Congenital Hypothyroidism

Szinnai G (ed): Paediatric Thyroidology.

Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)

Neonatal Screening for Congenital

Hypothyroidism
Toni Torresani 
Swiss Newborn Screening Laboratory, University Children’s Hospital, Zurich, Switzerland

Abstract
The possibility of measuring thyroid hormones from blood dried on filter paper opened the way to
identifying neonates with congenital hypothyroidism (CH) already in the first days of life. Conse-
quently the early initiation of adequate replacement therapy opened the way to an effective preven-
tion of mental retardation. Timely and complete specimen collection, transport logistics, rapid anal-
ysis and communication of results are key points for the organization of a CH newborn screening
program. Close collaboration between laboratory and treating specialists is necessary to ensure an
adequate treatment and follow-up of babies identified by CH screening programs. Topics for further
investigations remain in the fields of which forms of CH should be identified by screening (only se-
vere or also very mild forms) and on the long-term outcome of the individuals identified by CH
screening. © 2014 S. Karger AG, Basel

Congenital hypothyroidism (CH) is one of the most frequent preventable causes of

mental retardation. It was therefore only a matter of time until an adequate ­neonatal
screening (NS) test for the early diagnosis of CH was developed and i­ntroduced.
2014 will mark the 40th anniversary of the establishment of the first screening pro-
gram for CH in 1974 in Quebec (Canada) [1]. Since then NS for CH has been estab-
lished both in the developed world and more and more in developing countries. The
American Office of Technology Assessment [2] concludes that screening for CH is
one of the few programs in preventive medicine that has an impact on public health
with a positive cost-to-benefit ratio (10:1).

History of Neonatal Screening for Congenital Hypothyroidism

In the early 70s, reports were published outlining the effectiveness of early interven-
tion in the treatment of CH [3]. Almost simultaneously reports appeared describing
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the possibility of measuring thyroid hormones from cord blood [4] or from dried
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blood spots (DBS) [5]. DBS were already being used for collecting specimens for the
NS for phenylketonuria and became immediately the sample material of choice for
CH screening. While the choice of sampling device (the filter paper card for DBS) was
widely accepted, the choice of which thyroid hormone should be measured, i.e. thy-
roid-stimulating hormone (TSH) or thyroxine (T4), was the subject of lengthy argu-
ments. The controversy was at that time focused mainly on specificity compared to
sensitivity. TSH was thought to be the optimal analyte to detect primary hypothyroid-
ism, but there were limitations in the TSH assays in those days, due to a relatively poor
sensitivity. In contrast T4 assays were somewhat more sensitive but lacked the speci-
ficity and resulted in frequent false-positive results particularly in premature babies.
In the early days NS using T4 as the detection marker was common in North America
[6], while TSH was the analyte of choice in Europe [7] and Japan. Today screening for
CH is in operation in most parts of the world and is, together with the screening for
phenylketonuria, the first program that is implemented in the countries just starting
an NS program. With few exceptions TSH is the analyte of choice. Few jurisdictions
are using T4 followed by one or more secondary parameters. Almost everywhere DBS
specimens are generally used. There are exceptions where cord blood specimens are
used instead of DBS (generally very small jurisdictions where births occur at few or
only a single location) [8].

Screening Organization

NS in general is a public health initiative. Therefore most programs are organized and
financed by the respective health departments. In some jurisdictions the participation
to the screening is mandatory and regulated by law, in others is it usually based on
informed dissent. This means that parents have the possibility to opt out from NS.
Screening is unique in that it is not performed as part of the investigation or treatment
of symptomatic individuals, but it is usually offered to all individuals in a community
not known to be at risk of having the condition. This implies that NS is not a diagnos-
tic test and results from it should not be treated as such and therefore be confirmed
before intervention.
NS is usually performed at large laboratory units, processing several thousands of
samples per year. Such a laboratory should ideally be located at an academic facility,
preferably a pediatric one. A minimal size for an NS laboratory has been put in the
range of around 50,000–100,000 samples per year [9]. The rationale behind such a
recommendation is derived from the fact that with less than about 50,000 samples the
screening process may become inefficient. A low sample number can lead to a poor
cost-benefit ratio and provide an insufficient base for statistical analysis. An NS labo-
ratory must also participate in external quality control programs, ideally in an inter-
national one like the Newborn Screening Quality Assurance Program run by the Cen-
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ters for Disease Control in Atlanta (USA). External quality control programs allow a
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Neonatal Screening for Congenital Hypothyroidism 45

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Szinnai G (ed): Paediatric Thyroidology.

Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
laboratory to test and meet the requirements of all aspects of an NS like training of
personnel and sample processing organization.
In order for an NS laboratory to perform adequately, a continuous communication
with the specialists involved in taking care of the neonates with positive screening re-
sults is of the outmost importance and is also part of the process of quality control.
The shorter the communication lines between laboratory and treating specialist, the
better the outcome of the screening process. Ideally the pathological results of the
screening and the corresponding case outcome should be registered in a centralized
national register, in order to allow epidemiological studies.

Screening Strategy

Screening for primary CH has been introduced in most countries worldwide. It is es-
sential that, when starting a new program, a decision is taken on the scope of the
screening, defining the strategy for selecting the test to be used. The goal of screening
for CH should be to detect all forms of primary CH – mild, moderate and severe, with
particular efforts to detect those patients with severe CH, where morbidity is high if
the disease is not detected and treated until several months after birth [10]. The most
sensitive test for detecting primary CH is the assay of TSH. Because iodine deficiency
is one of the most common preventable causes of mental retardation, developmental
disabilities and CH worldwide [11], NS for CH using TSH is also an excellent tool to
monitor the iodine nutritional status in both the neonatal and maternal populations
[12].

Screening Protocols

Screening for CH is effective for the testing of cord blood as well as for blood collect-
ed on filter paper after 24 h of age. The ideal time for sample collection is 48–72 h of
age. Blood is applied directly to the filter paper, and the card is sent immediately after
drying to the laboratory for analysis. The TSH method detects primary CH more ef-
fectively than T4 screening. Analysis of T4 followed by a confirmatory TSH testing has
the drawback of missing cases of mild forms of primary CH. On the other hand, if the
screening program strategy defines it, this approach can detect cases of central CH
(CCH). To be effective the protocols for the detection of CCH are based on one of two
approaches: either a simultaneous determination of T4 and TSH in DBS or a combi-
nation of T4 followed by a secondary TSH testing and in a third step an assay of T4-
binding globulin (TBG). The inclusion of TBG determinations decreases the number
of false-positive results [13].
Because screening for CH is usually embedded in comprehensive NS programs,
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some compromise has to be made with respect to the timing of sample collection.
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46 Torresani
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Szinnai G (ed): Paediatric Thyroidology.

