Hypothyroidism in Infants after Enteral Administration of Iodinated Contrast Media: A Rare but Serious Complication

Excessive exposure to iodine from both intravenous iodinated contrast media (ICM) used in radiological imaging and the use of topical iodine early in life may cause hypothyroidism [1, 2]. Omnipaque is a nonionic iodinated contrast agent commonly used in radiological imaging. Exposure to iodine in excess to the daily iodine requirement for preterm born neonates (30 µg/kg) may have effects on thyroid function [3]. Iodine exposure induces the Wolff-Chaikoff effect, in which thyroid hormone synthesis is temporarily downregulated to prevent hyperthyroidism [4]. Preterm born young infants may fail to timely escape the Wolff-Chaikoff effect resulting in prolonged hypothyroidism [5]. Early detection of hypothyroidism in the neonatal period is important because of its potential negative impact on brain development [6].

A recent case of prolonged severe hypothyroidism in a preterm born neonate after exposure to enteral administrated ICM in our center [7] led to the implementation of a local post-exposure thyroid function testing protocol to ensure early detection of hypothyroidism. The aim of this prospective cohort study was to evaluate our protocol and determine the occurrence of hypothyroidism after enteral ICM administration in the first months of life.

Prospective observational study was conducted between November 1st, 2022, and July 1st, 2024, in the Emma Children’s Hospital, Amsterdam University Medical Center. All hospitalized infants younger than 6 months who underwent radiological examination (abdominal X-ray, AXR) with enteral ICM (Omnipaque 240 mg iodine (I)/mL [IOHEXOL 518 mg/mL], or 140 mg iodine (I)/mL [IOHEXOL 302 mg/mL]; the used volume differed per examination) were included in this study. Infants receiving intravenous ICM or topical iodine were excluded.

All included infants had been screened for congenital hypothyroidism (CH) by the Dutch newborn screening (NBS) program between day four to seven of life. In the Netherlands, a three-step NBS approach is used: T4-reflexTSH-reflexTBG, allowing detection of primary and central CH, with fewer false positives due to TBG deficiency. Preterm born children (≤2,500 g and gestational age ≤36 weeks) were only screened for primary CH as T4 levels may be low associated with prematurity or illness resulting in a false-positive NBS result [8]. A normal NBS result for CH was interpreted as absence of primary CH. Thyroid function after enteral ICM administration was evaluated by a local protocol.

Serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) were measured around 5 and 10 days after contrast administration and, if abnormal, repeated on day 15. ICM-induced hypothyroidism was defined as persistent (>2 weeks) TSH elevation in combination with normal or decreased fT4 levels after administration of ICM.

Approximately 2 days after ICM administration, AXR was performed to evaluate for contrast stasis. The AXR was assessed by a pediatric radiologist. Contrast stasis was defined as residual contrast within the filled bowel lumen 2 days after ICM administration. Ideally, ICM should be completely absent.

Thirty-three infants undergoing AXR with enteral ICM administration were included in the study. Baseline characteristics are shown in Table 1. Median gestational age was 35+6 weeks (interquartile range [IQR]: 31+5–38+1), median birthweight 2,540 g (IQR: 1,258–2,977). Eighteen infants (54.5%) were male, seventeen (51.5%) were born preterm. Subsequently, 28 infants (84.8%) underwent surgery. The three most frequent reasons for AXR with ICM and surgery were Hirschsprung disease (N = 6, 18.2%), esophageal atresia (N = 6, 18.2%), and necrotizing enterocolitis (N = 4, 12.1%). Five infants (15.2%) had a cardiac anomaly (three major, two minor), two (6.1%) had trisomy 21. Details on the radiological procedure are shown in Table 1. In all infants, the ICM Omnipaque was administered in a concentration of 240 (N = 31) or 140 mg I/mL (N = 2). The ICM administration route was retrograde in the majority of the infants (63.6%). In twelve of 28 infants (42.9%), ICM was still visible on an AXR performed after 2 days (IQR: 2–7).

