Newborn Screening Results in Children with Central Hypothyroidism

Todd D. Nebesio, MD, Michael P. McKenna, MD, Zeina M. Nabhan, MD, MSc, and Erica A. Eugster, MD
Objective To investigate newborn screening results in children with congenital hypopituitarism, including central
hypothyroidism, and to determine whether there were differences between children who had abnormal results and
children with normal newborn screening results.
Study design Medical records of children with central hypothyroidism observed in our pediatric endocrinology
clinics from 1990 to 2006 were reviewed.
Results Forty-two subjects (22 boys) were identified. Eight children (19%) had a low total thyroxine level (<5.0
mcg/dL) on the newborn screening test. The average total thyroxine level in the remaining 34 subjects was 9.8 
3.4 mcg/dL. Thyrotropin levels were within the reference range in all children. No differences were found in the 2
groups for birth history, jaundice (53% overall), hypoglycemia (36% overall), or micropenis (43% of boys). Fiftyseven percent of children had septo-optic dysplasia, and 98% had multiple pituitary hormone deficiencies. Children
with an abnormal newborn screening results were initially examined by a pediatric endocrinologist at an average
age of 4.6  5.0 months, and children with normal newborn screening results were initially examined at an average
age of 16.9  26.7 months (P = .037).
Conclusions Most children with congenital central hypothyroidism have normal thyroid function at birth. Normal
newborn screening results can be falsely reassuring and may contribute to a delay in diagnosis of hypopituitarism
despite classic clinical features. (J Pediatr 2010;156:990-3).

entral hypothyroidism is a rare yet important cause of congenital hypothyroidism. Initial estimates on the basis of early
newborn screening programs suggested a prevalence of approximately 1 in 100 000 infants.1 As additional infants were
screened, the prevalence was revised to 1 in 16 000 to 29 000 infants.2-4 Despite efforts to improve detection of all forms
of congenital hypothyroidism with newborn screening, cases of central hypothyroidism have been missed.2,4,5
Newborn screening programs in the United States use either a primary thyrotropin screen with thyroxine (T4) backup, a primary T4 screen with thyrotropin backup, or a combined thyrotropin plus T4 approach.6 The simultaneous measurement of T4
and thyrotropin is considered to be the ideal screening method,6 because this combination strategy is considered useful in detecting cases of central hypothyroidism.4,5 According to the National Newborn Screening and Genetics Resource Center,7 there
are 8 states that use the combined screening method.
Until September 2007, the state of Indiana measured both T4 and thyrotropin. However, our anecdotal experience indicated that
several children with central hypothyroidism had initially normal newborn screening results. Therefore, we sought to systematically investigate newborn screening results in children with congenital hypopituitarism including central hypothyroidism during
a 17-year period when combination screening was used. Clinical and historical data were collected to determine whether differences existed between children with abnormal newborn screening results and children with normal newborn screening results.

Methods
After institutional review board approval, a retrospective chart review was performed in all children with central hypothyroidism seen in the pediatric endocrinology clinics at Riley Hospital for Children from 1990 to 2006. Eligible subjects were identified
by searching a clinical database for International Classification of Diseases, Ninth Revision codes, including hypothyroidism (243,
244.8, and 244.9), hypopituitarism (253.2), and other specified anomalies of the nervous system (742.8) such as septo-optic
dysplasia. Inclusion criteria were children in whom congenital central hypothyroidism had been diagnosed and who had newborn screening results available. Abnormal newborn screening results consistent with central hypothyroidism were defined as
a low T4 level (T4 reference range, 5.0-25.0 mcg/dL) with an inappropriately normal thyrotropin level. Serum thyroid studies,
including a thyrotropin and free T4 or free thyroxine index, were obtained to confirm central hypothyroidism, and a pediatric
endocrinologist examined each child. Exclusion criteria included children with thyroid-binding globulin (TBG) deficiency, primary forms of congenital hypothyroidism, acquired primary hypothyroidism,

CNS
MRI
T4
TBG

Central nervous system

Magnetic resonance imaging
Thyroxine
Thyroid-binding globulin

From the Indiana University School of Medicine,

Department of Pediatrics, Riley Hospital for Children,
Indianapolis, IN
The authors declare no conflicts of interest.
0022-3476/$ - see front matter. Copyright 2010 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2009.12.011

