PAGE 375

2020 July; 26(3): 375-380

p-ISSN 0854-4263 e-ISSN 2477-4685
Available at www.indonesianjournalofclinicalpathology.org

Congenital Hypothyroidism: Incidence, Etiology and Laboratory

Screening

Liong Boy Kurniawan

Department of Clinical Pathology, Faculty of Medicine, Hasanuddin University/Dr. Wahidin Sudirohusodo, Makassar, Indonesia. E-mail:
liongboykurniawan@yahoo.com

ABSTRACT

Congenital hypothyroidism is a condition resulting from a deficiency of thyroid hormone in newborns. Congenital
hypothyroidism has no specific signs and symptoms at birth. It may lead to severe mental retardation and growth, and
developmental disorders. Therefore, it is essential to perform newborn laboratory screening tests for prompt diagnosis and
treatment to minimize the sequels. Laboratory screening tests are performed by taking prick blood from the heel of newborn
and testing either TSH or T4 or both of them. Currently, the congenital hypothyroidism screening is not mandatory in
Indonesia, but some multicentered screening programs have been performed. In Indonesia, a TSH level above 20 µU/mL is
used as a cutoff that needs a confirmatory test using serum samples to confirm congenital hypothyroidism diagnosis. Once
the diagnosis is established, prompt treatment and laboratory monitoring are needed for a better outcome.

Keywords: Congenital hypothyroidism, laboratory, screening

INTRODUCTION and will cause a disturbance in brain development.

Due to this, it is urgent and important to screen,
Hypothyroidism term refers to an endocrine diagnose CH, and begin CH treatment immediately
disorder resulting from the lack or deficiency of after birth. The best way to prevent late-diagnosis of
thyroid hormone (thyroxin) and effecting peripheral CH is by performing large population screening in
tissues.1 Congenital Hypothyroidism (CH) can be newborns.4
simply defined as deficiency of thyroid hormone
present at birth.2 Congenital hypothyroidism is a Epidemiology
common term for deficiency of thyroid hormone due
to dysfunction of the thyroid gland or abnormality in Before the era of newborn screening programs
thyroid gland morphology which develops during started, the occurrence of CH was diagnosed based
the fetal or perinatal stage.3 It is one of the most on delayed clinical findings between 1:7,000 to
common conditions in neonates which may lead to 1:10,000.5 Following the time of large population
mental retardation. It is preventable if the diagnosis screening, the incidence was reported to increase
and treatment are not performed in a few weeks after between 1:3,000 to 1:4,000. 6 Unfortunately,
birth. Most of the neonates with CH do not have clear Indonesia still does not have the national data of CH.
hypothyroidism manifestations making the In Indonesia, data of CH could be obtained from
diagnosis a challenge. Infants have some residual Dr.Cipto Mangunkusumo Hospital in Jakarta, and
thyroid hormone that the symptoms and signs of Hasan Sadikin Hospital in Bandung. Through 2000 to
thyroid hormone deficiency are not specific. In the September 2014, there were 85 CH positive
condition of fetal total thyroid hormone deficiency (incidence 1:2,513) from 213,669 newborns that were
due to the absence of production/secretion, thyroid screened, which were higher than the reported
hormone derived from maternal transplacental global incidence (1:3,000). 7 Medical records
passage still provide protection until birth. It is evaluation in Dr.Cipto Mangunkusumo Hospital and
estimated that one-third of thyroxin (T4) from the Hasan Sadikin Hospital showed more than 70% of
mother crosses to the fetus during pregnancy. CH cases were diagnosed at the age older than one
Maternal T4, which has a half-life of six days, will be year with permanent mental deficit state. Only 2.3%
metabolized and excreted at the age of three or four of the cases were diagnosed at the age younger than
weeks. If CH is left untreated within the first few three months, who had minimal growth and
weeks or months, the symptoms will be worsening developmental disorders.7,8

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Indonesian Journal of Clinical Pathology and Medical Laboratory, 2020 July, 26 (3) : 375 - 380 PAGE 376

