We investigated the clinical course of infants with congenital heart disease (CHD) who experienced thyroid dysfunction within 100 days of birth.
We performed retrospective medical reviews of 54 CHD patients (24 male patients) who underwent a thyroid function test (TFT) between January 2007 and July 2016. Data were collected on birth history, diagnosis of CHD, underlying chromosomal or genetic abnormalities, medication history, surgery, ventilator care, and exposure to iodine contrast media (ICM). Results of neonatal screening tests (NSTs) and TFTs were reviewed.
A total of 36 patients (29 transient, 7 permanent) showed thyroid dysfunction. Among the seven patients with permanent hypothyroidism, three had an underlying syndrome, three showed abnormal NST results, and one was admitted to the intensive care unit for macroglossia and feeding cyanosis. We found that infants with transient thyroid dysfunction had a lower birth weight and were more commonly exposed to thyroid disrupting medication and/or ICM. However, these risk factors were not significant. A total of 8 patients with a history of ICM exposure showed thyroid dysfunction. Excluding 3 patients with elevated thyroid stimulating hormone before ICM exposure, 5 patients recovered from transient thyroid dysfunction.
We observed thyroid dysfunction in two-thirds of CHD infants (53.7% transient, 13.0% permanent) who had risk factors and received TFT screening within 100 days, despite normal NSTs. Further studies with larger sample sizes are required to revise the criteria for TFT screening in CHD infants.
Congenital hypothyroidism is one of the most preventable causes of neurocognitive impairment because early treatment is possible in neonates [
According to the Italian Registry of Congenital Hypothyroidism, congenital heart disease (CHD) is the most frequent disease condition associated with congenital hypothyroidism [
The 2014 European Society of Pediatric Endocrinology (ESPE) guideline recommends a second screening of thyroid function test (TFT) in neonates with the following high risk factors for hypothyroidism; preterm or low birth weight infants, critically ill infants who were admitted to intensive care unit (ICU), and monozygotic twins [
In this study, we aimed to identify frequency and clinical course of thyroid dysfunction in CHD infants who received TFT screening within 100 days according to current ESPE guidelines. We also aimed to identify the role of ICM exposure on developing thyroid dysfunction in CHD infants.
The medical records of infants diagnosed with CHD between January, 2007 and July, 2016 at Seoul National University Children’s Hospital were retrospectively reviewed. Those who had TFT results before 100 days of birth were included in this study. Early preterm infants (gestational age [GA]<34 weeks), late preterm infants (34 weeks≤GA<37 weeks) with spontaneously closed patent foramen ovale or patent ductus arteriosus, infants whose mother had a history of autoimmune thyroid disease, and patients who expired before 3 years of age were excluded. A total of 54 infants (24 male infants) were finally included in this study.
Clinical data were collected on GA, birth weight, type of cardiac disease, other congenital anomalies, underlying chromosomal or genetic abnormalities, and previous history of medication affecting the thyroid function (dopamine, dobutamine, amiodarone, steroid, and furosemide), exposure to ICM through cardiac computed tomography (CT) or catheterization, operation, and mechanical ventilator care.
Laboratory findings of serum free thyroxine (fT4) and TSH levels from the first to last follow-up were reviewed. Serum concentrations of fT4 and TSH were measured using immunoradiometric kits (RIAKEY; Shin Jin Medics, Seoul, Korea). The normal ranges of serum fT4 and TSH are 0.70–1.80 ng/dL (9.01–23.2 pmol/L) and 0.4–4.1 mIU/L, respectively. A capillary sample of blood was obtained from the heel to preform NST by chemiluminescent Immunoassay (Modular Analysis E 170 module, Roche, Germany). The cutoff values of TSH on NST were <12 mIU/L. NST results were also reviewed in infants who were transferred from outside hospital.
Patients were categorized into the 3 groups as follows; normal thyroid function, transient thyroid dysfunction, and permanent hypothyroidism. In infants who started levothyroxine medication, the dose, starting and ending dates of levothyroxine medication were reviewed. The transient thyroid dysfunction group included infants who showed transient hyperthyrotropinemia which spontaneously normalized or those who successfully discontinued levothyroxine during follow-up. Patients who failed to discontinue or withdraw levothyroxine medication till 3 years of age were categorized into permanent hypothyroidism.
Statistical analyses were performed using IBM SPSS Statistics ver. 24.0 (IBM Co., Armonk, NY, USA). Analysis for normality was performed first. All continuous variables were described as means±standard deviation. Binary logistic regression analysis was performed to investigate risk factors associated with transient thyroid dysfunction. A
The present study was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (approval number: 1702-021-829) and informed consent was waved.
