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48]

Review Article

Congenital Hypothyroidism: Screening, Diagnosis, Management, and

Outcome
Noman Ahmad, Asra Irfan, Saad Abdullah Al Saedi

King Faisal Specialist Congenital hypothyroidism (CH) is one of the most common causes of preventable

Abstract
Hospital and Research
Centre, Jeddah, Saudi Arabia
mental retardation. Thyroid hormone has an essential role in the brain development
during the first 2–3 years of life. Incidence of CH is 1:3000–1:4000 live births, but
there is evidence that its incidence is increasing. Majority of newborn babies do
not exhibit obvious clinical signs and symptoms until the age of 3  months due
to either some residual thyroid function or transplacental passage of maternal
thyroid hormone. Common clinical symptoms include lethargy, sleepiness, poor
feeding, constipation, and prolonged jaundice. Other common findings on clinical
examination include macroglossia, large fontanels, umbilical hernia, and hypotonia.
Neonatal screening for CH is practiced in the developed countries for the last three
decades, and various studies show that normal cognitive function is attainable
with early detection and treatment. This review discusses different protocols being
used for screening. It highlights recent recommendation of screening and retesting
cutoffs. Thyroid imaging can help in differentiating underlying etiology, either
thyroid dysgenesis or dyshormonogenesis. Treatment with levothyroxine  (L‑T4)
10–15  mcg/kg should be started immediately after diagnosis without delaying for
imaging purposes. Frequent and vigilant monitoring with L‑T4 dose adjustment
is mandatory in infancy and childhood to achieve normal physical growth and
neurodevelopment. Children with CH are followed by different pediatric specialties
including general pediatricians, neonatologists, developmental pediatricians, and
endocrinologists and in primary care; therefore, it is essential to increase the
awareness of monitoring protocols among all physicians.
Keywords: Dyshormonogenesis, newborn screening, thyroid dysgenesis, thyroid
scintigraphy

Introduction various studies show that normal cognitive function

C ongenital hypothyroidism  (CH) is one of the
most common causes of preventable mental
retardation. Thyroid hormone has an essential role
in the brain development during the first 2–3  years
of life.[1,2] Majority of newborn babies do not exhibit
obvious clinical signs and symptoms until the age
of 3  months due to either some residual thyroid
function or transplacental passage of maternal thyroid
hormone.[3] Clinical features [Table 1] become evident
if diagnosis is missed or treatment is delayed or
suboptimal. Neonatal screening for CH is practiced in
the developed countries for the last three decades, and
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is attainable with early detection and treatment.[4]
Children with CH are followed by different pediatric
specialties including general pediatricians,
neonatologists, developmental pediatricians, and
endocrinologists and in primary care; therefore, it
is essential to increase the awareness of monitoring
protocols among the physicians.
Address for correspondence: Dr. Noman Ahmad,
King Faisal Specialist Hospital and Research Centre,
Jeddah, Saudi Arabia.
E‑mail: anoman@kfshrc.edu.sa
This is an open access article distributed under the terms of the Creative Commons
Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak,
and build upon the work non-commercially, as long as the author is credited and the new
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For reprints contact: reprints@medknow.com

DOI: How to cite this article: Ahmad N, Irfan A, Al Saedi SA. Congenital
10.4103/jcn.JCN_5_17 hypothyroidism: Screening, diagnosis, management, and outcome.
J Clin Neonatol 2017;6:64-70.

