TECHNICAL REPORT Guidance for the Clinician in Rendering Pediatric Care
Congenital Hypothyroidism: Screening
and Management
Susan R. Rose, MD, FAAP,a Ari J. Wassner, MD,b Kupper A. Wintergerst, MD, FAAP,c Nana-Hawa Yayah-Jones, MD,d
Robert J. Hopkin, MD, FAAP,e Janet Chuang, MD,a Jessica R. Smith, MD,b Katherine Abell, MD,f,g Stephen H. LaFranchi,
MD, FAAP,h and the AAP SECTION ON ENDOCRINOLOGY, AAP COUNCIL ON GENETICS, PEDIATRIC ENDOCRINE SOCIETY,
AMERICAN THYROID ASSOCIATION
Untreated congenital hypothyroidism (CH) leads to intellectual disabilities.
Prompt diagnosis by newborn screening (NBS) leading to early and adequate
treatment results in grossly normal neurocognitive outcomes in adulthood.
However, NBS for hypothyroidism is not yet established in all countries
globally. Seventy percent of neonates worldwide do not undergo NBS.
The initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The
goals of treatment are to maintain consistent euthyroidism with normal
thyroid-stimulating hormone and free thyroxine in the upper half of the
age-specific reference range during the first 3 years of life. Controversy
remains regarding detection of thyroid dysfunction and optimal
management of special populations, including preterm or low-birth
weight infants and infants with transient or mild CH, trisomy 21, or
central hypothyroidism.
Newborn screening alone is not sufficient to prevent adverse outcomes from
CH in a pediatric population. In addition to NBS, the management of CH
requires timely confirmation of the diagnosis, accurate interpretation of
thyroid function testing, effective treatment, and consistent follow-up.
Physicians need to consider hypothyroidism in the face of clinical symptoms,
even if NBS thyroid test results are normal. When clinical symptoms and
signs of hypothyroidism are present (such as large posterior fontanelle,
large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy,
and/or hypothermia), measurement of serum thyroid-stimulating hormone
and free thyroxine is indicated, regardless of NBS results.
BACKGROUND AND STATEMENT OF THE PROBLEM
Congenital hypothyroidism (CH) is one of the most common
preventable causes of intellectual disability worldwide. CH is an inborn
condition in which thyroid hormone (TH) levels are insufficient for the
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abstract
a
Divisions of Endocrinology, dEndocrinology and Diabetes, eHuman
Genetics, fDepartment of Pediatrics, Cincinnati Children’s Hospital
Medical Center, University of Cincinnati College of Medicine, Cincinnati,
Ohio; bDivision of Endocrinology, Boston Children’s Hospital, Harvard
Medical School, Boston, Massachusetts; cDepartments of Pediatrics,
Division of Endocrinology & Diabetes, Wendy Novak Diabetes Center,
University of Louisville, School of Medicine, Norton Children’s Hospital,
Louisville, Kentucky; gDivision of Genetics and Genomic Medicine,
Department of Pediatrics, Washington University School of Medicine, St.
Louis, Missouri; and hDepartment of Pediatrics, Doernbecher Children’s
Hospital, Oregon Health & Sciences University, Portland, Oregon
Drs Rose, Wassner, Wintergerst, Yayah-Jones, Hopkin, Chuang,
Smith, Abell, and LaFranchi were equally responsible for
conceptualizing, writing, and revising the manuscript and
considering input from all reviewers and the board of directors;
and all authors approve of the final publication.
This document is copyrighted and is property of the American
Academy of Pediatrics and its Board of Directors. All authors have
filed conflict of interest statements with the American Academy of
Pediatrics. Any conflicts have been resolved through a process
approved by the Board of Directors. The American Academy of
Pediatrics has neither solicited nor accepted any commercial
involvement in the development of the content of this publication.
Technical reports from the American Academy of Pediatrics benefit
from expertise and resources of liaisons and internal (AAP) and
To cite: Rose SR, Wassner AJ, Wintergerst KA, et al; AAP
Section on Endocrinology, AAP Council on Genetics, Pediatric
Endocrine Society, American Thyroid Association. Congenital
Hypothyroidism: Screening and Management. Pediatrics. 2023;
151(1):e2022060420
FROM THE AMERICAN ACADEMY OF PEDIATRICS
 normal development and function of
body tissues. In the majority of
affected infants, the disorder is
permanent and results from
abnormal thyroid gland
development or a defect in TH
synthesis. In rare cases, CH may
result from abnormal pituitary or
hypothalamic control of thyroid
function. In some infants with CH,
thyroid dysfunction is transient and
normalizes at a later time.1–4
Clinical and laboratory follow-up of
children with CH is essential for
appropriate management.5–7
Newborn screening (NBS) for CH
followed by prompt initiation of
levothyroxine (L-T4) therapy can
prevent severe intellectual disability,
psychomotor dysfunction, and
impaired growth.1,5–10 NBS has been
adopted in many countries
throughout the world.1,5–7,11,12
However, there continue to be
inconsistent diagnostic definitions
for CH and a need for further
research regarding preventable risk
factors for the development of
permanent and transient CH. In
addition, the influence of severity at
diagnosis, timing of treatment
initiation, and L-T4 dose on long-
term outcomes remains a matter of
debate. Although the majority of
treated patients achieve normal
cognitive outcomes, the influence of
L-T4 therapy on neurologic
development is less certain, and
some studies show persistent
deficits in treated patients compared
with euthyroid healthy controls.13,14
Much has been learned about the
pathophysiology, genetics,
diagnosis, and management of CH
in recent years. Lowering of
screening TSH cutoffs has resulted
in detection of milder, sometimes
transient forms of hypothyroidism.
If a permanent form of CH has not
been established, L-T4 treatment is
maintained until 3 years of age,
after which thyroid function is
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reevaluated following a 4- to
6-week discontinuation of L-T4.5–7
New data, particularly on long-term
neurodevelopmental outcomes,
provide opportunities to refine
diagnostic criteria and optimize
monitoring and treatment protocols.
A review of past practices and
future directions, as well as updated
evidence for the management of CH,
are provided.15
PATHOPHYSIOLOGY
Most cases of CH are caused by
dysfunction of the thyroid gland
(primary hypothyroidism). The most
common causes are a defect in
thyroid gland development (thyroid
dysgenesis) and an intrinsic defect in
TH synthesis (dyshormonogenesis).
Less commonly, neonatal thyroid
function may be transiently impaired
by extrinsic factors, such as maternal
antithyroid medications, TSH
receptor-blocking antibodies
(TRBAb) acquired through
transplacental passage, or maternal
or infant iodine deficiency or excess.
Rarely, CH is caused by hypothalamic
or pituitary defects that lead to
inadequate secretion and/or
bioactivity of TSH (central
hypothyroidism).16
The normal development of many
fetal tissues, especially the nervous
system, is critically dependent on
TH. The fetal thyroid begins to form
around 3 weeks of gestation and
begins to synthesize TH at around
10 to 12 weeks of gestation.
Hypothalamic and pituitary control
of the thyroid is asserted around
midgestation and develops through
the third trimester, reaching
maturity around term gestation.
