Neonatal Thyrotoxicosis

Amanda L. Ogilvy-Stuart, DM, FRCP*

*Neonatal Unit, Rosie Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England

Education Gap
1. A protocol for managing and following up infants at high risk due to
neonatal thyrotoxicosis may prevent death and morbidity.
2. Clinicians should recognize that infants at risk for immune thyrotoxicosis
may have central or primary hypothyroidism, which can follow or be
followed by thyrotoxicosis.
3. Clinicians should be aware that thyroid function tests in at-risk infants
need to be compared with normal values for day of age.

Objectives After completing this article, readers should be able to:

1. Describe the etiology of neonatal thyrotoxicosis.

2. Identify which infants are at high risk for neonatal thyrotoxicosis.
3. Perform appropriate monitoring of high-risk infants.
4. Apply appropriate management strategies for neonatal thyrotoxicosis.

INTRODUCTION

Neonatal thyrotoxicosis is rare. In most cases, the cause is transplacental

passage of thyroid-stimulating immunoglobulin (TSI) from a mother with
Graves disease. In these infants, thyrotoxicosis may be anticipated by
knowing the mother’s thyrotropin receptor antibody (TRAb) level in the AUTHOR DISCLOSURE Dr Ogilvy-Stuart has
third trimester and/or cord blood levels. High-risk infants should be kept disclosed no financial relationships relevant to
under surveillance, because neonatal thyrotoxicosis can be life-threatening. this article. This commentary does not contain
a discussion of an unapproved/investigative
Treatment, usually with thionamides in infants of mothers with Graves use of a commercial product/device.
disease, is usually only required for a few weeks while the antibodies remain
within the infant’s circulation. Other causes of neonatal thyrotoxicosis are ABBREVIATIONS
extremely rare. ATD antithyroid drug
cAMP cyclic adenosine monophosphate
fT3 free triiodothyronine
fT4 free thyroxine
ETIOLOGY
T3 triiodothyronine
Most infants with neonatal thyrotoxicosis are born to mothers with autoimmune T4 thyroxine
TRAb thyrotropin receptor antibody
thyroid disease. This is usually Graves disease, but it also has been described in
TSH thyroid-stimulating hormone
women with Hashimoto thyroiditis (1)(2) and is caused by transplacental passage TSHR thyrotropin receptor
of TSI. Although most laboratories measure TRAb levels (which do not differ- TSI thyroid-stimulating
entiate between stimulating or blocking antibodies), the most accurate test is immunoglobulin