Endocr Dev. Basel, Karger, 2014, vol 26, pp 44–49 (DOI: 10.1159/000363154)
Home deliveries, early discharge and the increasing economic pressures on the health
care systems worldwide have resulted in the timing of specimen collection being put
as much forward as to less than 24 h after birth. It is therefore important that in the
screening laboratory the results of the TSH assay are interpreted in relation to time of
sampling, i.e. by using cutoff values accordingly stratified.
Furthermore the CH screening results obtained in some groups of neonates at risk
of transient and permanent CH must be evaluated separately. It is customary that in
preterm neonates (gestational age less than 37 weeks), those with birth weight less
than 2,000 g and all neonates admitted to an intensive-care unit have more than 1 NS
specimen taken: 1 within the first 48 h and another around 14 days of age or at dis-
charge [14]. Similarly, in the case of a specimen being collected in the first 24 h or in
the case of multiple births (particularly same sex twins), there should be at least a sec-
ond specimen collected. In all these instances the interpretation of the TSH values
must be made taking into account all specimens collected from the same neonate.
Several publications have dealt with this issue [15]. The underlying idea is that in
these infants the TSH could be low-normal even in a case of CH. TSH suppression
following drug administration in the intensive-care unit, hypothalamic immaturity or
fetal blood mixing in multiple births are quoted as the most likely causes. Whether the
possible cases of CH detected after a second specimen represent true permanent hy-
pothyroidism or whether these are mostly transient cases is still a debated issue that
needs further studies.
Usually the strategy of a screening for CH is aimed at detecting all the severe forms
of CH and this as early as possible. For this purpose TSH screening is the most sensi-
tive test in detecting primary CH. This approach is nowadays being used in most CH
screening programs with good success. The detection rate of cases of CH, both per-
manent and transient, is around 1:2,500–1:3,500 at screening. This corresponds to the
cases needing at least a temporary replacement therapy, and it does not represent the
‘real’ incidence of CH.
In recent years the scope, and accordingly the strategies, of several CH screening
programs has been revised, and their aim is not only the detection of the severe forms
of CH but more and more it is focusing on the detection of possibly ‘all’ forms of CH.
The screening cutoff levels have been gradually decreased, and as a consequence an
increase in the screening incidence of CH cases has been reported [16]. Studies on long-
term outcome are now under way to try to determine whether there is a risk of perma-
nent disability in these milder cases with only moderate TSH elevation and usually
normal T4 levels and whether these individuals present with a permanent or a transient
thyroid dysfunction. A further shift in the scope of CH screening is aiming at a possible
use of the neonatal test to detect cases of CCH. The rationale behind these initiatives is
that in some populations CCH is a relatively frequent disease with prevalence similar
to that of phenylketonuria and that the possibility of an unfavorable outcome in cases
of delayed diagnosis is documented [17]. On the downside the lack of a DBS-based
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free-T4 assay, the ideal analyte for the diagnosis of CCH, represents a severe obstacle.
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Confirmation of Congenital Hypothyroidism

Confirmation of a positive screening result is necessary before an infant is declared a

CH case. Screening is not a diagnostic test and the possibility of mislabeling samples
in the nursery should not be dismissed. Particularly in multiple births mislabeling of
specimens happens relatively frequently. The confirmation of the pathological screen-
ing result must be made rapidly by measuring at least TSH and free T4 in a new venous
blood sample. Replacement therapy may be started immediately after drawing the
blood sample and without waiting for the analytical result. In many programs a sam-
ple is drawn also from the mother of the neonate and analyzed for thyroid hormones
and for thyroid antibodies. Positive antibodies in the mother can be the cause of a
transient form of CH in the baby. It is good practice that the diagnosis of CH is re-
evaluated at about 2 years of age, in order to avoid unnecessary treatment in cases of
transient CH.

Follow-Up

The neurodevelopmental outcome in children with CH detected by NS and started on

thyroid hormone treatment early is normal or near-normal [18]. Importantly initial
early high-dose therapy must constitute the first component of an adequate substitu-
tion therapy. Regular therapy monitoring taking care of maintaining appropriate thy-
roid hormone levels remains of the utmost importance.

Conclusion

NS for CH is a great success story, and it is very likely that it will continue to be and
to expand worldwide. Very recently new guidelines have been published defining rec-
ommendations for NS [19, 20]. As it has been the experience with all new disorders
added to existing NS programs, the results obtained when a large birth population
undergoes a comprehensive NS for CH will show some new and previously not known
forms of thyroid dysfunction. CH has been shown to be a heterogeneous group of
disorders with a spectrum going from severe, permanent hypothyroidism to mild,
transient hypothyroidism. The significance of thyroid dysfunction characterized by
delayed elevation of serum TSH in preterm infants and acutely ill term infants needs
further evaluation.
Even 40 years after the start of NS for CH, many of the questions concerning the
etiology remain unexplained.
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Dr. Toni Torresani
Büelstrasse 84
CH–8132 Hinteregg (Switzerland)
E-Mail toni@torresani.ch
Neonatal Screening for Congenital Hypothyroidism
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