Before the onset of TH synthesis, the
fetus is completely dependent on
maternal thyroxine (T4), which
crosses the placenta in limited
amounts throughout gestation.17,18
In infants who are unable to
synthesize T4, cord blood T4
concentrations are one third to one
half of normal because of transfer of
maternal T4.19 Maternal T4, along
with increased conversion of T4 to the
more bioactive triiodothyronine
(T3),20 is partially protective against
the adverse developmental
consequences of fetal hypothyroidism.
For this reason, normal or near-
normal neurocognitive outcome is
attainable even in infants with severe
CH, as long as maternal thyroid
function is normal and adequate
postnatal L-T4 treatment is initiated
early. In contrast, when combined
maternal and fetal hypothyroidism are
present—as may occur with severe
iodine deficiency or untreated
maternal hypothyroidism—significant
neurodevelopmental impairment can
occur despite adequate postnatal L-T4
therapy. This highlights the
importance of timely prenatal care
that includes careful detection and
management of maternal thyroid
disease before and during
pregnancy. This report focuses
exclusively on the problem of CH;
identification and treatment of
maternal hypothyroidism have been
addressed in recent reviews and
consensus guidelines.21
Iodine is a critical component of TH
production, and hypothyroidism
caused by iodine deficiency remains
1 of the most common preventable
causes of intellectual disability
worldwide. However, adequate
iodine supplementation before and
during pregnancy will normalize
thyroid function in the iodine-
deficient mother and newborn
infant.22 Universal salt iodization is
recommended by the World Health
Organization and the United Nations
Children’s Fund23 and has been
implemented in more than
100 countries.24 Nevertheless,
iodine deficiency in pregnant
women remains common in many
areas of the world.21 Although North
America is an iodine-sufficient
region overall, recent data indicate
 that more than half of pregnant
women in the United States may
have mild iodine deficiency.25 Intake
of a prenatal vitamin containing
150 mcg of iodine daily by all
women before and during
pregnancy and lactation will
promote iodine sufficiency in
mother and newborn infant.21,26
NBS for CH was introduced in the
1970s and is now practiced across
North America, Europe, Australia,
and parts of Asia, South America,
and Africa.12 The incidence of CH
ranges from approximately 1 in
2000 to 1 in 4000 newborn infants
in countries from which NBS data
are available.12 This incidence
is significantly higher than that
reported in the early years of NBS
(around 1 in 4000), primarily
because of changes in screening
strategies that have led to increased
detection of milder cases of CH.27–29
Genetic factors may also be
influential as data suggest that
CH is more common in certain
populations.30 There is a 1.5 to
2-fold greater incidence in
females than in males of thyroid
ectopia (but not of agenesis or
dyshormonogenesis), and there is an
increased risk for CH in infants with
trisomy 21.
The hypothalamic-pituitary-thyroid
axis is finely tuned to maintain a
stable concentration of free T4
(FT4) in each individual. In primary
hypothyroidism, the serum TSH
concentration increases in response
to decreased thyroidal production of
TH. Because TSH secretion is
sensitive to small changes in
serum FT4 levels, in primary
hypothyroidism the serum TSH
increases before FT4 concentrations
decrease below normal. In central
hypothyroidism, serum FT4 is
reduced, although often still
remaining in the low normal range,
but the pituitary is unable to
respond appropriately, and serum
levels of TSH usually remain
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inappropriately normal or low.
These principles form the basis of
NBS strategies for diagnosing CH.
NEWBORN SCREENING FOR CH
Newborn Screening Programs
Detection of CH in newborn infants
is accomplished by screening a
population of newborn infants
within a defined geographic area
(eg, a state, province, or region).
Population screening is performed
cost-effectively by state or
provincial public health laboratories
working closely with birthing
hospitals or other birthing centers
within their geographic area. NBS
programs that employ a
multidisciplinary team are best able
to conduct comprehensive care of
detected cases. NBS programs
undertake communication with the
infant’s primary care provider
(PCP), along with ongoing education
of pediatric providers and birthing
hospitals or centers.
NBS Specimen
A dried blood spot (DBS) for NBS is
obtained by heel stick on an
approved filter paper card using
appropriate collection methods.
After drying, filter paper specimens
are transmitted to the NBS
laboratory for testing. Failure to
follow NBS program instructions for
collection may result in an
unsatisfactory specimen that will
not undergo testing.
The preferred age for collection of
the NBS specimen to screen for CH
is 48 to 72 hours of age. This timing
reflects the normal surge in TSH
concentration (to 60–80 mIU/L) that
occurs within hours after birth in
term newborn infants and resolves
over the next 5 days.31 Specimens
collected in the first 24 to 48 hours
of life may lead to false-positive TSH
elevations when using any screening
test approach.32,33 However,
obtaining a specimen for NBS at the
preferred time may be challenging
given the trend toward early
postnatal discharge of infants: up to
90% of healthy term newborn
infants in the United States and
Europe may be discharged from the
birthing hospital before 48 hours of
age.34 For such patients, obtaining a
sample before discharge is
preferable to potentially missing a
diagnosis of CH. Similarly, collection
of a specimen for NBS before blood
transfusion, even if before 48 hours
of life, is important to avoid missing
a diagnosis of CH. However,
collection of the NBS specimen
before 48 hours of age, and
particularly before 24 hours of age,
necessitates the use of age-specific
TSH reference ranges or repeat
screening, particularly to avoid
false-positive results. False-negative
NBS results may occur when
screening an acutely ill newborn
infant or after transfusion or from
errors in the processing of
specimens or reporting of results.
Some hospitals have adopted the
practice of screening all infants at
the time of admission to the NICU,
with the goal of collecting samples
before possible transfusion of blood
products. This practice results in
most samples being obtained too
early (often before 24 hours of life),
which may increase the risk of false-
positive results. Therefore, it is
preferable to screen infants
admitted to the NICU at 48 to
72 hours of age, but before any
actual transfusion of blood products,
if required earlier.
The responsibility for collecting the
NBS specimen rests with the
hospital or birthing center where
the infant is born or with the
midwife or other supervising
personnel in the case of home
delivery. When a newborn infant is
transferred to another hospital,
communication between the
transferring and receiving hospital
3
 is important to prevent missing
collection of the NBS specimen.
NBS thyroid test cutoffs (TSH or T4)
may vary from state to state,
reflecting their own population’s
experience with achieving desired
separation of true from false-
positive test results. If NBS is
performed after 30 days of life,
interpretation of results uses age-
specific reference ranges.
NBS Test Strategies
The chief priority of NBS programs
is the detection of infants with
moderate or severe primary
hypothyroidism, which results in
intellectual disability if not detected.
Secondary priorities include the
detection of infants with mild
primary hypothyroidism, primary
hypothyroidism of delayed onset
(“delayed TSH elevation”), or central
hypothyroidism.
Three test strategies are used to
screen for CH: (a) primary TSH –
reflex T4 measurement; (b) primary
T4 – reflex TSH measurement; and
(c) combined T4 and TSH
measurement. All 3 test strategies
detect moderate to severe primary
CH with similar accuracy.
