Transient neonatal hypothyroidism secondary to postnatal maternal exposure to contrast medium

Abstract

We report a preterm breastfed infant who developed a transient hypothyroidism after his lactating mother had a CT scan with iodinated contrast medium, despite the advised 24 hours’ pause in breast feeding. The aetiological assessment did not show any other cause for this hypothyroidism. Transient neonatal hypothyroidism after the use of topical iodine is well known, but it has not been described as a complication of intravenous contrast medium administration to a lactating mother. This case highlights the possibility of transient neonatal hypothyroidism secondary to contrast medium exposure to a lactating mother. When imaging is needed in the lactating mother, a longer break in breast feeding might be needed to prevent transient hypothyroidism in the preterm infant.

Background

Untreated congenital hypothyroidism (CH) will lead to severe mental and physical developmental delays. Through neonatal screening followed by early treatment, a normal development can be obtained. Transient neonatal hypothyroidism is defined as a transient abnormality of the thyroid function in the newborn, which later reverts to normal and which may or may not require replacement therapy. The transient thyroid dysfunction has become more frequent with the increasing number of surviving preterm infants.¹ Fetal thyroid development starts early in gestation. The production of thyroglobulin starts at 4–6 weeks, the thyroid-stimulating hormone (TSH) secretion begins at 12 weeks of gestation, and the fetal iodine uptake and thyroid hormone productions begin at more or less 18–20 weeks of gestation.

An iodine excess exposure of the thyroid gland leads to a decrease of thyroid hormone due to the Wolff-Chaikoff effect, followed by an escape and normalisation of thyroid hormone secretion after some days. The capacity to escape seems to mature only around 36 weeks and may hinder the immature thyroid gland to escape from this effect.^2–6 In Luxembourg, neonatal screening includes five diseases: hypothyroidism, phenylcetonuria, congenital adrenal hyperplasia, medium chain acyl CoA dehydrogenase deficiency (MCADD) and cystic fibrosis. The initial neonatal screening programme for hypothyroidism is not without difficulties, especially in preterm infants with both false-positive and false-negative results. This is explained by the physiological differences in thyroid function: the immaturity of the hypothalamic–pituitary–thyroid axis, the impaired synthesis and metabolism of thyroid hormones, the fluctuations due to non-thyroidal illness and insufficient or excessive iodine intake.^{7 8}

Because of the risk of false-negative and false-positive screening results in the preterm population, preterm infants with a birth weight of less than 1500 g or with a gestational age of less than 32 weeks should undergo a repeat screening at 2–4 weeks of age.^9–12 We report the first case of transient neonatal hypothyroidism with, at first, a normal screening outcome.

Case presentation

A preterm male infant was delivered by caesarean section due to maternal pre-eclampsia. He was born at a gestational age of 31 weeks 4 days with a birth weight of 1350 g (10th percentile), a height of 40 cm (10th percentile) and a head circumference of 27 cm (between the 3rd and 10th percentile). He had an Apgar score of 5–7–9.

His clinical evolution was characterised by respiratory distress syndrome but without needing surfactant treatment. This was followed by a moderate bronchopulmonary dysplasia (ongoing nasal oxygen therapy at 36 weeks of gestational age). He also developed a apnoea-bradycardia syndrome, requesting caffeine treatment. Except for these respiratory problems, the patient did well. He had parenteral nutrition until day 10 of life to complete the enteral nutrition, which was started from birth onwards. His only medication was the vitamin supplementation for preterm infants.

Investigations

His first neonatal screening was performed at day 4 of life and showed an elevated 17-hydroxy-progesteron (17-OH-P) at 58 nmol/L (normal range <25 nmol/L) and a normal TSH at 2.48 mUI/L (normal range <12 mUI/L). Based on the higher 17-OH-P values, a control was performed at postnatal day 17. This control showed a normal 17-OH-P, but an elevated thyrotropin (TSH) at 21.87 mUI/L on filter paper with a serum control 24 hours later of 87.60 mUI/L (normal range: 0.27–4.20 mUI/L) and free T4 (fT4) of 0.66 ng/dL (normal range: 0.93–1.70 ng/dL). Further biological assessment revealed an increased thyroglobulin at 811 ng/mL (normal range: 3.5–77 ng/mL), but no anti-TPO or antithyroglobulin antibodies. The cervical ultrasound showed a normal thyroid gland. Further clinical investigation revealed that 4 days after delivery, the mother had received a pulmonary angiography to exclude a pulmonary embolism. The contrast product used was an iodinated contrast medium called iomeron with a dose of 350 mg of iodine/kg. The mother received instructions to stop lactation during 24 hours during which time the child received formula milk. The mother followed this advice. The medical history of the 33-year-old mother reveals a subclinical hypothyroidism without positive thyroid antibodies, complicated by hyperprolactinaemia. She had been treated over the previous 8 years with 50 μg L-thyroxin/day. The father is in good health without any relevant medical background. The first child of the couple is a healthy girl. The maternal family history reveals that the father of the mother and his sister have subclinical hypothyroidism.