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measurement of TSI. These antibodies may persist in the
maternal circulation even after Graves disease has been
treated with surgery or radioiodine. (3)
Rare nonimmune causes of neonatal thyrotoxicosis
include:
• Gain-of-function mutations in the thyrotropin receptor
(TSHR) gene, which results in constitutive activation
of the cyclic adenosine monophosphate (cAMP) path-
way. This in turn results in thyroid hormone produc-
tion and thyrocyte proliferation. (4) Germline TSHR
mutations give rise to autosomal dominant hyperthy-
roidism, or with de novo mutations, sporadic congenital
hyperthyroidism.
• Activating mutations of stimulatory G protein in
McCune-Albright syndrome. The mutation results in
constitutive activation of the protein and production of
cAMP, bypassing the normal activation of the receptor
by thyroid-stimulating hormone (TSH). (5)
• Thyroid hormone resistance due to a mutation in the
thyroid hormone receptor b gene. (6) Biochemically
the infant has an inappropriately normal TSH level in the
presence of elevated free thyroxine (f T4) levels because of
pituitary insensitivity to thyroid hormone. The clinical
manifestations reflect the variable insensitivity of
peripheral tissues to thyroid hormone.
• Iodine use, for example, iodine dressings used to promote
escharification in an infant with a giant omphalocele. (7)
INCIDENCE
Graves disease occurs in approximately 0.2% of pregnant
women (8) and may present:
• As a recurrence or exacerbation of previous or existing
disease (most commonly)
• De novo
• With signs of fetal thyrotoxicosis (see below) in a
mother with no previous history
Between 1% and 5% of the offspring of women with Graves
disease will be diagnosed with thyrotoxicosis, (9)(10) which
equates to 1 in 10,000 to 1 in 50,000 newborns. The incidence
has been reported to be as high as 17% of live births to women
who were positive for TSI (11) and in 22% of infants in whom
antithyroid drugs (ATDs) were required at term. More than
90% of infants born at term to mothers with Graves disease
may have subclinical thyrotoxicosis with f T4 levels above the
95th percentile, peaking on day 5 after delivery. (12)
There is a relationship between the level of TRAb in the
third trimester (and cord blood) and the risk of neonatal
thyrotoxicosis, (9) which is most likely when the TRAb is
more than 3 to 5 times the upper normal limit. (11)(13)
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However, neonatal thyrotoxicosis can also occur at lower
TRAb levels (14) (unpublished observations).
THYROID FUNCTION IN THE FETUS OF THYROTOXIC
MOTHERS
Thyroid function in fetuses of mothers with Graves disease
is affected by the transplacental passage of thyroid blocking
or stimulating antibodies (both may coexist) and by ATDs.
By 10 to 12 weeks’ gestation, the fetal thyroid is capable of
concentrating iodide, accumulating colloid, and producing
thyroglobulin. By 25 weeks, the TSH receptor is capable of
responding to TSH (and TRAb), but fetal concentration of
TRAb is low until the end of the second trimester when
placental permeability to immunoglobulins increases. Hence,
fetal hyperthyroidism in infants of mothers with Graves dis-
ease will only occur in the second half of pregnancy.
EFFECT ON THE FETUS OF TREATMENT OF THE
THYROTOXIC MOTHER IN PREGNANCY
Mothers with a past or current history of thyrotoxicosis
should have their thyroid function and TRAb measured
at the first antenatal visit. If the TRAb is elevated, a repeat
level in the third trimester helps predict the risk of thyro-
toxicosis in the fetus and infant.
Treatment of maternal thyrotoxicosis involves 2 patients,
requiring a balance between optimizing the treatment for one
without compromising the other. The aim of maternal treat-
ment is to maintain her f T4 level at or slightly higher than the
upper normal range with the minimum ATD dose required to
prevent fetal hypothyroidism. This is because ATDs are more
potent in the fetus than in the mother (15); therefore, if the
mother is euthyroid, the fetus may be overtreated. This dose
can usually be reduced or stopped in the third trimester.
ATDs in pregnancy are potentially teratogenic. The use of
methimazole (to which carbimazole is metabolized) in
pregnancy has been associated with choanal atresia, esoph-
ageal atresia, cutis aplasia, abdominal wall defects, eye
anomalies, ventricular septal defects, and “methimazole/
carbimazole embryopathy” in 2% to 4% of exposed children.
(16)(17)(18)(19) Therefore, propylthiouracil is the preferred
ATD in the first trimester. Propylthiouracil exposure, how-
ever, has also been associated with minor birth defects,
primarily face and neck cysts in 2% to 3% of cases. (17)
As well as assessment of maternal thyroid function and
maternal TRAb levels, if the third-trimester TRAb is posi-
tive, ultrasound assessment of fetal growth, activity, heart
rate, and the fetal thyroid gland can aid management for
both the mother and fetus.
Vol. 18 No. 7 JULY 2017 e423
 CLINICAL FEATURES OF FETAL THYROTOXICOSIS
