Keywords
neonate - thyrotoxicosis - topical povidone-iodine - giant omphalocele
Neonatal thyrotoxicosis is an uncommon but portentous condition, characterized by
elevation of the active thyroid hormones in the circulation and clinical manifestation
of hyperthyroidism.
If left untreated, it can lead to irreversible neurologic sequelae.[1]
[2] The most common etiology is maternal Graves' disease, occurring as a result of transplacental
transfer of the thyroid stimulating immunoglobulins (TSI) from mother to the fetus.
Subsequently, TSI stimulates the thyroid stimulating hormone (TSH) receptor on fetal
thyroid gland to produce excess of free thyroxine (FT4).[3]
Other non-transient neonatal hyperthyroidism can be caused by a dominantly inherited
activating mutations in the TSH receptor gene,[4] in isolation, as well as by an early embryonic postzygotic somatic activating mutation
in the adenylate cyclase-stimulating G α protein gene,[5] both resulting in constitutionally active stimulatory α subunit of the G protein
receptor and involvement of multiple organs.[5] The presence of activating mutations of the TSH receptor results in permanent thyrotoxicosis.[4]
Iodine excess, whether topical, oral, or intravenous through radiocontrast agents,
can lead to thyrotoxicosis as well. This effect is described as the Jod-Basedow phenomenon,
which is the consequence of failed thyroid autoregulation during iodine excess, subsequently
leading to increased production of thyroid hormones and clinical thyrotoxicosis. To
date, multiple cases of thyrotoxicosis are reported in adult patients exposed to copious
topical iodine. On the other hand, in neonates, there are only two reported cases
of neonatal hypothyroidism associated with topical iodine treatment,[6]
[7] while the thyrotoxicosis has never been documented in this age range. Therefore,
our case represents the first report of topical iodine–induced neonatal hyperthyroidism.
Case Report
The patient was a premature female newborn born at 34 weeks of gestation with a giant
omphalocele. She presented, at day of life (DOL) 3, with hyperthyroidism while undergoing
conservative omphalocele management with daily topical povidone-iodine dressings.
Her mother did not have a history of chronic lymphocytic autoimmune thyroiditis or
Graves' disease, and has never been on any medications or over-the-counter supplementation.
Prenatal ultrasound at 20 weeks of gestation demonstrated multiple congenital anomalies,
including a giant omphalocele. The karyotype was that of a normal 46XX female. Due
to premature onset of labor, the baby was delivered at 34 weeks by vaginal delivery.
Apgar scores at birth were 5 at 1 minute, 6 at 5 minutes, and 7 at 10 minutes. Due
to lack of consistent spontaneous breathing and deep cyanosis with crying, the baby
was immediately intubated resulting in improved respiratory status. After birth, baby
was confirmed to have thoracolumbar scoliosis and a giant omphalocele with the liver
and intestines contained in the intact sac, and a large Wharton's jelly. Considering
the size of this lesion, conservative management with daily povidone-iodine dressings
was initiated and delayed surgical closure of omphalocele was planned at 1 year of
age. Topical povidone-iodine was used at 10% concentration to promote escharification
and epithelialization of the omphalocele sac; 3 to 4 povidone-iodine soaked gauges
per day were used to cover the sac starting at birth.
Thyroid function tests were obtained on DOL 3; TSH was suppressed (0.59 µIU/mL; reference
range, 0.73–4.60 µIU/mL) and FT4 was elevated (5.63 ng/dL; reference range, 0.58–1.64
ng/dL). By DOL 4, the newborn was symptomatic with frank cardiovascular manifestations,
including tachycardia (pulse rate, 190–200 bpm) as well as hypertension (blood pressure,
96–105/49–66 mm Hg). On DOL 5, povidone-iodine was stopped completely and replaced
with topical silver sulfadiazine. In consideration of the possibility of neonatal
Graves' disease (i.e., maternally inherited TSI), TSI level was obtained and was negative
(32%; reference range < 140% baseline).
The decision was made to monitor the cardiovascular parameters closely along with
the thyroid function tests every 24 hours. Considering the negative TSI antibody and
with the presumption that this was a transient hyperthyroid state, antithyroid treatment
in the form of methimazole was deferred. However, due to sympathetic hyper dynamic
state, presenting as tachycardia and hypertension, conferred by the hyperthyroidism,
propranolol was initiated in the interim at 0.04 mg/kg/day.