Comparison of cases detected by
these different methods within the
same population shows that a few
infants missed by one strategy will
be detected by another strategy,35
and most differences in case
detection between strategies likely
result from differences in test cut-
offs and in the timing and number
of specimens.36 The majority of NBS
programs in the United States,
Canada, and worldwide employ a
primary TSH test strategy.12
Although all NBS programs measure
TSH and T4 from whole blood
specimens obtained by heel stick,
some programs report results in
whole blood units, whereas other
programs report results in serum
units. Based on the assumption that
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the average newborn hematocrit is
55%, results expressed in serum
units are approximately 2.2-fold
those expressed in whole blood
units; for example, a screening TSH
of 15 mIU/L in whole blood is
roughly equivalent to a TSH of
33 mIU/L serum.37 Clinicians can
identify whether NBS results in their
region are expressed in whole blood
or in serum units. Most NBS
programs in the United States and
some in Canada express results in
serum units, and many in Canada
and the rest of the world express
results in whole blood units.
Throughout this report, results are
expressed in serum units, unless
otherwise noted.
Primary TSH – Reflex T4 Screening
NBS programs using this strategy
start with measurement of TSH in
the DBS specimen. When screening
TSH is elevated above the defined
cutoff, total T4 is measured in the
same DBS specimen. Depending on
the NBS program algorithm, an
elevated TSH and/or low T4 may
lead to recall for a confirmatory
serum sample or to collection of a
second DBS specimen for repeat
testing. Because many DBS
specimens are obtained before
48 hours of age or after the first
week of life, some NBS programs
have developed age-specific TSH
cutoffs.38,39
The primary TSH screening strategy
is more likely to detect mild cases of
CH than the primary T4 strategy.
Infants with delayed TSH elevation
will (by definition) have normal TSH
on initial testing and so will not be
detected by a primary TSH
screening programs unless a second
DBS specimen is collected either
from all infants or specifically from
infants at risk for delayed TSH
elevation (see section below on
Preterm or Low Birth Weight
Infants and other special
populations). Primary TSH screening
programs will not detect babies with
central CH, in which TSH
concentrations are not elevated and
low TSH values are not reported.
The recall rate (percentage of
infants recalled for testing because
of abnormal NBS results) generally
is lower in primary TSH programs
compared with programs employing
a primary T4 strategy, but this
varies depending on the TSH cut-off.
For example, the NBS program in
Newcastle, United Kingdom reported
a recall rate of 0.08% using a cutoff
of 10 mIU/L whole blood, but the
recall rate increased to 0.23% when
the cutoff was lowered to 6 mIU/L
whole blood.40
Primary T4 – Reflex TSH Screening
This strategy begins with
measurement of total T4 in the DBS
specimen. (FT4 is not measured by
most screening programs for
technical reasons.) If the total T4
concentration falls below the
defined cutoff, TSH is then measured
in the same DBS specimen. A low T4
and/or elevated TSH may lead to
recall for a confirmatory serum
sample or to collection of a second
DBS specimen for repeat testing.
Compared with the primary TSH
strategy, the primary T4 strategy is
less sensitive for detecting mild
cases of primary hypothyroidism in
which TSH concentrations are
elevated but T4 concentrations
remain low normal. However, the
primary T4 strategy is more likely
to detect cases with delayed TSH
elevation (if the program performs
repeat screening in cases with initial
low T4 and normal TSH), because
the infants at highest risk for
delayed TSH elevation are also likely
to have low total T4 concentrations
on initial screen (eg, preterm, low
birth weight [LBW], or acutely ill
newborn infants).
Primary T4 screening programs have
the potential to detect newborn
 infants with central CH.41,42 Such
cases are best detected by programs
that collect 2 screening specimens
either on all infants or on infants with
low T4 and normal TSH on the first
specimen. However, some cases of
central hypothyroidism are not
detected by this strategy, either
because they have a T4 concentration
in the lowest third of the normal
range, or because the NBS program
does not recall for repeat testing
infants with a low T4 and a
nonelevated TSH. These cases of
congenital central hypothyroidism
will usually present later in infancy
with additional pituitary hormone
deficiencies.42
The recall rate is approximately
0.3% in programs that follow-up
only cases with low T4 and elevated
TSH,41 similar to the primary TSH
screening programs using a lower
cutoff. In programs that collect 2
routine specimens or that follow-up
on infants with low T4 on both the
first and second specimen
regardless of the TSH level, the
recall rate is higher.43
Combined T4 and TSH Screening
Some state NBS programs in the
United States and elsewhere measure
both total T4 and TSH to screen for
CH.43,44 Criteria for recall vary by
program, but a combination of low T4
and elevated TSH generally leads to a
request for a confirmatory serum
sample. Other combinations of
screening results may lead to a
request for either a serum sample or a
second DBS specimen. Combined T4
and TSH screening will detect primary
hypothyroidism, including mild
hypothyroidism, and has the potential
to detect many cases of congenital
central hypothyroidism.45,46 The
combined screening will also detect
infants with delayed TSH elevation if a
second specimen is requested, either
in all infants or in those at high risk
for this disorder. As of 2015, 12 states
in the United States mandated or
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suggested that a second NBS specimen
be obtained at 2 weeks of age. The
recall rate in combined T4 and TSH
screening programs is higher than
primary TSH or primary T4 programs.
NBS in Special Populations
Preterm or Low Birth Weight Infants
Infants born preterm (<37 weeks’
gestation) and/or with low birth
weight (<2500 g) have lower serum
T4 levels after birth than do term
infants. The decrease in serum T4 is
proportional to the degree of
prematurity.47 In addition, preterm
infants have a reduced TSH surge
after birth compared with term
infants.48 Multiple factors affect
thyroid function in preterm infants:
early loss of maternal T4, decreased
production of thyroxine-binding
globulin (TBG) resulting in lower
total T4 levels, limited thyroid gland
reserve, and immaturity of the
hypothalamic-pituitary-thyroid axis.
Preterm infants are also at increased
risk of iodine deficiency because of
greater weight-based iodine
requirements and parenteral
nutrition and preterm infant
formulas commonly used in NICUs
may provide inadequate iodine
nutrition.49 In addition, preterm or
LBW infants often have
comorbidities that can result in the
nonthyroidal illness syndrome,
which has a typical pattern of low
T4 with normal to low TSH
concentrations. As a result, preterm
or LBW infants are often detected
with low T4 and normal TSH
(termed hypothyroxinemia) by NBS
programs that use a primary T4-
reflex TSH strategy. Although this
pattern of results is also compatible
with central hypothyroidism,
preterm or LBW infants are less
likely than infants with central
hypothyroidism to have low levels
of serum FT4, particularly if
measured by a dialysis method.50
Hypothyroxinemia appears to be
transient in most preterm babies,
and over time DBS T4 levels
increase to those present in term
infants.51
Although TSH concentrations are
often normal or low in preterm or
LBW infants, as they recover from
hypothyroxinemia serum, TSH levels
may rise transiently above normal
(6–15 mIU/L).52 In some infants,
this increase in TSH is significantly
greater (>100 mIU/L). This pattern
of “delayed TSH rise” is more
common in preterm or LBW infants
than in term or normal birth weight
infants. Reports from the New
England and Wisconsin NBS
programs indicate that delayed TSH
elevation occurred in 1 in 54 to 95
very low birth weight (VLBW
[<1500 g]) infants, 1 in 737
preterm infants (<32 weeks) with
birth weight >1500 g, and 1 in
30 329 infants of normal birth
weight (>2500 g).53,54 In these
reports, delayed TSH elevation was
first detected at 22 to 46 days; TSH
elevation peaked around 58 days of
life (range 11 to 101 days) in the
New England study. In the
Wisconsin study, a delayed TSH rise
that peaked above 100 mIU/L was
detected in infants at a mean of
3 weeks of age, and milder TSH
elevations were detected in infants
later (mean, 59 days). Most infants
with delayed TSH rise whose
confirmatory serum TSH was above
20 mIU/L had low serum FT4
concentrations, whereas FT4 was
normal in infants whose
confirmatory serum TSH was below
20 mIU/L3.54
With recognition of the relatively
high frequency of delayed TSH
elevation, many NBS programs have
elected to undertake repeat NBS in
infants born preterm (<32
weeks’ gestation) or with VLBW
(<1500 g).55,56 For routine
rescreening of these infants, repeat
NBS testing is preferred to
measurement of serum TSH and FT4
because of the much lower cost of
NBS. Gestational age-specific
5
 reference ranges for NBS TSH are
available according to gestational
age at birth (22 to 27 weeks versus
28 to 31 weeks).57
Acute Illness or Admission to a NICU
Newborn infants with acute illness,
particularly illness requiring
admission to a NICU, are likely to
experience a nonthyroidal illness.