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Ahmad, et al.: Congenital hypothyroidism screening
Epidemiology
The incidence of CH has significantly increased after
the initiation of newborn screening  (NBS) programs.
Before NBS, the incidence of CH was approximately
1:7000–1:10,000 live births usually diagnosed based
on the appearance of clinical manifestations.[5] The
incidence of CH reported after the introduction of NBS
has been 1:3000–1:4000 live births.[6] This increase
in incidence is probably explained by early detection
of cases, including the diagnosis of mild and transient
cases.[7] There is doubling of incidence reported from the
United States in 2007, increasing from 1:3985  (1987)
to 1:2273  (2002) and 1:1415  (2005).[8] The rise in
incidence could not be attributed solely to one reason,
but it is accounted by the change in demographics, such
as rise in Hispanic and Asian births, increase in preterm
and twin births, infants born to advanced age mothers,
and lower cutoff values on screening tests. A  similar
rise in incidence is reported from New  Zealand in 2010
associated with two‑fold increase in Asian births.[9]
CH is classified into two main types: transient and
permanent types.[10] Permanent CH requires lifelong
monitoring and treatment, whereas transient CH
shows normal thyroid hormone production after first
few months of life. Transient CH can be secondary
to maternal antithyroid medications, endemic iodine
deficiency, or iodine excess.
Permanent CH is mainly due to primary hypothyroidism
presented with elevated thyroid‑stimulating hormone
(TSH) levels. Secondary or central hypothyroidism is
very rare (incidence of 1:25,000) which may present with
isolated TSH deficiency or as a part of panhypopituitarism.
Primary CH cases are 80% due to thyroid dysgenesis
and 20% due to thyroid dyshormonogenesis. Isolated
thyroid dysgenesis is generally sporadic, but thyroid
dyshormonogenesis is associated with hormone synthesis
protein genes mutations.[11]
Table 1: Clinical features of congenital hypothyroidism
History
“Good baby”
Prolong sleeping time
Not awakening for feed
Slow feeding
Examination
Course facial features
Macroglossia
Wide fontanels
Easily palpable sutures
Umbilical hernia
Prolong jaundice
Dry skin
Journal of Clinical Neonatology  ¦  Volume 6  ¦  Issue 2  ¦  April-June 2017
Newborn Screening
The first pilot program for NBS for CH was started in
Quebec, Canada, in 1972.[12] New  York State made it
mandatory in 1978, and currently, it is a routine practice
in developed countries.[13] NBS brought a revolutionary
advancement in the preventive medicine and showed
promising result in preventing the cognitive dysfunction
secondary to CH; however, unfortunately, 71% of babies
currently born worldwide are in those areas where there
is no established NBS program.[14]
Saudi Arabia is one of the countries where incidence
of CH is relatively higher 1:2500.[15] The Ministry of
Health established a national screening program in
1989.[16] The majority of babies in the Kingdom are
born in hospital, but most of the mothers and babies
are discharged within 24  h of delivery. Advisory
committee for CH screening agreed to measure
TSH in cord blood as a primary screening test. TSH
concentration >60 mU/L is considered highly suspicious
for CH and advised for infant examination and repeat
testing. Cord blood TSH 30–60 mU/L initiates testing of
T4 in same sample; if T4 level is  <80 nmol/L, infant is
recalled for examination and testing. We did not find any
specific recommendation for cord TSH 30–60 mU/L and
T4 >80 nmol/L; we suggest repeat testing and follow‑up
with primary pediatrician. Cord blood TSH <30 mU/L is
considered as normal.[16,17]
Three major strategies for NBS [Table 2] are in practice
worldwide.[14] The majority of babies with CH would
be detected and later diagnosed with anyone of these
strategies. Measuring T4 with follow‑up TSH would
detect central/secondary CH and also late rise of TSH
in cases of primary CH. Initial TSH measurement
would not detect central/secondary CH but would detect
primary CH and also subclinical, mild, and transient
cases of primary CH.[10] NBS strategies changed in the
last three decades. In 1990, majority of US programs
used initial T4 with follow‑up TSH measurement,
and currently  (2010), majority is using initial TSH
measurement and some are measuring T4 and TSH