In pregnancies affected by maternal thyrotoxicosis, both
stillbirths and preterm births are increased.
Other features include:
• Goiter. This has a diffuse Doppler signal through-
out the gland. (This compares with signaling in the
periphery in a hypothyroid fetus).
• Tachycardia and dysrhythmias
• Hydrops
• Abnormally increased activity
• Premature bone ossification
• Oligohydramnios
• Intrauterine growth restriction
The diagnosis of fetal hyperthyroidism is usually made
on clinical grounds, from the maternal history, TRAb level,
and fetal ultrasonography. Cordocentesis to determine fetal
thyroid function is associated with morbidity and mortality
in the fetus. It is usually reserved for the rare circumstance
in which a fetal goiter is present and the mother is taking
ATDs, to determine if the fetus is hyper- or hypothyroid. (20)
Treatment of the thyrotoxic fetus is the administration of
ATDs to the mother at the lowest dose that normalizes the
fetal heart rate.
MANAGEMENT FOR INFANTS BORN TO MOTHERS
WITH A HISTORY OF THYROTOXICOSIS
Thyrotoxicosis should be anticipated in high-risk infants,
that is, those whose mothers have high TRAb levels in the
third trimester or who have been clinically thyrotoxic or
receiving ATDs in the third trimester, or if there was
evidence that the fetus was affected. If the TRAb has not
been measured, the infant should be considered at high
risk.
If there is a family history of a TSH receptor mutation,
the infant will be at high risk for thyrotoxicosis (50%).
Infants at high risk of being missed are those of hypo-
thyroid mothers with a past history of thyrotoxicosis, par-
ticularly if the mother has been treated with radioiodine or
thyroidectomy, because she may still have high levels of
TRAb that can cross the placenta and affect the infant’s
thyroid function. (3)
A suggested management plan for infants born to moth-
ers with Graves disease or a positive family history of TSHR
mutation is depicted in Fig 1.
If the TRAb is negative, the mother has been euthyroid,
and ATDs have not been used during pregnancy, the infant
does not require formal biochemical follow-up unless there
are symptoms or signs of thyrotoxicosis.
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If the maternal TRAb is unknown, the infant should be
treated as if the TRAb was positive.
If the TRAb in the mother is positive, cord blood spec-
imen should be examined for TRAb and TSH. Although
cord blood TSH and f T4 reflect fetal thyroid function and do
not necessarily predict neonatal thyroid function, (21) a
suppressed TSH suggests that the fetus has been thyrotoxic.
In this circumstance, the infant needs close monitoring.
Although a negative TRAb would negate any further
biochemical investigation (unless clinically indicated),
the turnaround time may be too long to be helpful in
the management in the first few days after birth.
The infant’s thyroid function (TSH and f T4) should be
measured at intervals commensurate with the TRAb level
(either cord blood [if rapidly available] or third-trimester
maternal TRAb). If the TRAb is greater than 3 times the upper
limit of the normal range, it is recommended that the infant be
kept under close review for the first few days after birth, paying
particular attention to the heart rate and blood pressure.
Thyroid function should be measured on days 3 to 5 and
again on days 10 to 14, or when clinically hyperthyroid. (22)(23)
The results of the thyroid function tests need to be
compared with the normal value for day of age because
thyroid function changes dramatically in the first few days
after birth. Briefly, immediately after delivery, TSH surges to
about 70 mU/L, peaking at 30 minutes of age. This usually
falls to normal levels by 3 to 5 days of age. There is a two- to
sixfold increase in f T4 and free triiodothyronine (f T3) levels,
which peak at 2 to 3 days of age and remain elevated for
several weeks. (24) Hence an infant is normally in a rela-
tively hyperthyroid state after delivery.
CLINICAL FEATURES OF THYROTOXICOSIS IN
THE NEONATE
Symptoms and signs may be present at birth, but more
typically are delayed for several days, particularly if the
mother was taking ATDs at the time of delivery, because
ATDs are more rapidly cleared from the infant’s circulation
than TRAb. Although symptoms and signs are usually
apparent by day 10, they may be delayed for 1 to 2 months
after delivery when coexisting higher affinity blocking anti-
bodies are cleared from the circulation and stimulating
antibodies predominate. (25)
Infants may have subclinical biochemical thyrotoxicosis.
It is unclear as to whether this should be treated. Mild, short-
lived biochemical thyrotoxicosis probably can be followed
biochemically and clinically. The author’s practice is to treat
with ATDs if the TSH level is suppressed and f T4 is more
Figure 1. Management of the infant at risk for neonatal thyrotoxicosis. ATD¼antithyroid drug; f T3¼free triiodothyronine; f T4¼free thyroxine; TRAb¼
thyrotropin receptor antibody; TSH¼thyroid-stimulating hormone; TSHR¼thyrotropin receptor gene.

