen on medical imaging such as CT scans.  ICAs can be administered intravascularly (intravenously or intra-arterially) or enterally.

Table 1: Iodine-containing contrast agents approved for use in New Zealand

Brand name	Ingredient name	Sponsor
Lipiodol	Iodised oil	Obex Medical
Visipaque	Iodixanol	GE Healthcare
Omnipaque	Iohexol	GE Healthcare
Urografin and Gastrografin	Diatrizoate meglumine with sodium amidotrizoate	Bayer NZ
Ioscan	Diatrizoate sodium	Regional Health
Optiray	Ioversol	Obex Medical
Iopamiro	Iopamidol	Regional Health

As of 1 January 2017, PHARMAC funds Lipiodol, Visipaque, Omnipaque, Urografin and Gastrografin through the hospital medicines list (Table 1).

ICAs are general sales medicines, therefore data sheets are not required. Of those products with data sheets, only the Omnipaque data sheet identifies hypothyroidism as a potential adverse effect.

Additional Information

ICAs provide iodine doses well in excess of recommended maximum daily doses for all age groups (²). In healthy individuals, exposure to excess iodine triggers the Wolff-Chaikoff effect which temporarily inhibits the formation and release of thyroid hormones. Normal thyroid function resumes within 1-2 weeks if the source of excess iodine is withdrawn. Failure to adapt to the Wolff-Chaikoff effect is thought to be the mechanism by which excess iodine can cause hypothyroidism (⁶).

As thyroid hormones are crucial to brain development (⁷), the consequences of even short periods of hypothyroidism could be more significant for infants (and children up to age 3) than other age groups. Infants may be more susceptible to hypothyroidism due to thyroid gland immaturity (particularly in premature infants), reduced renal clearance of iodine and increased skin absorption if iodine is also applied topically. In addition, sick infants may be less able to regulate their iodide balance and may require multiple scans using ICAs (⁸).

Symptoms of hypothyroidism in infants can include lethargy, hoarse cry, feeding problems, needing to be woken to feed, constipation, puffy face, hypotonia, dry skin, hypothermia and prolonged jaundice (⁹). As these symptoms are non-specific, hypothyroidism may be difficult to diagnose clinically in infants.

Medsafe considers the overall benefit-risk balance for ICAs remains positive; therefore no changes to the use of these products in infants are recommended.

Healthcare professionals should consider the possibility of hypothyroidism in infants presenting with unexplained non-specific symptoms, or deterioration in their clinical condition following imaging where an ICA was administered. Premature infants and those undergoing multiple imaging procedures are likely to be at increased risk. If ICAs are to be used in neonates or infants (less than 12 months of age), the suggested monitoring is thyroid-stimulating hormone (TSH) +/- free thyroxine (FT4) 5-7 days post contrast.

Parents and caregivers should discuss any concerns they may have with their baby's doctor.

More information about iodine-containing products can be found in the data sheets.

Search for data sheet information

Regulator Actions

Medsafe is placing this safety concern on the medicines monitoring scheme to gain more information about this safety concern. Please report any cases of hypothyroidism in infants or children exposed to ICAs. Please include information on the severity and duration of hypothyroidism; whether treatment was required; and whether hypothyroidism was diagnosed clinically or upon routine screening.

Medsafe will continue to monitor this issue and will produce updated advice for healthcare professionals and consumers as necessary.

Find out more about Medicines Monitoring

Reporting

Consumers and healthcare professionals are encouraged to send reports of suspected adverse reactions to the Centre for Adverse Reactions Monitoring (CARM)

Medsafe cannot give advice about an individual's medical condition. If you have any concerns about a medicine you are taking Medsafe encourages you to talk to your healthcare professional.

References

1. FDA. Drug Safety Communications. FDA advises of rare cases of underactive thryoid in infants given iodine-containing contrast agents for medical imaging. 2015. (www.fda.gov/downloads/Drugs/DrugSafety/UCM472938.pdf)
2. Surks M. Iodine-induced thyroid dysfunction. UpToDate. 2016.
3. Rhee CM, Bhan I, Alexander EK, Brunelli SM. Association between iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism. Arch Intern Med. 2012 Jan 23;172(2):153-9.
4. Kornelius E, Chiou J-Y, Yang Y-S, Peng C-H, Lai Y-R, Huang C-N. Iodinated contrast media increased the risk of thyroid dysfunction: A 6-year retrospective cohort study. The Journal of Clinical Endocrinology & Metabolism. 2015;100(9):3372-9.
5. Barr ML, Chiu HK, Li N, Yeh MW, Rhee CM, Casillas J, et al. Thyroid Dysfunction in Children Exposed to Iodinated Contrast Media. The Journal of Clinical Endocrinology & Metabolism. 2016:jc. 2016-1330.
6. Hudzik B, Zubelewicz-Szkodzińska B. Radiocontrast-induced thyroid dysfunction: is it common and what should we do about it? Clinical endocrinology. 2014;80(3):322-7.
7. Rovet JF. The role of thyroid hormones for brain development and cognitive function. Paediatric Thyroidology. 26: Karger Publishers; 2014. p. 26-43.
8. Brown RS. Disorders of the thyroid gland in infancy, childhood and adolescence (updated 21 March 2012). 2012. In: Endotext (internet) [Internet]. South Dartmouth (MA): MDText.com, Inc. (www.ncbi.nlm.nih.gov/books/NBK279032/)
9. LaFranchi S. Thyroid physiology and screening in preterm infants. UpToDate. 2013.

Update to Original Communication

5  December 2017
 

During the period (2 March to 30 September 2017), one case was reported to the Centre for Adverse Reactions Monitoring (CARM). The case concerned a premature newborn. A thyroid­ stimulating hormone (TSH) test at three days of age was normal, but TSH was elevated about two weeks after a single dose of Omnipaque. Urine iodine was high approximately 20 days after Omnipaque was given.

As outlined above, cases have also been identified in other countries.  Data sheets in the United States, Europe and Canada includes information about this risk. Of those products with data sheets in NZ, only the Omnipaque data sheet identifies hypothyroidism as a potential adverse effect, with limited  information.

Medsafe will be requesting sponsors to update data sheets for iodine-containing contrast agents should be updated with information on the risk of hypothyroidism in line with information in the European data sheets.  This will include information on thyroid function monitoring particularly in neonates.

The balance of benefits and risks of harm for iodine-containing contrast agents remains positive and no further action is required at this time.