simultaneously.[14] Changes in screening program
strategy resulted in increased incidence of CH.[8] The
most sensitive screening test for primary hypothyroidism
is initial measurement of TSH. Sample can be collected
Table 2: Newborn screening strategies
Initial blood T4 assay, with follow‑up TSH assay if the blood
T4 value is below a certain concentration (usually less than the
10th percentile)
Initial blood TSH assay
Simultaneous T4 and TSH assay
TSH – Thyroid‑stimulating hormone; T4 – Thyroxin
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Ahmad, et al.: Congenital hypothyroidism screening
from cord blood or after the age of 24  h, but best
window period is 48–72  h.[11] Blood sample is usually
collected by heel prick, spotted on filter paper, then
dried, and send for TSH analysis.
Second screening is recommended for certain group
of babies; sick babies may have TSH suppression
due to effect of drugs such as steroids, dopamine,
and iodine[18] or because of hypothalamic–pituitary
immaturity.[19] Fetal blood mixing in multiple pregnancies
can mask TSH level.[20] The European Society for
Pediatric endocrinology  (ESPE) guidelines  (2014)
advised repeat screening in preterm neonates with
gestational age  <37  weeks, low birth weight and very
low birth weight neonates, ill neonates admitted to
the Neonatal Intensive Care Unit, multiple births, and
in babies whom sample is collected in first 24  h. The
second screening sample should be collected at 2 weeks
of age or after 2 weeks of first sample.[11] All specimens’
results should be considered to interpret the result of
screening.
There is large variability in defining the cutoff values
between the NBS programs. This largely depends
on timings of sample collection to define cutoffs.
Specimen collected in the first 24  h may have TSH
cutoff of  >60 mU/L, whereas sample taken at 72  h has
a cutoff of  >15 mU/L.[21] Most of programs use the
cutoff value of 20 mU/L of whole blood on dried blood
spot  (DBS).[14] The ESPE guidelines 2014 have given
following advice.[11]
• TSH  ≥40 mU/L of whole blood on DBS; start
treatment immediately
• TSH  <40 mU/L of whole blood treatment can be
postponed for 1–2 days to get venous sample result
• TSH >20 mU/L on venous sample requires treatment,
irrespective of FT4 levels
• Low serum FT4 regardless of TSH level should be
treated immediately
• TSH of 6–20 mU/L on venous sample with normal
FT4 is a gray area; if TSH level remains high for
3–4  weeks or imaging results are suggestive of
thyroid dysgenesis, treatment should be started
immediately.
Radiological Workup
The imaging modalities such as ultrasound and
scintigraphy can help in defining the etiology of CH and
also predict whether it is transient or permanent type of
CH. Transient CH requires a reassessment with cessation
of therapy with thyroxin treatment at the age of 3 years.
Infants with elevated TSH on NBS should have both
ultrasound and scintigraphy; treatment should not be
delayed to perform the imaging. The scintigraphy after
66 Journal of Clinical Neonatology ¦ Volume 6 ¦ Issue 2 ¦ April-June 2017
the initiation of treatment may give false negative result
due to suppressed TSH level and poor tracer uptake. The
optimal results of scintigraphy can be achieved when it
is done within 7–10  days of treatment.[11,22] Combined
ultrasound and scintigraphy can give correct diagnosis
in 80% of CH patients presenting with elevated TSH.[18]
The technetium‑99m  (99mTc) or iodine‑123  (123I) can be
used to carry out scintigraphy. 123I is specifically taken
up by the thyroid gland and gives better scan than
99m
Tc.[23] Babies should be fed before scanning to empty
salivary glands; otherwise, tracer uptake in the salivary
glands can give false interpretation.[11] TSH levels
measured at time of scan would help in interpreting
the results.[18] Eutopic glands may not have tracer
uptake if TSH is suppressed due to thyroxin treatment,
excess iodine intake, maternal TSH receptor‑blocking
antibodies, inactivating mutations in TSH receptor, and
the sodium‑iodide symporter.[24,25]
The ultrasound imaging can investigate the absence
or presence of thyroid gland; it may also suggest size,
texture, and structure. This modality is, unfortunately,
highly observer dependent and not very sensitive in
detecting ectopic (lingual and sublingual) thyroid gland.[26]
Ami De Silva defined five major categories of scintigram