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Vol. 156, No. 6  June 2010

and acquired forms of central hypothyroidism, such as brain
tumor, radiation, surgery, trauma, or central nervous system
infection. Additional variables analyzed were birth history,
neonatal hospitalization with a prolonged hospital stay
(defined as >72 hours), presence of jaundice (as noted by
the referring physician), hypoglycemia (defined as a serum
glucose level <40 mg/dL), micropenis in boys (defined as
a stretched penile length <2.5 cm), central nervous system
(CNS) imaging, additional pituitary hormone dysfunction,
developmental delay, and time to initial examination by a pediatric endocrinologist.
Statistical Analysis
The descriptive statistics of the sample and the outcome measures were calculated. Data are expressed as mean plus or
minus SD. For normally distributed data, the t test was
used to compare the two groups. The c2 test was used for
all other data. All calculations were performed with SPSS
software version 16.0 (SPSS, Chicago, Illinois) or Microsoft
Excel 2007. The Alpha level was set at 0.05.

Results
Of 409 patients identified with central hypothyroidism, 181
children had unavailable or incomplete medical records. Of
the 228 remaining patients, 173 did not meet inclusion criteria
because their condition was miscoded and they did not actually have congenital central hypothyroidism. Of the 55 remaining patients, 13 did not have available newborn screening test
results. Therefore, 42 patients (52% male) with a current age of
8.9  4.7 years were included in the analysis.
Thirty-four children (81%) had normal newborn screening results, and 8 children (19%) had abnormal newborn
screening results (mean T4 level, 9.8  3.4 versus 3.7 
0.6; P < .001). Thyrotropin levels were in the reference range
in both groups. Forty-one patients (98%) had multiple pituitary hormone deficiencies, including growth hormone deficiency (76%), corticotropin deficiency (81%), and central
diabetes insipidus (21%). The remaining subject had isolated
central hypothyroidism, but central precocious puberty
developed at the age of 4 years. No difference in the incidence
of specific pituitary hormone deficiencies was seen in the 2
groups. All children underwent CNS imaging, with most
(93%) undergoing magnetic resonance imaging (MRI). All
children with abnormal newborn screening results had abnormal MRI results, including 4 with pituitary hypoplasia
(50%), 3 with an ectopic posterior pituitary (38%), 2 with
optic nerve hypoplasia (25%), 2 with absent septum pellucidum (25%), and 2 with an absent or thin corpus callosum
(25%). In children with normal results on newborn screening, 91% had an abnormal MRI or computed tomography
including 17 with pituitary hypoplasia (50%), 10 with an ectopic posterior pituitary (29%), 10 with optic nerve hypoplasia (29%), 8 with an absent septum pellucidum (24%), and 6
with an absent or thin corpus callosum (18%). Some children had >1 abnormal finding on MRI. There was no statis-

Table. Comparison of children with central

hypothyroidism on the basis of newborn screening
results

Variable
Sex
Initial T4 on newborn screening
Growth hormone deficiency
Corticotropin deficiency
Diabetes insipidus
Abnormal CNS imaging
(CT or MRI)
Prolonged neonatal
hospitalization
Developmental delay
Time to endocrine
consult (months)

Abnormal
results
(n = 8)

Normal
results
(n = 34)

P
value

6 male (75%)
3.7  0.6
7/8 (87%)
6/8 (75%)
1/8 (12%)
8/8 (100%)

16 male (47%)
9.8  3.4
25/34 (73%)
28/34 (82%)
8/34 (23%)
31/34 (91%)

.157
<.001
.405
.63
.49
.076

8/8 (100%)

26/34 (76%)

.087

19/34 (56%)
16.9  26.7

.115
.037

2/8 (25%)
4.6  5.0

CT, Computed tomography.

tical difference between the groups for the abnormalities

noted.
A prolonged neonatal hospitalization was noted in all children with abnormal newborn screening results and in 76%
with normal newborn screening results, although this difference was not significant. The time to initial endocrine evaluation was significantly longer in children with normal
newborn screening results (16.9  26.7 months) than children with abnormal newborn screening results (4.6  5.0
months; P = .037). All the children with abnormal newborn
screening results were referred to the pediatric endocrinology
department because of a low T4 level. Reasons for referral to
pediatric endocrinology in children with normal newborn
screening results included vision problems, nystagmus, or
optic nerve hypoplasia noted by an ophthalmologist (14 children, 41%), short stature and poor growth (7 children, 21%),
hypoglycemia (5 children, 15%), micropenis (5 children,
15%), diabetes insipidus (3 children, 9%), and a low serum
T4 level noted during laboratory studies for various reasons
(5 children, 15%). Some children were referred for >1 concern. Developmental delay was noted in 2 children (25%)
with abnormal newborn screening results and in 19 children
(56%) with normal newborn screening results. These results
are summarized in the Table.
Typical signs and symptoms of hypopituitarism were present in many subjects in the newborn period. These included
jaundice in 53%, hypoglycemia in 36%, and micropenis in
43% of boys. However, there was no difference in the percentages of patients exhibiting these features in the group
with abnormal versus normal newborn screening results
(Figure). Likewise, the number of children eventually diagnosed with septo-optic dysplasia, seizure disorder, or both
was similar in the 2 groups.