Five infants (15.2%) had abnormal serum TSH or fT4 levels after enteral ICM (Table 2). All five infants were male, four of them were born preterm. In three infants (cases 1–3), elevated TSH levels were attributed to the activation of the Wolff-Chaikoff effect; one of these three infants had trisomy 21 (case 3); the other infant with trisomy 21 had normal TSH and fT4 levels (data not shown). In cases 2 and 3, TSH levels normalized after approximately 1 week, interpreted as physiological escape of the Wolff-Chaikoff effect. However, in case 1 - a preterm born infant - hypothyroidism persisted (low fT4 and elevated TSH at day 11), consistent within the diagnosis of ICM-induced hypothyroidism, requiring levothyroxine treatment. In the two other infants (cases 4 and 5), the first thyroid function test showed low fT4 in combination with normal TSH levels, but fT4 normalized with 1 week. The probable diagnosis in these infants was non-thyroidal illness (NTI) or transient hypothyroxinemia of prematurity (THOP), although there may have been ICM-induced TSH elevation at day 14 in case 4 (Table 2).

In this prospective cohort study in which we determined thyroid function after enteral ICM administration in 33 consecutive infants younger than 6 months, we found 1 case of probably ICM-induced primary hypothyroidism requiring levothyroxine treatment, 2 cases of transient serum TSH elevation, and 2 cases of transient low fT4 levels attributed to NTI or THOP, although in 1 of the 2 latter cases there may have been transient ICM-induced TSH elevation. ICM use may lead to excessive iodine exposure. To prevent hyperthyroidism, the thyroid gland temporarily downregulates thyroid hormone production, the so-called Wolff-Chaikoff effect. Within a few days, escape from this effect occurs, with restoration of thyroid function usually within 2 weeks [9]. Preterm infants however, are at risk for ICM-induced hypothyroidism as the escape mechanism develops between 36 and 40 weeks of gestation [10, 11].

A recent case of prolonged severe primary hypothyroidism after enteral ICM administration led to a recently published systematic review on this topic and a local post-exposure thyroid function testing protocol, with first results in this study [7]. We hypothesized that ICM stasis in preterm newborns might be an additional risk factor for development of hypothyroidism. Twelve of 28 infants (42.9%) had stasis of ICM approximately 2 days after enteral administration. Two of the three infants with TSH elevation had ICM stasis, including the one with primary hypothyroidism who required treatment. So, stasis might play a role in hypothyroidism development, but in this study in only two of twelve infants (16.7%).

In our recent systematic review, we found that studies evaluating thyroid function after enteral ICM administration in children are lacking [7]. Given the importance of thyroid hormone for neurodevelopment early in life, we recommend monitoring of thyroid function in young infants after enteral ICM administration, especially in preterm born infants. This recommendation is in line with the guidelines of the FDA warning of March 2022, although this warning specifically addressed intravenous administration, the ETA Guidelines of July 2021, which recommends monitoring on thyroid function tests in infants after maternal or neonatal ICM exposure, and the recently published guidelines of the Federation of Medical Specialists of the Netherlands that recommends thyroid monitoring of preterm born neonates within 2 weeks after administration of enteral ICM [5, 12, 13]. In the meantime, further research on the effects of enterally administered ICM on thyroid function in young infants is necessary, also addressing the question of alternatives for enteral ICM.

A strength of this prospective study is the use of a standardized protocol. However, the small sample size made it impossible to analyze risk factors for ICM-induced hypothyroidism. Another limitation is that thyroid function was not measured prior to enteral ICM administration. Especially preterm born infants may have abnormal thyroid function tests because of THOP or NTI [14]. Elevated TSH levels after ICM administration in preterm newborns may both reflect the Wolff-Chaikoff effect or a physiological delayed TSH surge [14].

In conclusion, three of 33 infants had iodine-induced thyroid function test abnormalities following enteral ICM administration. We recommend thyroid function monitoring in infants younger than 6 months following this procedure to enable early detection and treatment of hypothyroidism to prevent its potential negative effects on neurodevelopment.

The Medical Ethics Review Committee of the Amsterdam UMC reviewed the study protocol and concluded that the Medical Research Involving Human Subject Act does not apply to this study following Dutch national guidelines (reference No. METC 2023.0516). Written informed consent for participation in this study was obtained from parents/legal guardians of the patients. Written informed consent for publication of all data mentioned in this manuscript was obtained from parents/legal guardians of the patients.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Adinda G.H. Pijpers, MD, and Christiaan F. Mooij, MD, PhD: data curation, formal analysis, methodology, and writing – original draft. Joep P.M. Derikx, MD, PhD, professor, and Christiaan F. Mooij, MD, PhD: supervision, conceptualization, and writing – review and editing. Joost van Schuppen, Wes Onland, A.S. Paul van Trotsenburg, L.W. Ernest van Heurn, and Nitash Zwaveling-Soonawala: investigation, resources, and writing – review and editing.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.