In a March 2022 Drug Safety Communication, the U.S. Food and Drug Administration (FDA) issued guidance recommending children “through three years old” be monitored for the possibility of hypothyroidism or a temporary decrease in thyroid hormone levels within three weeks of exposure to intravascular iodine-containing (iodinated) contrast material (ICM).
As part of this recommendation the FDA cited 11 research studies published between 1987 and 2020, which are summarized here. Six studies were prospective in design, with two concluding that ICM exposure had no impact on thyroid function and two more suggesting that ICMs are well-tolerated in premature and term infants with only transient alterations in thyroid function observed. Only three prospective studies included a control group of children not exposed to ICM, with the largest control group containing 26 individuals. Of the three studies with control groups, one used an ionic ICM no longer available in the U.S., one was confounded by exposure to a topical iodine-containing anti-septic, and one concluded ICM had no impact on thyroid function; all three of these studies were performed in premature infant populations. The majority of studies cited by the FDA were composed of unique pediatric patient subpopulations that limit the generalization of observations to a broader population. For example, five studies were composed either entirely or primarily of very young children with congenital heart disease (typically neonates or infants), four studies were performed in very low birth weight premature infants, and three studies were performed in term neonates. Only one cited study included a substantial number of children older than 6 months without congenital heart disease. This latter study was a large electronic health record-based study with considerable confounding, that only identified four children (n=2320) with an ICD-9/10 code of hypothyroidism, abnormal thyroid function laboratory testing, and receipt of treatment for hypothyroidism. Independent grading of study quality performed by the ACR suggests seven of the 11 studies cited by the FDA have a study quality score of 3 or 4, indicating that “there are important study design limitations” or “the study is not useful as primary evidence”, respectively.
At least two additional studies were published on the topic but not included in the FDA’s list of cited literature. A study by Gilligan et al., while retrospective, included a control cohort of children up to two years of age and found no independent effect of ICM on thyroid function after controlling for numerous other clinical variables using a multivariable analysis. The second study by Rath et al. was a prospective randomized, controlled investigation of preterm infants undergoing PICC placement, with (n=20) and without (n=21) the use of ICM for confirmation of tip location. No patients experienced hypothyroidism during follow-up in either group, and there was no statistical difference in thyroid function hormone levels between the exposed and control cohorts.
At this time, the evidence is weak to support thyroid function monitoring in very low birth weight preterm infants, neonates, and infants with congenital heart disease under three months of age following ICM administration. The majority of existing studies suggest that any depression in thyroid function is usually transient and of uncertain clinical significance. Evidence suggests that alterations in thyroid hormones in these subpopulations may potentially be related to ICM exposure; however, further prospective studies with control cohorts are needed to confirm this association. It is conceivable that in these particularly vulnerable patient populations the prevalence of abnormal thyroid function testing may be similar between ICM exposed and non-exposed cohorts, similar to the phenomenon of post-CT acute kidney injury.
At this time, no convincing scientific evidence exists to support routine thyroid function testing in children older than three months of age with or without congenital heart disease following intravascular ICM.
Furthermore, numerous unintended consequences potentially may occur as a result of this new FDA recommendation, including, but not limited to:
- Increased use of contrast-enhanced MRI, with associated gadolinium-based contrast material and sedation/anesthesia exposures
- Patient harm due to delayed diagnosis related to performing unenhanced CT imaging or avoiding CT imaging due to perceived risk
- Increased parental anxiety and concern about hypothyroidism
- Increased healthcare costs related to additional medical visits and testing
Based upon the research studies cited by the FDA, we consider the risk of clinically-relevant hypothyroidism related to ICM to be quite low in the pediatric population under three months of age, and minimal to absent in children three months of age and older. Based on the existing literature, we believe the decision to perform thyroid function testing following intravascular contrast material exposure should be on a patient-by-patient basis following the review of that patient’s specific risk factors. Universal testing in all young children is not warranted nor supported by the literature at this time.
The ACR will continue to evaluate the scientific evidence related to the use of these intravascular iodinated contrast materials in young children and update our recommendations accordingly.
Finally, the FDA statement indicates that:
In 2015, we required the manufacturers of ICM products to conduct a study to investigate this safety issue further. However, we have concluded based on our review of the published studies that there is compelling evidence of a significant risk for underactive thyroid or a temporary decrease in thyroid hormone levels in newborns and children through 3 years after exposure to ICM; therefore, the study by the manufacturers is no longer needed.
The ACR strongly disagrees with this statement and asks the FDA and our industry partners that manufacture ICM products to further evaluate the safety of these contrast agents in a rigorous, scientifically sound manner in order to ensure the safe use of these agents in young children.