Discussion
Thyroid hormone is critically important for normal brain
growth, cellular differentiation, and CNS development early
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www.jpeds.com

Figure. Associated features of hypopituitarism in children

with central hypothyroidism. There was no statistically significant difference (P < .05) between those children with abnormal newborn screening results and children with normal
newborn screening results. SOD, septo-optic-dysplasia.

in life.8 Unrecognized congenital hypothyroidism leads to

mental retardation.6 Newborn screening has resulted in
nearly all children with congenital hypothyroidism being
properly identified and treated before long-term neurological
consequences develop.9 Several states currently use a combination screening method for T4 and thyrotropin.7 One rationale for this approach is the ability to detect cases of
congenital central hypothyroidism. However, earlier studies
have suggested that congenital central hypothyroidism may
not be diagnosed at birth,4,5 but only may be detected later
after signs and symptoms of other pituitary hormone deficiencies have occurred.10 In contrast, many infants with
a low T4 level and normal thyrotropin level turn out to
have hypothyroxinemia of prematurity,11 severe illness, or
TBG deficiency.12 The finding of a low T4 level and nonelevated thyrotropin level is seen in approximately 3% to
5% on newborn screening, and most neonates do not have
true thyroid insufficiency.13 Therefore, false-positive results
likely far outweigh the number of true cases of congenital
central hypothyroidism, suggesting that the combined T4
and thyrotropin screening method is suboptimal for detecting this condition.
In our patients, only 8 of 42 with central hypothyroidism
were detected with the newborn screening, and 81% of cases
had normal results with the combination screening method.
This is much higher than has been suggested in earlier reports,
which found that 27%5 to 58%4 of infants with congenital
central hypothyroidism have normal results on newborn
screening with the thyrotropin and T4 method. However,
to our knowledge, our study is the largest cohort of patients
with congenital central hypothyroidism in which newborn
screening results have been analyzed. Similar to what has
been observed in other series,3-5 the presence of multiple pituitary hormone deficiencies in our patients with congenital
central hypothyroidism was nearly universal (98%).
An important finding from our study was the significant
delay in evaluation by a pediatric endocrinologist in chil992

Vol. 156, No. 6

dren who had normal newborn screening results. This delay
occurred despite no differences existing in the prevalence of
classic signs and symptoms of hypopituitarism in children
with abnormal versus normal newborn screening results.
This suggests that normal results on newborn screening
resulted in a false sense of security about pituitary function
in these patients. Due in part to our findings, the state of
Indiana stopped using a combination screening method in
September 2007 and now uses thyrotropin as the primary
screening test. Long-term studies will be needed to determine whether there is an increase in the number of missed
cases or a delay in diagnosis of congenital central hypothyroidism in the upcoming years in Indiana as thyrotropin
screening alone is used. An alternative screening method
used in some European countries includes a 3-tier assessment of T4, thyrotropin, and TBG. Studies from the Netherlands have found a 3-fold increase in the detection rate of
congenital central hypothyroidism with this approach.2
Another option would be to perform a second newborn
screen at 2 weeks of life, which is routinely done by some
screening programs.6 Although unproven, this would address a theoretical significant maternal contribution of T4
to neonatal thyroxine levels that could result in infants
with central hypothyroidism being missed on the initial
newborn screening.
Because our study was retrospective and relied on medical
records within a 17-year period, inherent limitations to our
analysis exist. Not all potentially eligible subjects were included because of a lack of newborn screening results. In addition, the diagnosis of central hypothyroidism was based on
classic clinical and laboratory features rather than dynamic
testing, such as the thyrotropin-releasing hormone stimulation test. Although this test has been shown to be useful in
identifying true cases of congenital central hypothyroidism,14
the thyrotropin-releasing hormone stimulation test is
currently not available in the United States15 and was not
used in our patients. n
Submitted for publication Jul 14, 2009; last revision received Nov 12, 2009;
accepted Dec 7, 2009.
Reprint requests: Todd D. Nebesio, MD, Riley Hospital for Children, 702
Barnhill Dr, Room 5960, Indianapolis, IN 46202. E-mail: tdnebesi@iupui.edu.

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