Thirteen patients (24.1%) were late preterm (34 to 36 weeks of GA) and 11 patients (20.4%) were small for GA. The CHDs of the patients were as follows; ventricular septal defect (n=21), atrial septal defect (n=15), atrioventricular septal defect (n=1), tetralogy of Fallot (n=6), pulmonary stenosis (n=5), Ebstein anomaly (n=2), functional single ventricle (n=1), thoracic aorta widening (n=1), mitral regurgitation (n=1), and truncus arteriosus (n=1). Twenty-three patients (42.6%) were diagnosed with chromosomal anomaly or genetic syndrome as follows: Down syndrome (n=11), other chromosomal defects (n=2, 46, XY, del(9)(p22), and 45, XX, -14, der(18), t(14;18)(q11.2;q23)), Digeorge syndrome (n=5), Williams syndrome (n=3), Beckwith-Wiedemann syndrome (n=1), and Alagille syndrome (n=1). Before evaluation of TFTs, 5 infants (9.3%) received cardiac surgery, 8 infants (14.8%) had a history of ICM exposure, and 15 infants (27.8%) had a history of thyroid disrupting medication such as dopamine, dobutamine, amiodarone, steroids, and/or furosemide (
Among 7 patients categorized into the permanent hypothyroidism group (
Among 29 patients categorized into the transient thyroid dysfunction group, 8 patients initially started levothyroxine and successfully discontinued medication at a later follow-up. The remaining 21 patients showed transient hyperthyrotropinemia which was spontaneously normalized without medication (
The transient thyroid dysfunction group (n=29) had higher proportions of patients with a chromosomal anomaly or genetic syndrome, preterm birth, small for GA, history of ICM exposure, and use of thyroid disrupting medication than the normal thyroid function group (n=18). However, none of aforementioned risk factors including ICM exposure was statistically significant as a result of binary logistic regression analysis (
A total of 8 patients who had a history of ICM exposure were categorized into permanent hypothyroidism (n=3) or transient thyroid dysfunction (n=5,
The prevalence of vitamin D deficiency in pediatric patients Two-thirds of the 54 CHD infants who received TFT screening within 100 days according 2014 ESPE guideline showed thyroid dysfunction. Seven patients (13%) were categorized into permanent hypothyroidism requiring persistent levothyroxine medication. Twenty-one infants (53.7%) with transient thyroid dysfunction had lower birth weight, and had more exposure to ICM and/or thyroid disrupting medication than those with normal thyroid function; however, none of risk factors including ICM exposure were statistically significant in this study. Despite normal NST results, delayed TSH elevation was detected in critically ill patient with CHD during ICU care. Unless CHD infants had elevated TSH levels before ICM exposure, thyroid dysfunction was transient in this study.
Seven patients with permanent hypothyroidism received TFTs according to the 2014 ESPE guideline [
Half of CHD infants (53.7%) with risk factors showed transient thyroid dysfunction. Preterm birth and/or low birth weight [
Recently, three term CHD infant cases were reported, who developed iodine-induced hypothyroidism 5 to 11 days after exposure to ICM and/or disinfectant containing iodine [
This study is limited by a retrospective design and small sample size. Since infants at high risk for developing thyroid dysfunction selectively received TFTs in our study, we could not know the incidence of congenital hypothyroidism for the total CHD infants due to selection bias. Since the possibility of common mechanisms such as the pathologic role of
In conclusion, thyroid dysfunction was detected in two-third of CHD infants who received TFT screening within 100 days according to current ESPE guidelines (53.7% transient, 13.0% permanent), although NST results were normal. The independent effect of ICM exposure on thyroid dysfunction was not identified in this study. Further studies with larger sample sizes are required to revise criteria for TFT screening in CHD infants.
Supplementary Table 1 can be found via
Clinical course of total subjects.
Characteristics of total subjects
Characteristic | Total | Normal | Transient thyroid dysfunction | Permanent hypothyroidism |
---|---|---|---|---|
No. of patients | 54 | 18 (33.3) | 29 (53.7) | 7 (13.0) |
Male sex | 24 (44.4) | 6 (33.3) | 14 (48.3) | 4 (57.1) |
Gestational age (wk) | 37.8±1.7 | 38.2±1.7 | 37.6±1.8 | 37.7±1.0 |
Birth weight (kg) | 2.9±0.7 | 3.1±0.6 | 2.9±0.7 | 2.5±0.5 |
Preterm | 13 (24.1) | 3 (16.7) | 9 (31.0) | 1 (14.3) |
Small for gestational age | 11 (20.4) | 2 (11.1) | 7 (24.1) | 2 (28.6) |
Chromosomal anomaly or genetic syndrome | 23 (42.6) | 6 (33.3) | 14 (48.3) | 3 (42.9) |
Cyanotic heart disease | 17 (31.5) | 6 (33.3) | 8 (27.6) | 3 (42.9) |
Ventilator care history | 8 (14.8) | 3 (16.7) | 5 (17.2) | 1 (14.3) |
History of surgery | 5 (9.3) | 1 (5.6) | 3 (10.3) | 1 (14.3) |
Exposure to iodine contrast media | 8 (14.8) | 0 (0) | 5 (17.2) | 3 (42.9) |
Thyroid disrupting medication | 15 (27.8) | 2 (11.1) | 10 (34.5) | 3 (42.9) |
Values are presented as number (%) or mean±standard deviation.
