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The potential for iodine overload in neonates: a short review |
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KEY
POINTS
INTRODUCTION TSH is measured on the Guthrie card at postnatal days 5-6; if TSH levels are elevated the infant is recalled and TSH and FT4 measurements are made. If TSH levels remain persistently high and FT4 levels low, the infant is diagnosed with permanent congenital hypothyroidism (incidence approx 1:3500). Transient congenital hypothyroidism is defined by high TSH levels and low FT4 levels soon after birth but with spontaneous resolution over time (1). Transient hyperthyrotropinaemia is defined by elevated TSH levels but normal FT4 levels and most resolve spontaneously (1). Transient congenital
hypothyroidism and hyperthyrotropinaemia in Europe are largely associated
with iodine deficiency as the incidence is high in areas of endemic goitre
(2). Iatrogenic iodine overload
in fetal and neonatal life is the other major cause of transient congenital
hypothyroidism and hyperthyrotropinaemia (3). The developing thyroid is inordinately sensitive to the inhibitory effect of excess iodine with the subsequent development of goitre and/or hypothyroidism (4). It is unclear whether the inhibitory effect of excess iodine, the Wolff-Chaikoff effect (5), is exerted on the organification mechanism or the release of thyroid hormones (6). Studies since the 1970s have highlighted that direct iodine overload of
the new born is caused either by disinfection agents or use of contrast
media in the neonatal period (e.g. 7,8).
The fetus and newborn can also be exposed to high maternal iodine
concentrations either prenatally via transplacental transfer or postnatally
through breast milk (9, 10). Preterm
infants are substantially more sensitive to the effects iodine overload
compared to term infants or adults (11,12,13).
A disproportionately high incidence of transient hypothyroidism, but
not permanent hypothyroidism, has been reported in very low birth weight
infants (14). INFANT
IODINE exposure FROM Maternal sources The adverse effect of
maternal iodine intake on the neonate was first reported by Parmalee et al
in 1940 (15) as goitre in three infants of mothers who had taken iodine
containing cough medicine through pregnancy (9). This
source of infant exposure to excess iodine is now rare.
Another uncommon transplacental source of fetal iodine exposure is as
a consequence of amiodarone, which is iodine rich and prescribed for
maternal and fetal tachyarrhythmias (16). The major maternal source of excess iodine exposure to infants is through skin disinfection using povidone-iodine before delivery. Topical iodine as a skin disinfectant prior to Caesarean section was associated with higher postnatal day 3 TSH levels in infants compared to those infants delivered vaginally without iodine disinfection (17); iodine load in the mother was correlated with the iodine of her breast milk (18). The iodine overload to the infant was predominantly via breast milk from mother’s exposed to iodine both from skin disinfection for Caesarean section and/or epidural anaesthesia. The consequence of the iodine exposure was a 25-30 fold increase in the recall rate at screening for congenital hypothyroidism, defined as TSH >50mU/L, (10). A significant increase in cord TSH levels was seen in infants exposed to povidone-iodine during Caesarean section, median TSH 4.6mU/L unexposed versus 6.47 exposed; a difference that was evident 20 minutes following application (19). Povidone-iodine
is also used for vaginal disinfection.
Total iodine levels were increased 5-15 fold in non-pregnant women
within 60 minutes of vaginal disinfection with povidone-iodine (20).
And, in a study of in utero exposure to iodine from vaginal douching
the iodine content of the fetal thyroid in the iodine exposed group was 7.7
mcg compared to 1.0 mcg in gestationally age matched controls (21).
However, the impact on urinary iodide excretion and TSH levels in
infants exposed to povidone-iodine during
vaginal delivery was not different from control infants in an iodine
sufficient Japanese population (22). Neonatal
exposure to iodine Neonates
are exposed to excess iodine mainly through three routes: as a disinfectant
used during routine umbilical cord care, or as a skin disinfectant prior to
procedures such as insertion of intravenous cannula etc., and through
injection of iodinated contrast media for the visualization of central
venous catheters. The increase in incidence of hypothyroidism detected in routine neonatal screening is increased in infants exposed to povidone-iodine for umbilical cord care (22). For example, the false positive rate in Taiwan was 4.6% when povidone-iodine was used and 0.7% when alcohol or triple dye was used (23). The
consequence of topical povidone-iodine use as
a skin disinfectant is variable.
A study from Australia reported serum hypothyroidism (TSH levels
>20 mU/L) in 25% of very low birth weight infants exposed to iodine
compared to none in the control group (13).
Whereas a study from Germany reported that 78% of infants born <37
weeks gestation and exposed to iodine through skin disinfection had serum
TSH >20 mU/L with T4<77 nmol/L (11).
Transient hypothyroidism was reported in 20% infants exposed to
iodine during labour, both transplacentally due to vaginal disinfection and
also directly via skin disinfection prior to insertion of fetal scalp
electrode (24). By
contrast, in two reports from the USA an increased incidence of transient
hypothyroidism was not evident in neonatal intensive care infants treated
topically with povidone-iodine (25, 26).
The dichotomy of effect seen in these studies is difficult to explain
and is likely to be the result of several interacting factors (see below). The most frequent source of iodine exposure in
neonates is through the use of iodinated contrast media for the
visualization of central venous catheters. Several studies have
confirmed transient hypothyroidism or transient hyperthyrotropinaemia
consequent to exposure to iodinated contrast media (11,27,28,29). But
the results are not consistent and, for example, Dembinski et al (30) found
no evidence of transient hypothyroidism following exposure to an iopromide (Ultravist
300) used as a contrast agent. However, interpretation of cause and
effect is difficult as the range, concentration and dosage of media used is
wide (e.g. Niopam, Omnipaque, Ultravist, Amipaque, and Visipaque at
strengths of 150, 200, 240, 300, 370) and each liberates different
quantities of free iodide. possible
explanations for the variability in results The
numbers of infants recruited in all of the studies were few (ranging from
31-84) and encompassed a wide range of gestational ages (24 weeks to term,
or unspecified) which makes interpretation of TSH and T4 levels problematic.
Larson et al (31) provide evidence that infants with a birth weight
<1500g are at greater risk per se of hypothyroidism than are greater
weight infants (1:250 compared to 1:3500). There is evidence that
preterm infants are more vulnerable to iodine exposure than term infants (11-14).
Presumably in reflection of this, the British National Formulary
for Children 2005 lists neonates under 32 weeks and infants under 1.5kg as
contra-indications to the use of povidone-iodine for skin disinfection.
The dosage of iodine
received by infants in the various studies was variable and not quantified.
Although in some studies iodine excretion was clearly elevated there was no
concomitant increase in TSH levels. However, this may simply reflect an
insufficient gap between exposure and effect given the 6-10 day half life of
T4. The effect of iodine
exposure seems higher in areas of iodine insufficiency (32) and there is
animal evidence (33) that the amount of iodine needed to interfere with
thyroid function is 10 fold less in rats who are iodine depleted compared to
iodine sufficient. Infants
born into iodine sufficient areas (e.g. USA) rather than iodine deficient or
borderline areas (e.g. Berlin) might therefore be protected to some extent
from an additional iodine exposure from medical care.
Finally there might be genetic susceptibility to hypothyroidism. For example, monoallelic mutations in THOX2 gene have been associated with transient hypothyroidism; whereas biallelic mutations have been associated with total disruption of thyroid hormone synthesis and are associated with severe and permanent congenital hypothyroidism (34). |
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