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Newborn screening for congenital

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J Inherit Metab Dis
DOI 10.1007/s10545-011-9286-8

ORIGINAL ARTICLE

Newborn screening for congenital hypothyroidism

in very-low-birth-weight babies: the need for a second test
Sunita Bijarnia & Bridget Wilcken & Veronica C. Wiley

Received: 7 November 2010 / Revised: 12 January 2011 / Accepted: 24 January 2011

# SSIEM and Springer 2011

Abstract Newborn screening samples for TSH measurement were

Background Very-low-birth-weight babies (VLBW) with
hypothyroidism may show a delayed postnatal rise in
thyroid stimulating hormone (TSH), mainly due to imma-
turity of the hypothalamic-pituitary-thyroid axis. Transient
hypothyroidism is prevalent in VLBW babies and some
affected babies are considered to need treatment. There is
disagreement about whether a second screening test is
needed in VLBW babies to detect all cases that need
treatment.
Methods We included in the study all babies with a birth
weight 1,500 g born in New South Wales and the Australian
Capital Territory between January 2006 and December 2008.
Communicated by: Rodney Pollitt
Conflict of interest: None declared
S. Bijarnia
The Childrens Hospital at Westmead,
Westmead, NSW, Australia
e-mail: bijarnia@gmail.com
taken in the first days of life and again at 1 month. During
week 1, a blood-spot TSH level of20 mIU/L was considered
positive, and at 1 month a positive level was7 mIU/L, and
triggered full investigation.
Results In the cohort of 301,000 babies, 2,313 VLBW
babies survived for testing, and 2,117 repeat screening
samples were received. Forty-three babies had transient
hypothyroidism, with thyroid function normalising before
2 months of age, usually without treatment. Eighteen babies
required treatment beyond 2 months of age (1:128 of
surviving babies), 16 having had normal TSH results on
initial testing, and 12 having levels below 6 mIU/L.
Conclusion Significant hypothyroidism, transient or per-
manent, but persisting beyond 2 months of age is common
in VLBW babies. There is a delayed rise in TSH in some,
and secondary screening at 1 month of age detects babies
deemed by local paediatric endocrinologists as needing
treatment.

S. Bijarnia : B. Wilcken : V. C. Wiley Introduction

The University of Sydney,
Sydney, Australia
Newborn screening strategies for congenital hypothyroidism
B. Wilcken
have recently been reviewed (LaFranchi 2010). While many
e-mail: bridgetw@chw.edu.au
newborn screening programmes continue to use a strategy of
B. Wilcken : V. C. Wiley (*) measuring thyroxine (T4) initially, with a secondary mea-
New South Wales Newborn Screening Programme, surement of thyroid stimulating hormone (TSH) on samples
The Childrens Hospital at Westmead,
with low T4, it is commoner world-wide to measure TSH as
Locked bag 4001, Westmead, NSW 2145, Australia
e-mail: veronicw@chw.edu.au the primary screening test. Very-low-birth-weight (VLBW)
babies, defined as birth weight 1,500 g, may show a
Present Address: delayed rise in thyroid stimulating hormone (TSH) after birth
S. Bijarnia
in comparison with larger babies (Mitchell et al. 1994).
Sir Ganga Ram Hospital,
Rajinder Nagar, Immaturity of the hypothalamic-pituitary-thyroid axis is a
New Delhi, India major factor, but other factors that can have an impact on the