than 2 times the upper limit of the normal level for day of
age, or persists beyond the first 2 weeks after birth.
Symptoms and signs include (Fig 2):
• Small for gestational age (or evidence of intrauterine
growth restriction—weight may be within normal range)
• Preterm birth
• Goiter
• Central nervous system signs, including irritability
and restlessness
• Eye signs, including lid retraction, periorbital edema,
and proptosis (which can occur even in the absence of
maternal eye signs)
• Cardiovascular signs, including tachycardia, which
may progress to tachyarrhythmia and cardiac failure
• Systemic and pulmonary hypertension
• Hypermetabolism presenting as flushing and sweat-
ing, avid feeding, diarrhea, excess weight loss, and
failure to thrive
• Hepatosplenomegaly
• Lymphadenopathy
• Thrombocytopenia, coagulopathy
• Craniosynostosis and advanced bone age
• Microcephaly
• Frontal bossing
• Jaundice and liver disease
The infant of a thyrotoxic mother may also be at risk for
hypothyroidism. This might be caused by the transplacental
passage of maternal thionamides or even thyroid-blocking
immunoglobulin. Central hypothyroidism may also be seen.
The mechanism of the latter is thought to be excessive
thyroxine from an untreated or undertreated mother caus-
ing suppression of the hypothalamic-pituitary-thyroid axis
in the fetus. Both primary and central hypothyroidism are
usually transient, but require monitoring and treating with
thyroxine if they persist (Fig 3). Central hypothyroidism
may be permanent in some infants. (26) Hypothyroidism
may be followed by hyperthyroidism after clearance from
the circulation of ATDs or blocking antibodies but with
persistence of TSI. In addition, central hypothyroidism has
been described after thyrotoxicosis. Hence, surveillance
should be continued until the infant is stably euthyroid.
TREATMENT OF THE THYROTOXIC NEONATE (FIG 3)
The main treatment is with a thionamide, either carbima-
zole (750 mg/kg per day—single daily dose until euthyroid,