Most newborn infants admitted to a
NICU are born preterm and/or are
LBW, and many are treated with
drugs that can impact thyroid
function, such as glucocorticoids or
dopamine, which decrease TSH
secretion.52,58,59 The combination of
acute illness, preterm birth, and
treatment with these medications
results in low T4 levels without TSH
elevation that may be detected by
primary T4-reflex TSH NBS
programs.60 These infants have a
higher risk for delayed TSH
elevation (see section on Preterm or
Low Birth Weight Infants, above).
Term newborn infants of normal
birth weight who are admitted to a
NICU may have a risk of delayed
TSH elevation as high as that of
VLBW newborn infants.61
Multiple Births, Same-Sex Twins, In Vitro
Fertilization
The incidence of CH appears to be
increased in pregnancies with
multiple births (1:876 in twin births
and 1:575 in higher-order multiple
births in 1 study).61 Another study
showed the incidence of CH in
same-sex twins to be 1 in 593,
compared with 1 in 3060 in
different-sex twins.62 Most twin
pairs (>95%) are discordant for
CH.61,63 However, in monozygotic
twins who share placental
circulation, blood from a euthyroid
fetal twin with normal TH levels
may cross to a fetal twin with CH,
temporarily correcting the
hypothyroidism and preventing its
detection by initial NBS at 24 to
72 hours of life. Thus, all
monozygotic twins, or same-sex
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twins for whom zygosity is
unknown, should undergo repeat
NBS around 2 weeks of age.
Elevated TSH that would be detected
by collection of a second NBS has
been reported at 2 to 4 weeks of age
in up to 10% of neonates following
in vitro fertilization.64 However, in all
cases TSH elevation was mild
(<10 mIU/L) and FT4 was normal.
The clinical significance of these
findings remains uncertain, and
evidence is insufficient to recommend
repeat NBS in infants conceived by
in vitro fertilization.
Trisomy 21
Infants with trisomy 21 have a high
incidence of CH that ranges from
1% to 12% in various reports.65–69
For reasons that are not understood,
newborn infants with trisomy
21 tend to have lower T4 concentrations
and higher TSH concentrations than do
infants without trisomy 21.69,70 Trisomy
21 is associated with other comorbidities
(such as congenital heart disease) that
may further increase the risk of
abnormal NBS results because of acute
illness or excess iodine exposure.
Infants with trisomy 21 who do not
have CH are still at significant risk of
developing primary hypothyroidism
during the first year of life
(approximately 7% in 1 prospective
study).66 Therefore, in these infants, a
second NBS should be performed at 2
to 4 weeks of life and serum TSH
should be measured at 6 and 12
months of life. Hypothyroidism may
develop before 6 months in some
infants with trisomy 21,69 so a high
level of clinical suspicion remains
important, but there is insufficient
evidence to suggest additional routine
TSH screening.
Communication of NBS Test Results
to the Primary Care Physician
Direct communication between the
NBS program and PCP is important
for timely receipt of abnormal
results and appropriate follow-up
care.43,71 Consultation with a
pediatric endocrinologist will
facilitate diagnostic evaluation and
management. Management of
abnormal NBS results is as
described in the clinical report.15
Confirmatory Serum Testing After
Abnormal NBS
In any child whose NBS results
suggest CH, the next steps are to
perform a physical examination (for
goiter, lingual thyroid gland, and/or
physical signs of hypothyroidism) and
to measure serum concentrations of
TSH and FT4 (or total T4), optimally
with use of a laboratory that has a
24-hour turn around. Measurement of
other thyroid hormones (such as T3,
free T3, or reverse T3) is rarely of
clinical value in the evaluation of
possible CH.
For confirmation of abnormal NBS
results, measurement of FT4 is
preferred over measurement of total
T4. However, the decision to measure
FT4 or total T4 is based on cost, time
to obtain results, and clinical factors.
For example, preterm or LBW infants
with normal thyroid function may
have alterations in protein binding
that result in low total T4
concentrations despite normal FT4.
Therefore, if TSH is normal, low
serum total T4 concentrations may be
evaluated by measuring FT4. If
concern for a binding abnormality
exists, measuring FT4 by a dialysis
method (which physically separates
free T4 from bound T4 before
measurement) performed in a
reference laboratory may be more
reliable than the standard analog
method.
Interpretation and Management of
Confirmatory Serum Testing Results
Elevated TSH and Low FT4
Elevated TSH with low FT4 on the
confirmatory serum testing indicates
overt primary hypothyroidism.
 Elevated TSH and Normal FT4
This pattern of confirmatory serum
results is termed hyperthyro-
tropinemia or subclinical
hypothyroidism and represents a
mild primary thyroid abnormality.
There is controversy regarding the
need for L-T4 therapy in this setting,
because there are few and
conflicting studies regarding the
effect of mild CH on cognitive
development. One study found that
children with TSH elevation on NBS
that remained persistent and
untreated at 6 years of age had an
increased risk of developmental
delay compared with control
children.72 Another study of nearly
500 000 Australian children
demonstrated an association of mild
TSH elevation on NBS with poorer
academic performance and an
increased risk of special educational
needs.73 In contrast, studies of
nearly 300 Belgian children showed
no association of their NBS TSH
with adverse cognitive,
psychomotor, or behavioral
outcomes at 4 to 6 years of age.74–76
Similarly, a study in New Zealand
showed that children with mild or
moderately elevated TSH on NBS
(8–14 mIU/L blood or 17–31 mIU/L
serum) who received no treatment
or follow-up had similar
neurocognitive outcomes to sibling
controls at 10 years of age.77 There
are currently no studies
demonstrating a beneficial effect of
L-T4 therapy on outcomes in
patients with mild CH. In particular,
heterozygous inactivating mutations
of the TSH receptor gene may cause
mild hyperthyrotropinemia that
does not progress over time and
may not benefit from L-T4
treatment.78,79 No evidence exists to
define the precise TSH thresholds
associated with potential adverse
outcomes in mild CH.