Differential diagnosis

Based on the blood analyses, we excluded a central hypothyroidism, CH and auto immune disease. Dyshormogenesis or potential exposure to iodine inducing the hypothyroidism was considered.

Treatment

After the second confirmation of high TSH and low fT4, substitutive treatment was started with L-thyroxin with a dose of 10 μg/kg.

Outcome and follow-up

The thyroid function quickly normalised. Based on the follow-up blood values, L-thyroxin dosing was slowly reduced and could be stopped after 35 days of treatment. Follow-up up to 7 months revealed a normal TSH, fT4 and the achievement of age-adequate developmental milestones.

Discussion

In our patient, the first neonatal screening showed normal thyroid values, but the repeat screening at 17 days postpartum revealed hypothyroidism, confirmed by low fT4, high TSH values in combination with absent autoimmunity and high thyroglobulin values.

As discussed earlier, the fetus and the newborn are sensitive to the iodine excess, administered to the mother during pregnancy or lactation or directly administered to the baby.¹³ Due to the immaturity of the thyroid gland in the preterm infant, with an impaired reaction to excess iodine, the thyroid hormone synthesis and release to the blood circulation remain suppressed.^4–6 This mechanism is partially explained by an inhibition of the thyroid peroxidase activity, which is necessary for thyroid hormone synthesis. The mechanism may also implicate a decrease in thyroglobulin hydrolysis, which induces a decrease in thyroid hormone secretion.^{6 14–17} Some studies show that after an exposure to iodinated contrast media, the thyroid gland is exposed for at least 7 days and up to more than 2 months to increased iodine levels.^{2 18 19} The source of exposure may include drugs, amniofoetography, topical antiseptic iodine solutions and iodinated contrast media. Transient neonatal hypothyroidism due to contrast media directly administered to the child, due to a prenatal exposure to contrast media or due to iodine antiseptic use in children or lactating mothers is well known. However, transient neonatal hypothyroidism due to contrast medium use in a lactating woman has never been described.^{2 13} One case series did not show neonatal hypothyroidism after in utero exposure to contrast media.⁵

The risks for the baby after contrast media exposure through breast milk are theoretical, and there is little literature. Iodinated contrast media have shown very low excretion levels in the breast milk. After 50 mL intravenous iodinated contrast media in two lactating mothers, no detectable contrast medium excretion in milk was found up to 16 hours using spectrophotometric analysis.²⁰ After the injection of 350 mg I/kg of iohexol in four women and metrizoate in two women, low levels of contrast media excretion in milk were detected using liquid chromatography. With a milk intake of 0.151 L/kg per day, it was calculated that these infants could have received 1.7 mg I/kg with iohexol and 0.78 mg I/kg with metrizoate. These values correspond to 0.5% and 0.3% of the maternal dose of iohexol and metrizoate, respectively.²¹ Furthermore, iodinated contrast media are poorly absorbed from the breast milk by the gastrointestinal tract into the blood. Only 0.4% of the iodine content of orally administrated metrizamide was excreted in the urine during the first day and only 0.8% by the end of the third day.²² Based on these data, international recommendations do not support discontinuation of breast feeding anymore, even not for 12–48 hours after administration of contrast media.^23–25

In our case, the concentration of iodine in the breast milk and in the urine of the infant has not been analysed. Without the concentration of iodine in the breast milk, it is impossible to estimate the iodine ingestion.²⁶ Although some data suggest a relationship between urine iodine concentration and iodine intake from breast milk in term babies, this may not hold true for preterm infants with a reduced renal clearance of iodine (and an increased skin absorption).^{1 13 27}

Our case report demonstrates that one should be careful with the most recent international recommendation, allowing breast feeding after the administration of contrast media to the mother, especially in preterm infants because of the immaturity of the thyroid axe autoregulation and of the other organs.

Moreover, long-term effects of iodinated contrast media are unclear. It has been suggested that iodine-induced transient neonatal hypothyroidism may be associated with an increased risk of hypothyroidism at adulthood. This suggests the necessity of a long-term follow-up.^{14 28}

Although the risk of neonatal transient hypothyroidism through lactation after maternal exposure to contrast media in term babies seems rare, this may not be extrapolated to the preterm infants. The transient hypothyroidism in a 31-week-old infant, probably caused by maternal exposure to the contrast media, was observed despite interruption of 24 hours of lactation. This observation suggests that—if imaging in the lactating mother of (premature) infants is indicated—current timelines for lactation interruption may need adjustment.

Learning points.

• The neonatal screening for hypothyroidism must be repeated in preterm infants due to the physiological differences of the thyroid function.

• Even if contrast media level is suggested to be low in breast milk, the thyroid function of preterm infants can still be affected postexposure to iodinated contrast media.

• It seems important to discuss the recommendations for lactation in this population.