Etiology iodotyrosine deiodinase.4,9

Secondary or central congenital hypothyroidism
The failure of thyroid gland development (thyroid is commonly caused by isolated Thyroid-Stimulating
dysgenesis) is the main cause of permanent primary Hormone (TSH) deficiency or congenital
congenital hypothyroidism. It occurs sporadically, hypopituitarism (multiple pituitary hormone
contributing around 85% of CH cases. Two-thirds of deficiencies). As for the peripheral congenital
thyroid dysgenesis caused by ectopic thyroid gland hypothyroidism, it can be caused by thyroid hormone
location, with minor cases caused by aplasia or transport defect (monocarboxylate transporter 8),
hypoplastic gland. The exact etiology for most of thyroid hormone metabolic defect (selenocysteine
thyroid dysgenesis cases remain unclear. Some insertion sequence binding protein 2) or thyroid
genetic mutations in genes related to transcription hormone resistance.4
factors that regulate the development of thyroid Transient congenital hypothyroidism may occur
glands such as thyroid transcription factor 2 (TTF-2), in several conditions such as; maternal or neonatal
NKX2, PAX8 may explain these defects. However, excess iodine exposure, maternal or neonatal iodine
only 2% of dysgenesis cases were reported to have deficiency, maternal consumption of antithyroid
these kinds of genetic mutation.4,9 drugs, a maternal antibody which block TSH
Another main cause of permanent primary receptor, THOX2 or DUOXA2 heterozygous
congenital hypothyroidism is thyroid hormone mutations or congenital hepatic hemangioma.4
synthesis/production defect, which is termed as Mothers with Grave's disease who ingest antithyroid
thyroid dyshormogenesis that contributes nearly drugs may inhibit the synthesis of fetal thyroid
15% of the cases. These defects are inherited hormone that can occur from several days to 2 weeks
through autosomal recessive pattern and related to after birth.3 Maternal antithyroid antibodies may
genes mutations that coded the Sodium-Iodine cross through the placenta resulting in the blocking
Symporter (NIS), Thyroid Peroxidase (TPO), of thyroid TSH receptors in neonatal. This situation
hydrogen peroxide generation such as Thyroid can last between three to six months after birth as the
Oxidase (THOX) and Dual Oxidase Maturation maternal antibody levels decline.2 Etiology of
Factors (DUOXA), Thyroglobulin (Tg) and congenital hypothyroidism are shown in Table 1.

Table 1. Etiology of congenital4

Primary CH
Thyroid dysgenesis
Aplasia
Hypoplasia
Ectopic gland
Thyroid dyshormogenesis
Sodium-iodide symporter (trapping) defect
Thyroid peroxidase defect
Hydrogen peroxide generation or maturation defects
Tg defect
Deiododinase defect
Resistance to TSH binding or signaling
TSH receptor defect
G protein defect
Secondary (central) CH
Isolated TSH deficiency
Congenital hypopituitarism (multiple pituitary hormone deficiencies)
Peripheral CH
Thyroid hormone transport defect
(monocarboxylate transporter 8)
Thyroid hormone metabolism defect
(selenocysteine insertion sequence-binding protein 2)
Thyroid hormone resistance
Transient CH
Maternal or neonatal excess iodine exposure
Maternal or neonatal iodine deficiency
Maternal antithyroid drugs
Maternal TRB-Ab
Heterozygous THOX2 or DUOXA2 mutations
Congenital hepatic hemangiomas

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Indonesian Journal of Clinical Pathology and Medical Laboratory, 2020 July, 26 (3) : 375 - 380 PAGE 377