Despite the lack of clear evidence
regarding outcomes of hyperthyro-
tropinemia and whether L-T4
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treatment is of clinical benefit, there
is physiologic reason to believe that
an elevated TSH concentration
indicates that the hypothalamic-
pituitary axis is sensing less TH than
required by the body’s endogenous
set-point. Therefore, on the basis of
expert opinion, if the confirmatory
serum TSH is >20 mIU/L, L-T4
treatment should be initiated even if
FT4 is normal. If the confirmatory
serum TSH is elevated but #20
mIU/L, treatment may be initiated,
or alternatively serum TSH and FT4
may be followed closely every 1 to
2 weeks without treatment.
However, repeated TSH elevation
above 10 mIU/L has been associated
with adverse outcomes in children
with CH.80 Therefore, expert opinion
suggests that persistent TSH
elevation >10 mIU/L is an
indication to initiate L-T4 treatment.
Consultation with a pediatric
endocrinologist can facilitate a
patient-specific management plan.
The management of infants with
persistent serum TSH elevations
between 5 and 10 mIU/L after
4 weeks of age is even more
controversial. The upper limit of
normal TSH in infants age 1 to
3 months is around 4.1 to 4.8
mIU/L.81–84 TSH elevation above
5 mIU/L beyond 1 to 3 months of
life is generally abnormal but does
not demonstrate that L-T4
treatment is necessary or
beneficial. Thus, in infants with
serum TSH elevation between 5
and 10 mIU/L that persists beyond
4 weeks of age, there is insufficient
evidence to support treatment
versus observation. Consultation
with a pediatric endocrinologist
can facilitate a patient-specific
management plan.
Normal TSH and Low T4
This pattern of thyroid function
tests is observed in patients with
central hypothyroidism, prematurity,
LBW, acute illness, or TBG
deficiency.41,42,85 Central
hypothyroidism may be suspected in
the presence of midline defects,
visual abnormalities (blindness or
nystagmus), or findings consistent
with other pituitary hormone
deficits (such as hypoglycemia,
conjugated hyperbilirubinemia,
microphallus, and/or
cryptorchidism). The presence of
multiple pituitary hormone
deficiencies suggests a defect in
hypothalamic or pituitary
development.86,87
The incidence of central CH is
between 1 in 16 000 and 1 in
25 000.41,42,85,88 Although the
chief objective of NBS programs is
detection of primary
hypothyroidism, some primary T4
test programs can detect infants
with central hypothyroidism.
However, some neonates with
central CH commonly have T4
levels within the lowest third of
the normal range, so CH will not
be diagnosed until later in life.40–43
Detection of central CH is facilitated
in NBS programs that collect a
second specimen from all infants
with T4 below a specified cutoff.41
Primary TSH testing programs will
not detect central hypothyroidism.
To assist in distinguishing central
hypothyroidism from TBG
deficiency, a TBG concentration can
be obtained, although this
distinction can be challenging.85
The concept that central
hypothyroidism is usually mild
appears unfounded: a study from
the Netherlands found that mean
pretreatment serum FT4 levels in
central CH were similar to those of
patients with moderately severe
primary CH.45 Therefore, L-T4
treatment of central CH is indicated.
In addition to permitting early
treatment of infants with central CH,
detection of neonates with this
disorder by NBS facilitates
identification of associated pituitary
hormone deficiencies (some of
7
 which may be life-threatening) and
congenital anomalies, such as optic
nerve hypoplasia and brain
malformations.
IMAGING
Imaging with thyroid
ultrasonography or scintigraphy,
performed in an experienced center,
may assist in establishing the
etiology of CH.87 Controversy exists
regarding the utility of routine
thyroid imaging for patients with
CH. Imaging may inform prognosis if
it identifies an ectopic or a dysgenic
thyroid gland suggesting a
permanent form of CH, or if it
guides counseling on the likelihood
of disease recurrence in a future
child of the same parents (see
“Genetic Testing”). However, in most
cases imaging does not alter clinical
management of the patient before
age 3 years.
Thyroid ultrasonography can
identify the presence and location of
thyroid tissue without radiation
exposure89–92 and can be performed
at any time after the diagnosis of
CH. Ultrasonography has lower
sensitivity than scintigraphy for
detecting ectopic thyroid tissue,93
the most common cause of CH,
although its sensitivity is improved
by the use of color Doppler.92,94 The
absence of a normally located
thyroid gland on ultrasonography
confirms a permanent form of CH,
whether or not an ectopic gland is
detected. A eutopic thyroid gland in
combination with a low serum
thyroglobulin concentration (in the
setting of elevated TSH) is
consistent with a thyroglobulin
synthesis defect or a defect in TSH
receptor signaling (including
maternal TRBAb or a mutation in
thyroid-stimulating hormone
receptor (TSHR) or guanine
nucleotide-binding protein
[G-protein] subunit a [GNAS].95 An
enlarged, eutopic thyroid,
particularly in combination with
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elevated serum thyroglobulin,
indicates a defect in TH synthesis.95
Thyroid scintigraphy allows
localization of functional thyroid
tissue based on its uptake of either
123
I or 99mTc. 123I may provide more
accurate uptake and images but may
not be available in all imaging
centers. 99mTc is less expensive and
is widely available. 131I is not used in
infants because of the higher
exposure to ionizing radiation. A TSH
concentration less than 30 mIU/L or
performing scintigraphy more than
20 days after initiating therapy may
result in falsely low uptake.96
If scintigraphy demonstrates an
ectopic thyroid, a permanent form of
CH has been established. The
absence of eutopic thyroid iodine
uptake is most often associated with
thyroid aplasia or hypoplasia (or,
less frequently, exposure to excess
iodine). However, iodine uptake may
be absent from a eutopic thyroid
gland because of a genetic iodine-
transport defect (SLC5A5) or a
defect in TSHR signaling (including
maternal TRBAb or a mutation in
TSHR or GNAS). In the case of
TRBAb, this may lead to an
erroneous, permanent diagnosis of
thyroid agenesis in a patient with
transient CH. A defect in iodine
transport may be suspected when
normal 123I uptake in the salivary
glands is absent.97
Iodine uptake in an enlarged,
eutopic gland is consistent with a
defect in TH synthesis. Measurement
of serum thyroglobulin will
distinguish a thyroglobulin synthesis
defect from other genetic causes of
dyshormonogenesis or exposure to
an exogenous goitrogen other than
iodine, such as antithyroid drugs.98
Infants with normal thyroid imaging
at birth may have a transient form
of hypothyroidism. In these patients,
reevaluation off TH therapy after
3 years of age to assess for
persistent hypothyroidism may be
useful (see “Assessment of
Permanence of Hypothyroidism”).
GENETIC TESTING
CH has a complex etiology and is
sporadic in most cases. However, CH
can be associated with one of
several known monogenic causes or
broader syndromes.99 Monogenic
causes of CH may be categorized
generally as causing thyroid
dysgenesis or dyshormonogenesis.