Within two days of discontinuing the iodine containing dressings, a downward trend
of FT4 was noted ([Fig 1]). Blood pressure and heart rate subsequently normalized, and propranolol was stopped
after a total of eight days. By DOL 17, twelve days after ceasing the iodine containing
dressing applications, the baby was both clinically and biochemically euthyroid with
a FT4 of 1.47 ng/dL and a TSH of 0.88 µIU/mL. ([Table 1]). A subsequent follow-up of the thyroid function at DOL 35 revealed continued euthyroid
status (FT4, 1.26 ng/dL, FT3, 2.34 pg/mL, and TSH, 2.21 IU/mL).
Fig. 1 Transition from hyperthyroid to euthyroid state after stopping povidone iodine dressings.
(TSH in µIU/mL and FreeT4 in ng/dL). TSH, thyroid stimulating hormone.
Table 1
Changes in the levels of free T4, free T3, and TSH at different days of life
|
DOL
|
FT4 (ng/dL)
|
FT3 (pg/mL)
|
TSH (µIU/mL)
|
|
3
|
5.63
|
|
0.59
|
|
4
|
5.42
|
2.29
|
0.31
|
|
5
|
5.89
|
2.51
|
0.62
|
|
7
|
5.72
|
2.4
|
0.13
|
|
8
|
5.31
|
2.38
|
–
|
|
9
|
4.67
|
2.11
|
–
|
|
11
|
5.36
|
–
|
0.08
|
|
13
|
3.6
|
–
|
0.06
|
|
17
|
1.47
|
–
|
0.88
|
|
35
|
1.26
|
2.21
|
2.34
|
Abbreviations: DOL, day of life; FT3, free T3; FT4, free T4; TSH, thyroid stimulating
hormone.
Discussion
We present a case of iodine-induced neonatal hyperthyroidism with overt clinical manifestations
of hyper dynamic cardiovascular state. Clinical and biochemical hyperthyroidism completely
resolved twelve days after the discontinuation of iodine-containing dressings, without
antithyroid drugs.
Giant omphaloceles, especially when containing liver tissue, as in our patient, remain
a therapeutic challenge to pediatric surgeons and neonatologists due to the large
area of the defect. Topical iodine is used for desiccation and escharification of
the sac; therefore, it is an important conservative measure in the management of large
omphaloceles. Whitehouse et al reported six cases of giant omphaloceles treated with
povidone-iodine that underwent weekly and then monthly thyroid function monitoring.
Out of the six patients, one demonstrated persistent hypothyroidism and subsequently
died secondary to cardiac complications. Five patients had no thyroid function perturbation
and ultimately achieved fascial closure.[6] A second report by Cosman et al described a neonate who developed hypothyroidism
when a giant omphalocele was conservatively managed by topical iodine.[7]
This previously mentioned phenomenon resulting in hypothyroidism is known as the Wolff–Chaikoff
effect, when there is a compensatory down regulation of the sodium–iodide symporter
in the thyroid gland in the event of excessive iodide levels, resulting in low levels
of circulating thyroid hormones.[8] In contrast, the Jod-Basedow phenomenon is when iodine overexposure leads to thyrotoxicosis,
and is described as an autonomous thyroid state associated with loss of the normal
regulatory control of the hypothalamic–pituitary–thyroid axis[9]; the precise mechanism of thyroid hyper function is unclear. The failure of autoregulation
of hypothalamic–pituitary–thyroid axis in the event of exposure to high amount of
iodine in neonates and children is rare, whereas it has been reported in few adult
cases. In these cases, the iodine exposures were typically dietary supplements and
iodine-containing medications, including topical iodine antiseptic solutions and intravenous
contrast radiographic agents. Additionally in the adult patients, it has been proposed
that iodine–induced thyrotoxicosis is more likely associated with underlying multinodular
goiters, however, our newborn patient had no identifiable underlying thyroid abnormality.[10]
[11]
[12]
Conclusion
Our case demonstrates that copious topical iodine exposure can lead to thyrotoxicosis
in newborns, even in the absence of an underlying thyroid abnormality. Presumably,
this impact might be even more pronounced in newborns considering the larger body
surface area to volume ratio, especially if iodine exposure is across denuded skin
and/or other mucosal surfaces with high absorptive potential. The knowledge and understanding
of the mechanisms involved are critical in optimal management of affected newborns
and to prevent fatal outcomes. In the circumstance when such treatments are required,
it is imperative for the clinician to monitor thyroid function tests frequently and
closely.