findings in babies with primary CH;  (1) normal site,
normal uptake,  (2) normal site, increased uptake,
(3) normal site, decreased uptake,  (4) no uptake,
and  (5) ectopic uptake [Figure  1].[27] Highest predictive
value  (100%) is seen in ectopic gland for permanent
primary hypothyroidism. The scintigram uptake can help
in diagnosing the underlying etiology of CH. Majority
of primary CH cases are sporadic and secondary to
thyroid dysgenesis, but small percentage is due to
dyshormonogenesis; therefore, prediction of underlying
cause would suggest genetic testing and counseling.
Figure  1: The technetium‑99m or iodine  ‑  scintigraphy findings in
congenital hypothyroidism
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Ahmad, et al.: Congenital hypothyroidism screening
Long bones epiphysis X‑ray gives an indication for the
severity of CH. Absent epiphysis on X‑ray is associated
with significant in utero compromise due to severe
CH [Figure 2].[10]
Genetic Mutation Analysis
A careful family history and thyroid morphology on
imaging may indicate genetic mutation and risk of
recurrence. Each family with a baby born with primary
CH deserves genetic counseling from an expert and
specially those who have goiter or abnormal thyroid
morphology suggestive of dyshormonogenesis. Thyroid
dyshormonogenesis gene mutations are autosomal
recessive in inheritance; these include SCL5A5/NIS iodide
transporter defect, SCL26A4/PDS pendrin  (Pendred
syndrome), thyroglobulin, thyroid peroxidase, dual
oxidase 2 (DUOX2), and iodotyrosine deiodinase.[28]
There is some evidence that sporadic thyroid dysgenesis
resulting in primary CH may also have a genetic
basis. The observations suggesting this association
are  >15  times higher rate of familial cases than by
chance alone; minor morphological abnormalities in
euthyroid first‑degree relatives and increase incidence of
extrathyroidal malformations.[29,30]
Treatment
The prevention of mental and growth retardation
associated with CH is only possible with prompt
treatment and vigilant monitoring throughout childhood
and adolescence. The treatment should be commenced
immediately after confirmation of diagnosis based on
NBS or follow‑up blood test. The initiation of treatment
within first 2  weeks of life is crucial for the normal
neurodevelopment.[31]
Dosing
Levothyroxine  (L‑T4) is the only recommended
treatment for replacement therapy. Triiodothyronine (T3)
is biologically active hormone but it is efficiently
formed by endogenous deiodination of L‑T4. The
treatment with combination of L‑T4 and T3 has not
shown any extra benefit than treatment with L‑T4 alone
in terms of neurodevelopment.[32,33] L‑T4‑recommended
dose is 10–15  µg/kg/day as a single dose. High dose
can be started in severe cases of CH, defined by very
low FT4 (<5 pmol/L), and delayed bone age. The lower
dose can be given in mild  (FT4  5–10 pmol/L) and
moderate (FT4 10–15 pmol/L) cases.[11]
Administration
The L‑T4 is available in tablet form worldwide and is
recommended to be used in tablet form by crushing
Journal of Clinical Neonatology  ¦  Volume 6  ¦  Issue 2  ¦  April-June 2017
Figure 2: The left lower extremity of two infants; absent distal femoral
epiphysis on left while in the normal infant on the right the distal femoral
epiphysis is present
and mixing in few milliliters of water or breast milk
immediately before administration. Suspensions prepared
by pharmacies are unreliable in dosing.[10] The L‑T4 is
available in liquid form in Europe which is produced
pharmaceutically and licensed for use. This liquid form
is reliable in dosing and convenient for infants.[34,35]
Oral forms can be given either before feeding or with
food; bioavailability can be influenced by the presence of
some food or minerals.[11] Food and drugs which interfere
with absorption are soy protein formulas, concentrated
iron, calcium, aluminum hydroxide, cholestyramine and
other resins, fiber supplements, and sucralfate.[10]
Monitoring
Normalization of TSH within the first 2  weeks and
maintaining FT4 in the upper half of normal range
results in better intellectual outcome.[36] Treatment
should be monitored and adjusted by measuring
TSH and FT4 serum or plasma concentrations.
ESPE consensus guidelines[11] recommended frequent
monitoring in infancy and childhood for TSH and
FT4  [Table  3]. Monitoring may be performed more
frequent if results are abnormal or there are concerns