Thyroid dysgenesis is usually
sporadic, but in rare cases may be
related to mutations in specific
genes (Table 1).100,101 Many of these
genes encode transcription factors
that are important during
embryogenesis in multiple tissues,
and therefore mutations in these
genes frequently cause other
abnormalities in addition to CH.101
Thyroid dyshormonogenesis is usually
caused by defects in genes involved in
thyroid hormone synthesis, such as
TSH receptor signal transduction or
iodide transport or organification
(Table 2).101 Recent studies show
some phenotypic overlap between
genes classically associated with
thyroid dysgenesis and
dyshormonogenesis; indeed, a
significant proportion of CH cases
may be caused by interactions
among mutations in 2 or more CH-
related genes.102–104
Dual oxidase 2 (DUOX2) is an
enzyme that generates the hydrogen
peroxide required for TH synthesis.
Genetic defects in DUOX2 cause CH
with a eutopic thyroid gland.105 CH
caused by DUOX2 mutations can be
transient or permanent, but there is
little correlation between the
resolution or persistence of
hypothyroidism and the number of
DUOX2 mutations present
(monoallelic or biallelic) or their
severity.105
 TABLE 1 Genes Associated With Thyroid Dysgenesis100,101
Gene Name Clinical Manifestations Associated Syndrome Inheritance Pattern
NKX2-1 Interstitial lung disease, chorea, — Autosomal dominant, variable
hypotonia, developmental delay expressivity
FOXE1 Cleft palate, bifid epiglottis, choanal Bamforth-Lazarus syndrome Autosomal recessive
atresia, spiky hair
PAX8 Urogenital abnormalities — Autosomal dominant
TSHR — — Autosomal dominant or recessive
NKX2-5 Congenital heart disease — —
GLIS3 Neonatal diabetes, congenital glaucoma, — Autosomal recessive
developmental delay, hepatic
fibrosis, polycystic kidneys
JAG1 Congenital heart disease, involvement Alagille syndrome Autosomal dominant
of liver, heart, eye, skeleton, facial
defects
TBX1 Congenital heart malformations 22q11 deletion syndrome Autosomal dominant, variable
expressivity
NTN1 Arthrogryposis — Unknown
CDCA8 — — Autosomal recessive
TUBB1 Abnormal platelets — Autosomal dominant
—, not applicable.

Abnormalities in the development or
function of the hypothalamus or
pituitary can result in central CH.86,87
Genetic causes of central CH include
mutations in a variety of transcription
factors involved in pituitary and
hypothalamic development, including
HESX1, LHX3, LHX4, SOX3, OTX2,
PROP1, or POU1F1.84,85 These genetic
defects also cause associated
abnormalities specific to the causative
gene. Additional pituitary hormone
deficits are present in most cases of
central CH (about 75%). Isolated
central CH is rare, and the most
common genetic cause are mutations
in IGSF1, which cause an X-linked
syndrome of central CH and macro-
orchidism. Rare genetic causes of
isolated central CH include mutations
in the thyrotropin-releasing hormone
receptor, the b subunit of TSH
(TSHB), TBL1X, or IRS4.86,87
Syndromes associated with CH can
be monogenic or can be part of
other conditions or syndromes. In
addition to trisomy 21, CH may
be associated with CHARGE
syndrome and Williams syndrome.
Even in the absence of an evident
syndrome, infants with CH are at
increased risk of congenital
anomalies, which are present in
10% of infants with CH compared
with 3% of the general population.
The most common are
cardiovascular anomalies, such as
pulmonary stenosis, atrial septal
defect, and ventricular septal
defect, but dysmorphic features,
neural tube defects, hip dysplasia,
and renal or other urinary
tract anomalies are also
documented.106–110
Recent advances in genetic testing
allow for the assessment of many
genes simultaneously, at lower cost
and with faster turnaround time
than in the past. Genetic information
may be perceived as valuable by
families, but genetic testing can
present challenges of cost and
interpretation of indeterminate
results, and in many cases a genetic
diagnosis may not alter clinical

TABLE 2 Genes Associated With Thyroid Dyshormonogenesis6,101

Gene Name Clinical Manifestations Associated Syndrome Inheritance Pattern
TSHR — — Autosomal dominant or recessive
GNAS Brachydactyly, round facies, ectopic Pseudohypoparathyroidism if Autosomal dominant with imprinting
ossifications, short stature, maternally inherited; Albright
obesity, intellectual disability, hereditary osteodystrophy if
hormone resistance paternally inherited
SLC5A5 — — Autosomal recessive
SLC26A4 Sensorineural deafness with Pendred syndrome Autosomal recessive
enlarged vestibular aqueduct
DUOX2 — — Autosomal dominant or recessive
DUOXA2 — — Autosomal recessive
TPO — — Autosomal recessive
TG — — Autosomal recessive
IYD — — Autosomal recessive
—, not applicable.

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 management. For children with
isolated primary CH, genetic testing
should be considered when a
genetic diagnosis would alter clinical
management. For cases that have a
recognizable syndrome, central CH,
or clinical features that suggest a
genetic condition, referral to a
geneticist is recommended. In such
cases, genetic findings may enable
counseling of families about
recurrence risks or may identify
other family members at risk. In all
cases, the choice of whether to
pursue genetic testing is made in
consultation with the patient’s
family.
TREATMENT
CH is treated with enteral L-T4 at a
starting dose of 10 to 15 mcg/kg
per day, administered once daily.
L-T4 tablets are the treatment of
choice. Use of a brand name L-T4
formulation to provide a consistent
formulation may be superior for
children with severe CH.111
However, generic tablets suffice
for most children. A commercial
oral solution of L-T4 is approved
by the US Food and Drug
Administration for use in children
of any age; however, limited
experience with its use showed
that dosing may not be equivalent
to dosing with tablet
formulations.112,113 L-T4
suspensions prepared by
compounding pharmacies may
result in unreliable dosing.114,115
Breastfeeding does not interfere
with L-T4 administration. 116 If
enteral administration is not
possible, L-T4 can be administered
intravenously at 75% of the
enteral dose. 117
The goal of L-T4 treatment is to
support normal growth and
neurocognitive development.
Achieving optimal outcome depends
on early initiation of adequate L-T4
treatment (generally by 2 weeks of
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life when detected with the first
NBS), particularly in severe cases of
CH.21,118 Therefore, the goal of
initial L-T4 therapy is to normalize
serum FT4 and TSH concentrations
as quickly as possible. The
prognosis is poorer for infants who
are detected later in life, receive
inadequate doses of L-T4, or have
more severe hypothyroidism.118–120
Rapid normalization of serum TH
levels leads to improved
neurocognitive outcomes.121–125
Normalization of serum TSH may
lag after the initiation of treatment,
particularly in severely affected
infants. Although age-specific TSH
reference ranges vary by
laboratory, recent studies indicate
that the upper limit of normal TSH
in infants 1 to 3 months of age is
4.1 to 4.8 mIU/L80–84; therefore,
TSH values above 5 mIU/L
generally are abnormal if observed
after 3 months of age. Whether
overtreatment (defined by elevated
serum FT4) is harmful remains
unclear and evidence is
conflicting.120,126–128
The typical L-T4 starting dose
(10–15 mcg/kg per day) frequently
results in elevated FT4 levels, so
dose reduction is often needed
2 weeks after starting L-T4
treatment.129
Some infants with CH have
persistent serum TSH elevation
despite FT4 levels at or above the
upper limit of the reference range.