screening programs policy such as the United States,

Clinical Manifestation of Congenital Canada, Japan, Australia, New Zealand, Western
Hypothyroidism: Symptoms and Signs Europe, the diagnosis of congenital hypothyroidism
is performed by the newborn screening test. While
Most of the newborns with congenital neonates in other non-provider countries, the
hypothyroid have no marked clinical signs and establishment of diagnosis is usually late, after
symptoms. Only 5 to 10% of them have shown the clinical manifestations of hypothyroidism already
manifestation of the symptoms at birth or occur.2,4
immediately after birth. The majority of the The timing for the collection of the specimen is
newborns will appear normal and healthy that the crucial to have the best diagnosis. Reported that the
clinician may not suspect them with CH.10 This is best time to collect a specimen for congenital
might due to the maternal thyroid hormone that hypothyroid testing is in 72 hours of age (normal
travels from the placenta to the fetus. This hormone newborn). This is the average time needed by the
may provide a transient protective effect in metabolism of the newborn to adapt, stabilize, and
newborns.2 Severe congenital hypothyroid baby who adjust to the new environment after birth. If TSH is
gets no treatment in four to six weeks may seem to the chosen screening test, it is important to collect
be healthy with prolonging sleeping time, not the specimen after 24 hours of birth to minimize the
awakening for feed, slow feeding, lethargy, false positive number. This false-positive number
constipation, hoarse cry or excessive sleeping. The may happen due to the physiological of TSH surge in
physical examination may show macroglossia, wide the first hour after birth. If mass screening must be
fontanels, umbilical hernia, prolong jaundice, skin performed before 24 hours of age, then the T4 test is
mottling and dry skin (Figure 1).2,11 the best choice because it is relatively more stable
during this period.12
DIAGNOSIS The chosen specimen for the newborn screening
test is blood pricking. The blood sample is taken from
In most countries that provide newborn the newborn's heel and collected on standard paper

A C
Figure 1. An infant with congenital hypothyroidism. A. 3-month-old infant with untreated CH; picture
demonstrates hypotonic posture, myxedematous facies, macroglossia, and umbilical hernia. B. The
same infant, close up of face, showing myxedematous facies, macroglossia, and skin mottling. C. The
same infant, close up showing abdominal distension and umbilical hernia.2

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cards. Most of the specimens are collected between lower to 6 and 10 µU/mL, a significant number of
two and five days after born. The specimen is children with true and transient congenital
collected before the baby is being discharged. The hypothyroidism is diagnosed.13
filter paper cards are sent to the reference laboratory In Indonesia, TSH cut-off 20 µU/mL is used. When
for the thyroid hormones test.2 There are three the test shows the TSH level is below 20 µU/mL, the
common testing protocols including TSH or T4 as the test is considered normal. Then, the result must be
primary screen, or both T4 and TSH. As for the delivered within seven days. In contrast, if the TSH
primary screening of congenital hypothyroid, it level is >20 µU/mL (considered high), the resampling
depends on the ability of the program in obtaining or Duplo test must be performed. Lastly, if the TSH
blood specimens. In the United States, the newborns level is >20 µU/mL, confirmatory TSH and T4 serum
are mostly being discharged from the hospital within must be performed to establish the diagnosis.8
the first 24 hours after birth. The T4 test was being
picked as the screening method. In other countries Confirmatory Serum Thyroid Test
such as Japan and Europe, if the hospital discharge
occurs later, the selected screening method is TSH.12 If an infant is detected with abnormal thyroid
Congenital hypothyroidism testing is not hormones during the screening test, a confirmatory
affected by the baby's diet. If the newborn is to serum thyroid test must be performed as soon as
receive a blood transfusion, the specimen must be possible by recalling the patient and obtaining
collected before the transfusion takes place. Instead, a venipuncture blood sample for the test.
if the specimen cannot be obtained beforehand, the Thyroid-stimulating hormone and the confirmatory
collection of the specimen must be done four test either free T4 or total T4 must be done.2
months after the recent transfusion. This is to avoid Once the confirmatory tests have been
getting false-negative result due to the blood mixing performed, it is essential to compare the results with
between the baby and the donor.12 the appropriate reference ranges according to the
Newborns with the specific condition have a risk baby's age. In the early few days after born, serum
to develop transient congenital hypothyroidism. TSH can rise as high as 39 µU/mL due to the surge of
They are the premature neonates (gestation age less TSH during this time. Most confirmatory serum tests
than 37 weeks), infants with low birth weight are performed at the age of one to two weeks when
(<2000 g), and hospitalized babies in a Neonatal the upper range of TSH falls around ten µU/mL.2 The
Intensive Care Unit (NICU). Among infants with low thyroid function tests (free T4, Total T4, TSH)
birth weight and neonates in NICU, the first blood reference age range from one to four days and two
sampling can be obtained at the age of four to six to four weeks are shown in Table 2.14 All thyroid
days. Although the first screening at age of four to six hormones levels are higher in one to four days after
days was done and shown ordinary result, the second born. However, at the age of two to four weeks, the
screening must be performed in premature neonates levels fall closer to the reference typically seen in
and one-month-old baby with low birth weight, the infancy.2
bodyweight reaches 2,500 g or is discharged from If the serum TSH level is elevated and free T4 or
hospital.3,8 total T4 is low, then the primary hypothyroidism is
While if TSH is used as primary screening, most established. If the serum TSH level is elevated, but
programs use cutoff 20-35µU/mL, depending on the the free T4 or total T4 is within the normal range,
reagents and method used to determine the risk of primary subclinical hypothyroidism is confirmed.
newborns having congenital hypothyroidism.12 On This is because the development of the brain is
the contrary, if T4 is used as primary screening, most dependent on the optimal level of thyroid hormone.
programs use initial T4<10th percentile as the In most cases, treating infants with subclinical
cut-off to have additional follow up TSH test.2,12 In hypothyroidism is recommended.2 In most preterm
one report, by decreasing the TSH cut-off point infants or acutely ill infants with primary