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 Figure 2. Infant with neonatal thyrotoxicosis. Reprinted with permission from the New England Journal of Medicine.

then gradually reducing to a maintenance dose of 30% to
60% of the initial dose) or propylthiouracil (2.5–5 mg/kg
twice daily until euthyroid, then gradually reducing to a
maintenance dose of 30% to 60% of the initial dose). Both
block the synthesis but not the release of thyroid hormones;
so a response may not be seen until the thyroid hormone
store in the colloid is depleted. Propylthiouracil also
blocks the peripheral conversion of T4 to T3, but because
of the risk of hepatic failure, carbimazole (methimazole)
would be the preferred drug. Carbimazole also has the
advantage of a once-daily dose, but there is a risk of
agranulocytosis.
Iodine suppresses thyroid hormone synthesis and has a
prompt effect on blocking the release of thyroid hormones.

Figure 3. Management of abnormal thyroid function test results. ATD¼antithyroid drug; f T3¼free triiodothyronine; f T4¼free thyroxine; T3¼
triiodothyronine; TRAb¼thyrotropin receptor antibody; TSH¼thyroid-stimulating hormone; TSHR¼thyrotropin receptor gene.

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It is recommended in a very thyrotoxic infant (ie, one with
significant cardiovascular and/or hypermetabolic signs).
Either saturated potassium iodide (48 mg/drop, 1 drop/
day) or Lugol solution (5% potassium iodide, 8 mg/drop, 1–3
drops/day) may be used.
b-blockers (propranolol 250–500 mg every 8 hours) are
effective at controlling the symptoms caused by adrenergic
stimulation. The side effects of hypoglycemia, bradycardia,
and hypotension need to be monitored. The goal is to reduce
the heart rate to safe levels. Diuretics and treatment for heart
failure may be required.
The severely thyrotoxic infant may be treated with cor-
ticosteroids (prednisolone 2 mg/kg per day), which sup-
presses the deiodination of T4 to T3 and compensates for
the hypermetabolism of endogenous steroids by the exces-
sive levels of thyroid hormones.
Infants receiving treatment require regular monitoring
(biweekly to start with, reducing to weekly, then alternate
weeks once stable) of thyroid function to ensure accurate
treatment and prompt reduction, followed by discontinua-
tion of the ATD once TRAb is cleared from the circulation to
prevent iatrogenic hypothyroidism.
T3 tends to be disproportionally more elevated than T4 in
cases of thyrotoxicosis caused by direct thyroid activity;
therefore, T3 measurements (if available) can aid accurate
adjustments in ATDs. (15)
DURATION OF NEONATAL THYROTOXICOSIS
Thyrotoxicosis in infants of mothers with Graves disease
resolves with the clearance of TRAb from the infant’s
circulation. This generally takes 3 to 12 weeks, but may be
more than 36 months. (25)
Infants who are thyrotoxic because of an activating
mutation of the TSH receptor or activating mutations of
stimulatory G protein in McCune-Albright syndrome will
have permanent thyrotoxicosis and will require long-term
medical treatment, definitive surgical treatment (thyroidec-
tomy), or radioiodine therapy (when older).
Individuals with thyroid hormone resistance may have a
relapsing and remitting course, hence long-term treatment
may not be required.
BREASTFEEDING IN INFANTS OF MOTHERS
RECEIVING ATDs
Both propylthiouracil and carbimazole (methimazole) may
be detected in human milk. Propylthiouracil is highly pro-
tein bound, and therefore is at a lower concentration in the
milk compared with methimazole. Thyroid function and
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later neurodevelopment remain normal with maximal daily
doses of 20 mg methimazole or 450 mg propylthiouracil,
and therefore breastfeeding is regarded as safe with mater-
nal ATD use at or below these doses. (27)(28)(29)
PROGNOSIS
Normalization of thyroid function is usually rapid after
initiation of therapy in thyrotoxic infants.
There are few data on long-term outcomes. Frontal bossing,
craniosynostosis, growth retardation, hyperactivity, and devel-
opmental and behavioral problems have been described, (30)
(31) but it is unclear whether there is a relationship between
sequelae and adequacy of treatment. Historically, mortality has
been reported to be as high as 25%. It is therefore essential that
high-risk infants are kept under close review.
SUMMARY
Neonatal thyrotoxicosis is rare and usually caused by trans-
placental passage of TSI, with disease most likely with high
antibody levels. Thyrotoxicosis should be anticipated in
high-risk infants with careful clinical and biochemical sur-
veillance. In all but the mildest cases of biochemical thyro-
toxicosis, treatment with ATDs should be instigated. Thyroid
function should be closely monitored with discontinuation of
treatment, with clearance of TRAb from the infant’s circula-
tion. The mortality is high in untreated infants.
Infants of mothers with Graves disease may be hypothyroid.
This may be followed by or preceded by hyperthyroidism and
may require treatment with thyroxine. Thyroid function needs
to be monitored until the infant is stably euthyroid.
Infants who are thyrotoxic because of activating mutations
of the TSH receptor or activating mutations of stimulatory G
protein in McCune-Albright syndrome will have permanent
thyrotoxicosis and will require long-term treatment.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the proper use of laboratory tests (including screening
tests) in the diagnosis of thyroid dysfunction.
• Identify the etiology, clinical manifestations, laboratory features,
and management of neonatal thyrotoxicosis.
• Recognize drugs that, when taken by a nursing mother, are clearly
known to present health risks to her breastfeeding infant, and
know the factors that modify these.
Vol. 18 No. 7 JULY 2017 e427
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1. A newborn infant is noted to have tachycardia and abnormally increased activity. He is NOTE: Learners can take
diagnosed with neonatal thyrotoxicosis. Which of the following is the most common cause NeoReviews quizzes and
of neonatal thyrotoxicosis? claim credit online only
A. Gain-of-function mutations in the thyrotropin receptor gene. at: http://Neoreviews.org.
B. Birth to a mother with autoimmune thyroid disease.
C. Activating mutations of stimulatory G protein in McCune-Albright syndrome. To successfully complete
D. Thyroid hormone resistance due to a mutation in the thyroid hormone receptor 2017 NeoReviews articles
b gene. for AMA PRA Category 1
E. Iodine application for wound care. CreditTM, learners must
2. A pregnant woman with Graves disease delivers a female infant at 40 weeks’ gestational demonstrate a minimum
age. The infant appears well and appears to have normal tone and activity. Which of performance level of 60%
the following statements regarding offspring of women with Graves disease is or higher on this
correct? assessment, which
A. Approximately 50% of infants will have clinical symptoms of thyrotoxicosis visible measures achievement of
in the first 10 minutes after birth. the educational purpose
B. There is no relationship between the level of thyroid receptor antibody in the third and/or objectives of this
trimester and the risk of neonatal thyrotoxicosis. activity. If you score less
C. If the woman is treated with surgery or radioiodine for Graves disease, there will be than 60% on the
no thyroid antibodies in the maternal or fetal circulation. assessment, you will be
D. More than 90% of infants born at term to mothers with Graves disease may have given additional
subclinical thyrotoxicosis with free thyroxine levels above the 95th percentile, opportunities to answer
peaking on day 5 after delivery. questions until an overall
E. The most accurate measurement of the potential for thyroid-stimulating activity 60% or greater score is
from the mother by transplacental passage to the fetus is free thyroxine level. achieved.
3. A pregnant woman has Graves disease and is being followed for prenatal care. Laboratory
evaluation reveals elevated free thyroxine level. Which of the following describes This journal-based CME
appropriate management for this patient? activity is available
A. The aim of maternal treatment will be to maintain the free thyroxine level at the low through Dec. 31, 2019,
range of normal. however, credit will be
B. Regardless of follow-up laboratory testing, antithyroid drugs should be adminis- recorded in the year in
tered at least until 2 days after delivery. which the learner
C. Both methimazole and carbimazole have been determined to be nonteratogenic completes the quiz.
and safe at therapeutic doses during pregnancy and lactation.
D. The dosing of antithyroid therapy in pregnant women should be guided by fetal
sampling of serum thyroid function tests every 2 to 3 weeks.
E. Propylthiouracil is the preferred drug in the first trimester, but it has been asso-
ciated with minor birth defects, primarily face and neck cysts.
4. A mother has been clinically thyrotoxic and has been receiving pharmacologic therapy
during pregnancy. The infant is delivered by cesarean section at 40 weeks’ gestational age
because of breech presentation. Which of the following steps are appropriate for the
management of this infant?
A. If the maternal thyrotropin receptor antibody has been negative, neonatal
treatment with iodine should begin within the first hour while awaiting laboratory
tests.
B. Cord blood specimen should be sent to test for free thyroxine as the main tool for
evaluation of neonatal thyroid status.
C. Regardless of the maternal history, thyroid function studies should only be ob-
tained if the infant displays symptoms of thyrotoxicosis, such as dysrhythmia or
poor feeding.