This central resistance to TH may
be caused by alteration of
pituitary-thyroid feedback caused
by intrauterine hypothyroidism.130–132
Resistance to TH is more common in
infants younger than 1 year and
typically resolves over time but may
persist in up to 10% of children with
CH.132 In patients with CH and
resistance to TH, there is insufficient
outcome-based evidence to determine
whether to prioritize normalizing TSH
or normalizing FT4 with L-T4
treatment. The addition of liothyronine
(L-T3) to L-T4 monotherapy (only in
consultation with a pediatric
endocrinologist) may normalize both
TSH and FT4 in patients with
resistance to thyroid hormone, but
there is no evidence that this improves
patient outcomes.133
The required dose of L-T4 may be
stable or may change with time.
L-T4 dose requirements can be
affected by chronic illness, organ
dysfunction, medications, or changes
in weight, dietary soy intake, L-T4
absorption, or serum estrogen
concentrations.
The endocrinologist and PCP
provide critical parental education
as detailed in the accompanying
clinical report.15,71 Educational
resources can be obtained from the
American Thyroid Association
(www.thyroid.org/congenital-
hypothyroidism/), the Pediatric
Endocrine Society (https://
pedsendo.org/patient-resource/
congenital-hypothyroidism/), the
Endocrine Society (education.endo-
crine.org/content/congenital-hypo-
thyroidism-pim-diagnosis-and-ma-
nagement), the National Institutes of
Health (ghr.nlm.nih.gov/condition/
congenital-hypothyroidism), the
Magic Foundation (www.
magicfoundation.org/Misc/
ViewContent.aspx?ContentID=
856ac9d3-dec2-4f96-81be-
b36e257afb88), and others.
MONITORING
Close laboratory monitoring is
necessary during L-T4 treatment to
maintain serum TSH and FT4 in the
target range and to avoid under- or
overtreatment.16 Because FT4
measurements vary among assays,
age- and assay-specific reference
ranges are necessary when
interpreting FT4 values133–136
(www.aap.org/en-us/Documents/
periodicity_schedule.pdf). Because of
relatively rapid growth and
FROM THE AMERICAN ACADEMY OF PEDIATRICS
 increased metabolic clearance of
thyroid hormone, studies support
measuring serum TSH and free T4
every 1 to 2 months in the first
6 months of life, every 2 to 3
months in the second 6 months of
life, and then every 3 to 4 months
between 1 and 3 years of age for
children with CH.15 In addition to
the role of the pediatric endocrinolo-
gist, the PCP has an important role in
promoting adherence to L-T4 therapy
by children with CH.71
LONG-TERM FOLLOW-UP
Particular attention to behavioral
and cognitive development is
necessary, because children with CH
may be at higher risk for
neurocognitive and socioemotional
dysfunction compared with their
unaffected peers, despite adequate
treatment of CH.137,138 Hearing
deficits are reported in
approximately 10% of children with
congenital hypothyroidism.139
Inadequate treatment of CH may
have negative consequences for
development. Nevertheless, a
significant proportion of children
diagnosed with CH do not continue
L-T4 replacement therapy until
3 years of age, and up to half of
patients with a diagnosis of CH may
be lost to follow-up.140–142
Institution of clinical follow-up
protocols may help prevent children
with CH from being lost to follow-up
and potentially experiencing adverse
outcomes.
ASSESSMENT OF PERMANENCE OF
HYPOTHYROIDISM
The increasing incidence of CH
largely is attributable to increased
detection of mild or transient
CH, often with a eutopic gland.27–29,
143–149
Overall, when patients with a
eutopic gland are trialed off L-T4
therapy, approximately 40% prove
to have permanent CH (low FT4 and
high TSH), 25% have persistent
hyperthyrotropinemia (normal FT4
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and high TSH), and 35% have had
transient CH (prior abnormality but
now normal FT4 and normal
TSH).147–155
CH is confirmed to be permanent in
cases of thyroid dysgenesis or if
the serum TSH increases above
10 mIU/L after the first year of life
(on treatment). In patients with a
eutopic thyroid, TSH concentration
at diagnosis is not necessarily
predictive of permanent versus
transient disease, and permanent
hypothyroidism cannot be assumed
solely on the basis of a very
elevated TSH level at diagnosis.147
Additional features that suggest
transient hypothyroidism include a
low L-T4 requirement (particularly
below 2 mcg/kg per day) to
maintain euthyroidism after 1 year
of age, lack of need for increasing
L-T4 doses over time, and absence
of abnormal TSH levels during
treatment.147,156–158
Unless a diagnosis of permanent CH
has been confirmed (by imaging or
TSH elevation while on treatment), a
trial off L-T4 therapy performed at
3 years of age can assess whether
lifelong L-T4 treatment is
necessary.5–7,15 It is critical that
patients not be lost to follow-up
while trialing off L-T4 therapy.
Specific Causes of Transient
Congenital Hypothyroidism
Maternal Graves Disease
Antithyroid drugs (carbimazole,
methimazole, or propylthiouracil)
used during pregnancy cross the
placenta and can cause transient CH
until they are cleared from the
infant’s circulation (about 7–10 days).
Mothers with autoimmune thyroid
disease may have circulating
immunoglobulin G antibodies that
block activation of the TSH receptor
(TRBAb). Transplacental passage of
these antibodies is a rare cause of
transient CH, accounting for
approximately 2% of CH detected by
NBS.159 A maternal history of
autoimmune thyroid disease
(including Graves disease) or of a
previously affected child (or
concurrently affected twin) may raise
suspicion for TRBAb. However, the
absence of such a history does not
reliably exclude this diagnosis.160 CH
resolves once TRBAb are cleared
from the serum of affected infants,
usually by 3 to 6 months of age.161
Maternal hyperthyroidism that is not
adequately controlled during
pregnancy can lead to neonatal central
hypothyroidism after birth, probably
resulting from suppression of the fetal
hypothalamic-pituitary-thyroid axis by
excess maternal TH that crossed the
placenta.162 Such central
hypothyroidism is usually transient
but can persist in rare cases.163 TH
treatment may be required for 6 to
24 months or until reevaluation after
3 years of therapy.163
Iodine Deficiency
Iodine is required for TH synthesis,
and iodine deficiency is an
important cause of CH worldwide,
but iodine supplementation will
restore normal TH production.
Iodine Excess
Excessive iodine intake causes
reduced synthesis of TH (the Wolff-
Chaikoff effect), which can cause
hypothyroidism in infants. Because
the fetal thyroid gland is highly
sensitive to this effect, preterm
infants are at particular risk of
iodine-induced hypothyroidism.
Excessive iodine exposure may
occur prenatally from maternal use
of amiodarone164 or postnatally
from iodine-containing
antiseptics,165,166 radiologic contrast
agents,167,168 or excessive maternal
iodine intake.169,170 Infants with
iodine deficiency or excess that
occurs after birth may have normal
NBS results in the first few days
after birth, but CH may be detected
11
 on a second test performed at 10 to
14 days of age.171
DEVELOPMENTAL OUTCOME
Growth and adult height are
generally normal in children with
CH in whom L-T4 therapy is
maintained with TSH and FT4 in
target range.172,173 NBS has
substantially improved
neurodevelopmental outcomes from
CH, and severe intellectual
impairment does not occur in
patients who are diagnosed and
treated early and adequately.