detection of congenital hypothyroidism (CH) in this group of
babies include medications and blood transfusion (Fisher
1998; Larson et al. 2003). Hypothyroidism (combined
transient and permanent) is more common in VLBW babies
(Larson et al. 2003; Mandel et al. 2000; Grueiro-Papendieck
et al. 2005), and the strategy of retesting for congenital
hypothyroidism has been followed at many centres; VLBW
babies may be tested in their first days of life, according to
usual practice, and then again after a period of time that
differs among laboratories (either 36 weeks post conception-
al age or 11.5 months after birth, depending on individual
protocol) (Vincent et al. 2002; Korada et al. 2008). So far
there is disagreement in the literature about whether or not
the retesting is necessary.
Before 2005, neonatal units across New South Wales
(NSW) routinely tested VLBW babies for thyroid function
at 2 weeks or at the time of discharge from hospital,
irrespective of their newborn screening results. This
practice was partly related to the use of povidone-iodine
as a disinfectant either in the mother, peripartum, or the
infant. Routine testing was gradually abandoned as the
neonatal units changed their protocol for disinfection. In
2005 the NSW newborn screening laboratory started re-
screening all VLBW babies at 1 month of age. While a
second screening test is routine for all babies in a few
screening programmes, particularly in the United States,
and a second screen has been recommended for all VLBW
babies (CLSI 2009), in this project we aimed to investigate
the effectiveness of the routine second screen specifically
for the detection of hypothyroidism.
Materials and methods
Patients
The NSW Newborn Screening Programme provides screen-
ing for all babies born in NSW and the Australian Capital
Territory (ACT) for several treatable disorders including
primary congenital hypothyroidism (Wilcken and Wiley
2008). Data were collected for all VLBW babies born from
1 January 2006 to 31 December 2008, and the retesting
protocol was evaluated.
Sample collection and testing
A routine newborn screening blood sample was collected
from each baby by heel prick between 48 and 72 h onto
pre-printed filter paper (Whatman BFC180). For VLBW
babies a second sample was requested at 1 month of life.
The second samples were subjected to the same full range
of tests as the initial samples were.
J Inherit Metab Dis
Detection of hypothyroidism
Thyroid stimulating hormone (TSH) was measured on
blood samples eluted from filter paper using a dissociated
enhanced fluoroimmunoassay kit with readings performed
on an AutoDELFIA (Perkin-Elmer). The unit of measure
for TSH is milli-international units per litre whole blood
(mIU/LWB). For the conversion of whole blood results to
serum/plasma equivalent, assuming a haematocrit of 50%,
multiply the value by 2. The between-assay coefficient of
variation for internal quality control samples was 6.9% at
16 mIU/LWB, and 5.3% at 66 mIU/LWB. The assay
detection limit was 0.5 mIU/LWB. The age-related refer-
ence ranges established in-house included <20 mIU/LWB
for 4872 h, <15 for days 714, and <7 at days 3060.
Samples with initial TSH greater than 13 mIU/LWB were
re-assayed in triplicate, with a mean of the triplicate values
adopted, and otherwise assays were performed in singlicate.
For all babies, a repeat dried blood spot sample, to be
assayed in triplicate, was requested for any primary
screening sample with a final TSH 2049 mIU/LWB. For
babies with an initial sample with TSH50 mIU/LWB or a
repeat dried blood spot TSH 15 mIU/LWB, further
investigation was requested, including plasma thyroid
function tests (free T3, free T4, TSH), a thyroid ultrasound,
a technetium scan (unless the ultrasound clearly showed an
ectopic thyroid gland), and a bone age x-ray. Figure 1
shows the algorithm used for differential diagnosis. In
VLBW babies, a second screening test card was requested
to be taken at 1 month of age and a level7 mIU/LWB was
considered a positive result requiring further testing for
congenital hypothyroidism including plasma thyroid func-
tion tests, ultrasound and a technetium scan of the thyroid
gland and a bone age x-ray. If either of a twin pair was a
VLBW baby, both twins were re-tested. In babies with
persistent hypothyroidism on treatment, we recommend a
trial withdrawal of treatment for 24 weeks, at about 3 years
of age, with monitoring of TSH levels.
Results
A total of 301,000 babies were born in NSW and the ACT
from 1 January 2006 to 31 December 2008. Among the
3,193 who were VLBW, 663 were still-born and 217 died
in the immediate post-natal period, and these are not
included in our analysis. Fifteen babies did not have a
blood sample drawn in the first 7 days, and another 21
samples were unsuitable for testing having contamination
or insufficient blood spot for full testing. (These needed a
repeat sample anyway, although the initial cards were tested
as far as possible.) There were also two refusals from
parents. An initial newborn screening card was received
J Inherit Metab Dis

Screening Protocol
Sample Collection
Day 3
- TSH Assayed

TSH (mIU/LWB) <20 20-39 40-49 >50

NFT Repeat TSH or TFT's TFT's

dried blood spot Depending on Bone age x-ray
sample - TSH birth weight Thyroid ultrasound
day of sample (If u/sound normal, TSH remains
clinical information elevated & T3, T4 low/normal)
Normal TSH + ; T3,T4 -
TSH (mIU/LWB <15 >15 Thyroid Scan
NFT TFT's; X ray; NFT TFT's; X ray;
Scan Scan

TFT's and Scan N

TFT's Abnormal
Normal Thyroid Normal Thyroid Lingual Thyroid No Thyroid Hemithyroid
NFT CH CH CH CH CH
Dyshormonogenesis Transient Ectopic Thyroid Athyrotic Thyroid Hemithyroid