regarding compliance. Changes in dose or formulation
of L‑T4 should be followed with laboratory evaluation
after 4–6 weeks.
The reevaluation may be considered in those patients
who do not have definite diagnosis in the neonatal
period. The central nervous system myelination is
completed by the age of 36–40  months;[37] therefore, it
would be safe to do reevaluation at the age of 3  years
when children are also more cooperative for imaging
of thyroid gland. Reevaluation is not necessary in those
who have definite diagnosis of thyroid agenesis, ectopic
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Ahmad, et al.: Congenital hypothyroidism screening
thyroid, and dyshormonogenesis with DUOX2 mutation
or Pandered syndrome. The rising TSH with age due
to insufficient dose or poor compliance also rules out
the need of reassessment. The L‑T4 therapy should be
discontinued for 4–6 weeks, followed with measurement
of TSH and FT4, and if biochemical profile confirms
hypothyroidism, repeat thyroid imaging will be
performed.[11]
Intellectual Disability and
Neurodevelopmental Outcome
The early detection and appropriate treatment of CH is
associated with normal neurodevelopment. Universal
NBS in developed countries has shown disappearance of
intellectual disability  (IQ  <70) in treated patients with
CH.[4] Children with CH should have regular monitoring
of psychomotor and language development. School
progress needs to be monitored and recorded.[11]
The earlier data estimated that 35%–40% cases
diagnosed clinically before the introduction of NBS
experienced overt disability.[38,39] The analysis of
current data suggests that it is more reasonable to
conclude that approximately 25% children born with
clinically diagnosed CH  (1 in 25000 births) may have
experienced overt disability before introduction of NBS.
Despite an overestimation of intellectual disability,
studies with long‑term follow‑up have proven excellent
neurodevelopmental outcome in children with CH
diagnosed and treated soon after birth.[40‑42]
Children born with mild CH are treated routinely, but
there is lack of good evidence that treatment affects
long‑term neurodevelopment.[4] The long‑term studied
cohorts who were screened for CH suggest that children
with severe CH based on very low FT4 at diagnosis and
delayed bone maturation are at risk to have lower IQ.[43,44]
However, rapid normalization of TSH and FT4 in upper
normal range, vigilant monitoring with appropriate dose
adjustment would result in normal intelligence.
Conclusion
The NBS program is a major success to prevent
CH‑related neurodisability. The majority of cases
can be diagnosed by any of NBS strategies  [Table  2].
Table 3: Monitoring recommendation in infancy and
childhood
First test after 1‑2 weeks after initiation of therapy
Every 2 weeks till TSH completely normalized
Every 1‑3 months till the age of 12 months
Every 2‑4 months between ages of 1‑3 years
Every 3‑12 months till growth is completed
TSH – Thyroid‑stimulating hormone
68 Journal of Clinical Neonatology ¦ Volume 6 ¦ Issue 2 ¦ April-June 2017
Immediate treatment is necessary after establishing
the diagnosis. Frequent monitoring can avoid over‑  or
under‑treatment. TSH is a highly sensitive test but
needs further studies to define the cutoff and to avoid
false positive cases. Further studies are also needed to
identify transient cases. Families and caregivers need
detailed counseling about diagnosis, drug administration
method, compliance, and consequences of poor
treatment.
Practical points
• Start treatment with L‑T4  10‑15  mcg/kg single daily
dose without any delay
• Only pharmaceutically produced liquid formulation
should be used if available
• Maintain TSH in age‑specific range with FT4 in high
normal range
• Treatment should not be delayed for imaging
purposes
• Screening should be repeated in preterm, low birth
weight, multiple birth, and sick babies requiring
NICU admission
• Reevaluate TSH and FT4 in 4–6  weeks if change of
dose is required
• There is no evidence for combination therapy of LT3
and LT4
• There is no evidence for treating mildly elevated
TSH with normal FT4
• Off therapy trial should be considered after the age
of 3 years.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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70 Journal of Clinical Neonatology ¦ Volume 6 ¦ Issue 2 ¦ April-June 2017