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 D. If the infant’s thyrotropin receptor antibody is greater than 3 times the upper limit
of normal range, it is recommended that the infant be kept under close observation
for the first few days after birth, paying particular attention to the heart rate and
blood pressure.
E. To prevent false-positive results, laboratory testing in the infant should be delayed
for 1 to 2 weeks, because serum levels of antibodies and thyroid function will
primarily reflect placental passage of maternal hormones and antibodies.
5. A mother with Graves disease has been receiving medications during pregnancy for her
condition. After delivery, the infant is determined to be asymptomatic. The mother is
hoping to breastfeed. Which of the following statements is correct regarding this situation?
A. Both propylthiouracil and methimazole may be detected in human milk.
B. Compared with propylthiouracil, methimazole is highly protein bound.
C. Breastfeeding is contraindicated if the infant is asymptomatic.
D. An appropriate dose of propylthiouracil to ensure safety for the mother and infant
is 900 mg.
E. If the infant is using methimazole at doses above 5 mg, the mother should “pump
and dump” until she is off the medication for at least 1 week.

e430 NeoReviews
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 Neonatal Thyrotoxicosis
Amanda L. Ogilvy-Stuart
NeoReviews 2017;18;e422
DOI: 10.1542/neo.18-7-e422

Updated Information & including high resolution figures, can be found at:
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References This article cites 31 articles, 6 of which you can access for free at:
http://neoreviews.aappublications.org/content/18/7/e422#BIBL
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 Neonatal Thyrotoxicosis
Amanda L. Ogilvy-Stuart
NeoReviews 2017;18;e422
DOI: 10.1542/neo.18-7-e422

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/18/7/e422

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