Congenital heart disease infants with permanent hypothyroidism
Case | Sex | Congenital heart disease | Underlying disease | GA (wk) | Birth weight (kg) | TSH (NST) (mIU/L) | Age at detection of elevated TSH (day) | Serum fT4 (ng/dL) | Serum TSH (mIU/L) | Age at start levothyroxine (day) | Imaging study | Age at last follow-up (yr) |
---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | M | TOF | Down syndrome | 39 | 2.3 | Normal (2.9) | 26 | 1.7 | 8.9 | 628 | NA | 8.0 |
2 | F | AVSD, PDA | Down syndrome | 36 | 1.8 | Normal (6.8) | 7 | 1.9 | 8.2 | 21 | NA | 3.9 |
3 | M | AS, PS | Williams syndrome | 38 | 2.6 | NA | 83 | 1.0 | 5.5 | 130 | NA | 9.2 |
4 | F | Large VSD, ASD, PDA | None | 38 | 2.2 | Elevated (44.8) | 17 | 0.65 | 100 | 18 | NA | 8.3 |
5 | M | Functional single ventricle | None | 38 | 3.2 | Elevated (14.5) | 7 | 1.18 | 28.0 | 380 | NA | 3.7 |
6 | F | IAA, PDA,VSD | None | 37 | 2.6 | Elevated (157) | 17 | 0.10 | 801.0 | 17 | Lingual thyroid | 6.1 |
7 | M | Large ASD | None | 38 | 3.0 | Normal (NA, outside) | 92 | 0.89 | 22.3 | 92 | NA | 6.5 |
Normal values of TSH (NST), serum fT4, and serum TSH were ≤12 mIU/L, 0.70–1.80 ng/dL, and 0.4–4.1 mIU/L, respectively.
GA, gestational age; TSH, thyroid stimulating hormone; NST, neonatal screening test; fT4, free thyroxine; TOF, tetralogy of Fallot; AVSD, atrioventricular septal defect; PDA, patent ductus arteriosus; AS, aortic stenosis; PS, pulmonary stenosis; VSD, ventricular septal defect; ASD, atrial septal defect; IAA, interrupted aortic arch; NA, not available.
Congenital heart disease infants with transient thyroid dysfunction after exposure to iodine contrast media (ICM)
Case | Sex | Congenital heart disease | Underlying disease | Birth weight (kg) | TSH (NST) (mIU/L) | Serum TSH before exposure to ICM | Exposure to ICM (age [day] at exposure) | Serum TSH after exposure to ICM (age [day] at evaluation) | Levothyroxine medication (dose, age [day] at start) | Levothyroxine withdrawal (age [day] atdiscontinuation) | Imaging study |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | F | IAA, VSD, ASD | Digeorge syndrome | 2.5 | Normal (9.5) | 4.0 | CT angiography (13) | 23.04 (25) | Yes (15.5 µg/kg/day at 25) | Yes (33) | NA |
2 | F | TOF | Digeorge syndrome | 2.9 | Normal (7.6) | NA | CT angiography (4) | 5.4 (20) | No | - | NA |
3 | M | VSD, MR, ASD | 46,XY,del(9) (p22) | 3.7 | NA | NA | CT angiography (71) | 5.3 (74) | No | - | NA |
4 | F | AP window, ASD, VSD | None | 1.7 | Normal (1.7) | NA | CT angiography (6) | 13.7 (30) | Yes (6.6 µg/kg/day, 30) | Yes (889) | Normal |
5 | M | VSD, MAPCA | None | 2.3 | NA | 2.8 | Cardiac catheterization (417) | 22.6 (449) | Yes (3.8 µg/kg/day at 449) | Yes (894) | Normal |
Normal values of TSH (NST), and serum TSH were ≤12 mIU/L, and 0.4-4.1 mIU/L, respectively.
TSH, thyroid stimulating hormone; NST, neonatal screening test; IAA, interrupted aortic arch; VSD, ventricular septal defect; ASD, atrial septal defect; CT, computed tomography; TOF, tetralogy of Fallot; MR, mitral regurgitation; AP window, aortopulmonary windrow; MAPCA, major aortopulmonary collateral arteries; NA, not available.