Fig. 1 The screening protocol followed in the New South Wales further testing, TFT thyroid function tests, T3 triiodothyronine, T4
Newborn Screening Programme. TSH Thyroid stimulating hormone, thyroxine, + result above reference range, result below reference
mIU/L milli-international units per litre, WB whole blood, NFT no range, scan isotope scan, CH congenital hypothyroidism

from 2,275 babies, and a second card at about 1 month of The initial sample was drawn within the first 7 days of
age was received from 2,117. Birth weight was used as an life in all babies included in the study, with a median of
indirect measure of gestational age because information on 3 days. The timing of the second sample was variable with
gestational age was missing (for 116 samples) on NBS a median of 31 days (92% babies were re-sampled before
cards or thought to be inaccurate. The lowest gestational 2 months of age).
age with provision of a sample was 20 weeks. The
gestational age distribution is shown in Table 1. The mean TSH results
and median gestational age in the cohort was 28 weeks.
Of the 3,193 VLBW babies (1,699 males), 1,506 were Most VLBW babies had a normal TSH level in the initial
below 1,000 g, 477 of these being below 500 g. There were sample. Five had a high TSH (20 mIU/LWB or more)
814 VLBW babies from multiple births, including two sets and had immediate further investigation. In two the
of quadruplets and 34 sets of triplets. elevated TSH was persistent (Table 2). Of the 2,117
babies who underwent a second screen, 37 had an
abnormal result, with TSH levels 7 mIU/LWB (age
Table 1 Gestational age distribution appropriate cut-off for full-term babies). Eighteen of them
(1:116 of those from whom we received samples, 1:128 of
Gestational age (weeks) Number of babies all survivors) were classified as having persistent elevation
<24 528
of TSH after further investigations. These babies were
24 to <26 350
started on treatment with thyroxine soon after diagnosis
26 to <28 510
and 16 still remained on thyroxine supplementation at ages
2455 months (Table 2). Two babies (twins) were lost to
28 to <30 659
follow-up after 4 months of treatment. Plasma TSH
30 to <31 519
measurements at 1 month were 46 and 135 mIU/L. Not
31 511
all children have yet had a trial withdrawal of treatment.
Gestation unknown 116
Six babies had undoubted permanent hypothyroidism,
Total 3,193
with an increase in TSH developing after trial treatment
 J Inherit Metab Dis

Table 2 Babies with hypothyroidism treated for 2 months or more

Case Sex B Wt (g) TSH 1st test TSH 2nd test Age 2nd Plasma TSH Plasma Isotope Current Comment
(mIU/LWB) (mIU/LWB) test (days) (mIU/L) FT4 scan result duration of Rx
(months)

1 F 680 5 8 27 31 on Rx 16.7 on Rx N 23 Treatment ongoing

2 M 710 1 35 30 204 6.9 N, on Rx 38 Treatment restarted
after withdrawal test
3 M 710 4 20 40 27.7 14.9 Not done 51 Down syndrome,
treatment ongoing
4 F 760 4 7 28 22 16 Thyroid not detected 30 Treatment ongoing
5 F 770 116 21 4 449 7.4 Hemiagenesis 40 Treatment ongoing
6a F 810 3 12 27 56 10.8 Gland in situ 26 Treatment restarted
after withdrawal test
7 M 940 2 11 29 48 7.4 Increased size uptake 31 Treatment ongoing
8 F 980 10 7 32 11.5 on Rx 12.3 on Rx Hemiagenesis 30 Treatment ongoing
9a F 1,020 1 13 27 16 13 Gland in situ 26 Treatment restarted
after withdrawal test
10 M 1,060 20 120 5 325 5.1 N 21 Treatment ongoing
11 F 1,060 2 8 58 16.6 Very small 31 Treatment restarted
after withdrawal test
12 M 1,090 8 13 26 139 7.6 N 36 Treatment restarted
after withdrawal test
13 F 1,110 3 17 26 85 4.9 Small gland 24 Rx stopped at 24 m
after successful trial
withdrawal
14 M 1,150 0.1 10 31 18.3 16.9 Dyshorm 24 Strong FH of goitre;
treatment ongoing
15b F 1,160 3 14 28 46 17 N 4 Lost to follow-up
after 4 m
16 F 1,220 4 8 28 12.1 16.2 N 24 Treatment ongoing
17b F 1,300 3 88 28 135 9 N 4 Lost to follow-up
after 4 m
18 F 1,460 7 7 37 6 13.8 Small gland 53 Treatment restarted
after withdrawal test