Reference
Summary Table
| Author | Journal | Year | n exposed | Prospective vs. Retrospective |
Control Group (n)? | Exposure | ACR Study Quality Score (1-4) | Key Findings / Potential Confounders | Age Range |
| Ares et al. | Acta Pediatr | 1995 | 13 | Prospective | Yes (24) | CVC placement |
1 | Hypothyroidism in 1 patient requiring treatment; transient subclinical thyroid dysfunction in others; iodinated contrast media used is an ionic agent, no longer used in practice; preterm infants | Preterm (<34 wk gestation), mean age of exposure 4.9±0.6 postnatal days |
| Bona et al. | Eur J Radiol | 1992 | 10 | Prospective | Yes (20) | Intravenous pyelography | 4 | No change in thyroid function related to contrast exposure | Term neonates (10-28 days) |
| l'Allemand et al. | Hormone Res | 1987 | 51 | Prospective | No | Cardiac cath, CVC placement | 4 | Hypothyroidism in 6 preterm and 1 term neonates – treatment required in some; study confounded by topical iodine anti-septic use; preterm and term infants |
Preterm and term neonates |
| Dembinski et al. | Arch Dis Child Fetal Neonatal Ed | 2000 | 20 | Prospective | Yes (26) | CVC placement |
2 | No difference between exposed and control groups in thyroid function testing; very low birth weight preterm infants | Preemies (<30 wk gestation), exposure 4- 10 postnatal days |
| Jick et al. | Invest Radiol | 2019 | 2320 | Retrospective | No | CT, cardiac cath | 3 | 34 potential hypothyroidism cases – 24 transient and subclinical; higher rates in children younger than 3 months; ICD/CPT code-based study (only 4 patients had ICD- 9/10 diagnosis of hypothyroidism, abnormal lab values, and treated for hypothyroidism); 11 cases had potential confounding causes identified |
<4 yr |
| Parravicini et al. | Pediatrics | 1996 | 17 | Prospective | Yes (18) | CVC placement |
1 | 2 exposed and 0 control patients developed transient subclinical hypothyroidism; Very low birth weight preterm infants, study confounded by topical iodine anti-septic use | Preterm infants (30±2.3 wk gestation), exposure 3- 7 postnatal days |
| Thacker et al. | J Endocrine Soc | 2017 | 183 | Retrospective | No | Cardiac Cath, cardiac surgery (topical), or both | 2 | 46 patients diagnosed with hypothyroidism (20 treated); 11/73 cardiac cath only patients developed hypothyroidism; neonates with CHD; study confounded by topical iodine antiseptic use | Neonates (median age 3 days) |
| Belloni et al. | Pediatr Radiol | 2018 | 33 | Retrospective | no | CT | 3 | No patients with hypothyroidism. Transient reduction in TSH at population level; all returned to baseline by discharge without treatment; patients with CHD |
<4.5 yr (mean age 224±345 days) |
| Dechant et al. | Int J Cardiol | 2016 | 21 | Prospective | no | Cardiac cath | 4 | 5 of 10 neonates had transient TSH elevation with normal peripheral thyroid hormone levels (none required treatment); no thyroid dysfunction in older patients; patients with CHD |
≤6 mo (median age 30 days), 16 of 21 were <3 mo |
| Kubicki et al. | J Pediatr Endocrinol Metab | 2020 | 104 | Retrospective | no | CT, cardiac cath | 4 | 16 patients with hypothyroidism (10 transient with treatment, 4 transient without treatment, 2 long-standing with treatment), hypothyroidism (both treated), median age of cases 1.5mo; patients with CHD; authors conclude only 1 case likely related to iodinated contrast material |
<8 yr (median age 104 days) |
| Rosenberg et al. | Pediatr Endocrinol Rev | 2018 | 843 | Retrospective | no | CT, cardiac cath | 3 | 11 patients with hypothyroidism (3 likely had alternative diagnosis based on medical records, 2 were treated); ICD/CPT code-based study with numerous assumptions, including whether iodinated contrast material was actually administered for some patients; 58.7% had CHD |
≤3 yr (median age 38 days) |
| Gilligan et al.* | Pediatr Radiol | 2021 | 57 | Retrospective | Yes (57) | CT | 1 | Thyroid dysfunction in 8 exposed patients and 4 control patients based on TSH; no patient treated; iodinated contrast material not a significant univariable or multivariable predictor of thyroid dysfunction | 0-24 mo |
| Rath et al.* | Arch Dis Child Fetal Neonatal Ed | 2019 | 20 | Prospective | Yes (21) | CVC placement |
1 | No cases of hypothyroidism, and no statistical difference in thyroid hormone levels between exposed and control groups at follow-up; preterm infants | Preterm infants (<30 wk gestation; median age 4 days) |
*not included in U.S. FDA cited references.