Table 2. Reference ranges for thyroid function tests at ages 1-4 days and 2-4 weeks14
Total T4
Age Free T4 (pmol/L) (nmol/L) TSH (mU/L)

1-4 days 25-64 129-283 <39

2-4 weeks 10-26 90-206 <10

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Indonesian Journal of Clinical Pathology and Medical Laboratory, 2020 July, 26 (3) : 375 - 380 PAGE 379

Table 3. The schedules for thyroid tests during CH treatment8

At two weeks after starting with levothyroxine treatment
Every four weeks until reaching a normal TSH level
Every two months until the infant reaches the age of 12 months
At the age of 1 to 3 year, clinical and laboratory tests must be performed every four months
Later, the laboratory tests are performed every six months until growth is complete
After reaching 18 years old, the monitoring is under the responsibility of internist
Laboratory tests must be performed earlier if it is doubtful that the patient does not take, the treatment
regularly or when the dosage is adjusted (4-6 weeks after dosage adjustment)

Table 4. Targets for TSH, T4 and fT4 levels in the first year of life during CH treatment2,8
Serum free T4 or total T4 must be kept in the upper range of normal level
Serum T4 within 130-206 nmol/L (10-16 µg/dL)
Serum fT4 within 18-30 pmol/L (1.4-2.3 ng/dL)
Serum TSH must be kept under 5 mU/L

hypothyroidism, the elevation of TSH level on the while if the treatment started between the age of
first screening test might not be observed. Hence, three to six months, the mean IQ is 71; and if the
the second screening test is obligatory.14 Once treatment did not start after the age of six months,
congenital hypothyroidism is diagnosed, the the mean IQ is dropped till 54.17
treatment with levothyroxine must follow.2,4 After newborn screening programs were
introduced in the mid-1970s, earlier diagnose and
Monitoring TSH and T4/fT4 Levels treatment in infants with congenital hypothyroidism
were performed. Significant success in achieving
During the treatment, TSH and T4/fT4 levels better neurocognitive development was gained. One
monitoring are needed for levothyroxine dosage review of 51 published reports on the infants'IQ with
adjustment. The schedules for thyroid hormones congenital hypothyroidism compared to normal
tests are shown in Table 3 as follow:8 sibling or classmate was reported. This review
Targets for TSH, T4 and fT4 levels in the first year concluded that 18 studies reported no significant IQ
of life during CH treatment are shown in Table 4:2,8 difference, while 33 reported a significant five to 25
lower IQ points in congenital hypothyroidism
PROGNOSIS subjects.18

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