Adequate initial L-T4 treatment
of CH (early initiation of L-T4,
10–15 mcg/kg per day, with
normalization of thyroid function
within 2 weeks) results in grossly
normal neurocognitive function in
adulthood.118 However, detailed
studies report neuropsychological
deficits in some children with CH
compared with controls, including
impaired visuospatial processing and
deficits in memory and sensorimotor
function. Mild to moderate deficits
may be identified by early childhood
and may persist into adolescence and
adulthood.13,174,175 If a child is
adequately treated for CH but growth
or developmental progress is
abnormal, evaluation for potential
intercurrent illness, hearing deficit, or
other hormone deficiency is
warranted.
Some studies have found an
association between the severity of
CH (defined by pretreatment serum
T4 level, delayed skeletal maturation
at diagnosis, or the presence of
thyroid agenesis) and worse
developmental outcome, despite
early L-T4 treatment.14,126,176–180
However, other studies demonstrate
that early initiation of doses of
L-T4>10 mcg/kg per day may
abrogate the effect of initial CH
severity on developmental outcome,
with severely affected patients
achieving similar outcomes to more
mildly affected children.118,181,182
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Negative influences on cognitive,
psychomotor, and behavioral
development have been
demonstrated with delayed or
inadequate treatment; adverse
outcomes attributable to
overtreatment have been observed
in some studies, but evidence is
conflicting, and this association
remains unclear.121,122,126
In contrast to the overall favorable
outcome in infants with CH who are
treated early, the neurodevelopmental
prognosis is less certain in those in
whom CH is not detected and, as a
result, begin treatment late.
Although physical recovery is good
and stature is normal when L-T4
replacement therapy is begun
within the first 2 months of life,173
infants with severe CH and
intrauterine hypothyroidism (as
indicated by retarded skeletal
maturation at birth) may have a
low-to-normal intelligence.182
Similarly, although more than 80%
of infants given L-T4 replacement
therapy before 3 months of age
have an intelligence greater than
85, 77% of these infants show signs
of cognitive impairment in
arithmetic ability, speech, or fine
motor coordination later in life.
CONCLUDING COMMENTS
Despite the evident success of NBS,
physicians need to consider
hypothyroidism in the face of
clinical symptoms, even if newborn
screening thyroid test results were
normal. Failure of normal
neurodevelopment can result from
hypothyroidism in infants who
initially had normal NBS results
but in whom hypothyroidism
manifests or is acquired after NBS
or with errors in NBS tests.
Hypothyroidism can occur in
infants in whom NBS is not
performed (eg, some home
deliveries) or for whom results are
not properly communicated to the
infant’s PCP.183 Therefore, when
clinical symptoms or signs of
hypothyroidism are present (such
as large posterior fontanelle, large
tongue, umbilical hernia, prolonged
jaundice, constipation, lethargy, or
hypothermia), measurement of
serum TSH and FT4 is indicated,
regardless of NBS results.
This document is copyrighted and is
property of the American Academy
of Pediatrics and its Board of
Directors. All authors have filed
conflict of interest statements with
the American Academy of Pediatrics.
Any conflicts have been resolved
through a process approved by the
Board of Directors. The American
Academy of Pediatrics has neither
solicited nor accepted any
commercial involvement in the
development of the content of this
publication.
Technical reports from the
American Academy of Pediatrics
benefit from expertise and
resources of liaisons and internal
(AAP) and external reviewers.
However, clinical reports from the
American Academy of Pediatrics
may not reflect the views of the
liaisons or the organizations or
government agencies that they
represent.
The guidance in this report does not
indicate an exclusive course of
treatment or serve as a standard of
medical care. Variations, taking into
account individual circumstances,
may be appropriate.
All technical reports from the
American Academy of Pediatrics
automatically expire 5 years after
publication unless reaffirmed, revised,
or retired at or before that time.
LEAD AUTHORS
Susan R. Rose, MD, FAAP
Ari J. Wassner, MD, American
Thyroid Association Representative
Kupper A. Wintergerst, MD, FAAP
FROM THE AMERICAN ACADEMY OF PEDIATRICS
 Nana-Hawa Yayah Jones, MD Ingrid A. Holm, MD, FAAP STAFF
Robert J. Hopkin, MD, FAAP Wendy J. Introne, MD, FAAP Paul Spire
Janet Chuang, MD Kelly Jones, MD, FAAP
Jessica R. Smith, MD, Pediatric Michael J. Lyons, MD, FAAP
Endocrine Society Representative Danielle C. Monteil, MD, FAAP ABBREVIATIONS
Katherine Abell, MD Amanda B. Pritchard, MD, FAAP
Stephen H. La Franchi, MD, FAAP Pamela Lyn Smith Trapane, MD, FAAP CH: congenital hypothyroidism
DBS: dried bloodspot
Samantha A. Vergano, MD, FAAP
SECTION ON ENDOCRINOLOGY FT4: free thyroxine
Kathryn Weaver, MD, FAAP
EXECUTIVE COMMITTEE, 2020–2021 GNAS: guanine nucleotide-
binding protein
Kupper A. Wintergerst, MD, FAAP
(G-protein) subunit a
Kathleen E. Bethin, MD, FAAP
LIAISONS LBW: low birth weight
Brittany Bruggeman, MD, FAAP
L-T3: liothyronine (medication)
(Fellowship Trainee) Aimee A. Alexander, MS, CGC –
L-T4: levothyroxine (medication)
Jill L. Brodsky, MD, FAAP Centers for Disease Control and NBS: newborn screening
David H. Jelley, MD, FAAP Prevention PCP: primary care provider
Bess A. Marshall, MD, FAAP Christopher Cunniff, MD, FAP – TH: thyroid hormone
Lucy D. Mastrandrea, MD, PhD, American College of Medical T4: thyroxine
FAAP Genetics TBG: thyroxine-binding globulin
Jane L. Lynch, MD, FAAP (Immediate Mary E. Null, MD – Section on T3: triiodothyronine
Past Chairperson)
Pediatric Trainees TRBAb: thyrotropin receptor-
Melissa A. Parisi, MD, PhD, FAAP – blocking antibody
STAFF National Institute of Child Health & TSH: thyroid-stimulating
Laura Laskosz, MPH Human Development hormone
Steven J Ralson, MD – American College TSHR: TSH receptor
COUNCIL ON GENETICS EXECUTIVE of Obstetricians & Gynecologists VLBW: very low birth weight
COMMITTEE, 2020–2021 Joan Scott, MS, CGC – Health
Leah W. Burke, MD, MA, FAAP Resources and Services
Timothy A. Geleske, MD, FAAP Administration

external reviewers. However, technical reports from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations or
government agencies that they represent. The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical
care. Variations, taking into account individual circumstances, may be appropriate. All technical reports from the American Academy of Pediatrics
automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.
DOI: https://doi.org/10.1542/peds.2022-060420
Address correspondence to Susan R. Rose, MD, FAAP. E-mail: mslrose4@gmail.com
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2023 by the American Academy of Pediatrics
FUNDING: No external funding.
FINANCIAL/CONFLICT OF INTEREST DISCLOSURES: Dr LaFranchi reported a financial relationship with UpToDate as an author on the topic of congenital
hypothyroidism.
COMPANION PAPER: A companion to this article can be found at http://www.pediatrics.org/cgi/doi/10.1542/peds.2022-060419.

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