B Wt Birth weight, TSH thyroid stimulating hormone, WB whole blood (to convert whole blood to plasma equivalent assuming a haematocrit of
50%, multiply result by 2), FT4 free thyroxine, Rx treatment, N normal, dyshorm dyshormonogenesis
Superscripts identify twin pairs

cessation at 23 years. Permanent hypothyroidism has still
not been definitively ruled out in the remainder. They
include three with dysgenesistwo hemiagenesis and one
with apparent athyreosisone with a large thyroid with
increased uptake on scan, one with Down syndrome and
two who had had TSH levels in excess of 100 mIU/L at
1 month (see Table 2).
Nineteen babies with a second TSH7 mIU/LWB had
transient hypothyroidism. Thyroid function was normal
when formal thyroid function tests were undertaken usually
a few days later without any treatment or in one baby,
whose mother was on antithyroid medication, after only a
1 week treatment. A third category of babies came from one
centre where there is a protocol for testing with thyroid
function tests at 2 weeks of age as iodine was used
routinely as an antiseptic on newborn skins. Of the 385
babies born at this centre 382 had retesting, most having a
formal thyroid function test at 2 weeks and a newborn
screening blood spot at 1 month of age. Among them was
one baby (included in the 18 positive cases) who required
treatment beyond 2 months of age. An additional 24 babies
had a high TSH with either normal or low free T4, three of
whom were treated with thyroxine for only 2 weeks. All the
24 babies were categorised as having transient hypothy-
roidism secondary to exposure to povidone-iodine. Thus in
total there were 43 babies with transient hypothyroidism
which normalised by 1 month of age with no or only brief
treatment.
Other disorders
The repeat samples were tested for the whole range of
newborn screening disorders, and there were no other
abnormal findings.
J Inherit Metab Dis
Discussion
Increased survival of the very preterm babies has uncovered
a complex problem of hypothyroidism in the very-low-
birth-weight infants (Mitchell 1994). An immature
hypothalamic-pituitary-thyroid axis and postnatal depletion
of thyroxine stores by the end of the first week,
administration of drugs (dopamine, steroids) and iodine
exposure may all lead to thyroid insufficiency, albeit
transient, in these newborns (Fisher 1998; Larson 2003;
van Wassenaer et al. 1997; Filippi et al. 2006). It is still
unclear if transient hypothyroidism leads to intellectual
impairment, but in the absence of certainty some feel that
treatment with thyroxine is indicated (Calaciura et al. 1995;
Rapaport 2002).
However, there is also the possibility that permanent
congenital hypothyroidism may be masked by a delayed
rise in TSH in VLBW babies. To deal with this, many
screening programmes have incorporated a re-screening
strategy. This is supported by the Australasian Paediatric
Endocrine Group (2010), but there is disagreement about
the necessity for this. Several studies have suggested that
re-screening is important: Mandel and colleagues from
Massachussetts described the delayed rise in TSH especial-
ly in VLBW infants as atypical hypothyroidism. They
performed a retrospective review of approximately
1,674,000 newborns (of which 19,000 were VLBW infants)
born from January 1989 to June 2002 and reported a high
incidence of combined typical and atypical hypothyroidism
(1:153 as opposed to 1:3,051 normal birth weight infants)
(Mandel et al. 2000). The study reported by Larson, also
from Massachussetts, showed that there was a 14-fold
higher incidence of hypothyroidism in VLBW infants
(1:250) compared with non-VLBW infants (1:3,500).
Overall, 1:400 VLBW infants showed a delayed rise in
TSH and had hypothyroidism (Larson et al. 2003). In both
of these studies the majority of cases appeared likely to
have had transient hypothyroidism. Two more studies
(Tylek-Lemaska et al. 2005; Gruneiro-Papendieck et al.
2005) provide some evidence supporting repeat screening
in the special category of preterm/VLBW infants. The
Tylek-Lemaska study, from Poland, was in a population
with a high level of iodine deficiency. All patients were re-
assessed at 2 years of age. Among 11 VLBW infants with
permanent primary hypothyroidism, one was missed on the
first screen. A compelling case for further sampling is
presented in a recent study from Korea (Chung et al. 2009).
The authors performed serum thyroid function tests during
the first 10 days of life and then on three subsequent
biweekly intervals on 105 preterm infants, diagnosing 13
with hypothyroidism of whom 8 would have been missed
on the initial sample. There was no long-term follow-up in
this study, so it is unclear how many of these babies had
permanent hypothyroidism. A recent report from Brazil
(Silva et al. 2010) also shows a high prevalence of delayed
TSH rise in VLBW babies who subsequently needed
treatment.
On the other hand, two studies have shown apparently
opposite results. Vincent and colleagues studied 465
VLBW infants and could not identify any baby showing a
delayed rise of TSH. They concluded that a repeat
screening for detection of CH in VLBW infants was
unnecessary (Vincent et al. 2002). This was however a
very small sample size, and two of the four initial samples
that were elevated were only collected at 34 and 64 days of
age, which undermines their conclusion. Another study
(Korada et al. 2008) showed that repeat testing for CH in
preterm infants is unnecessary provided an appropriate TSH
threshold is used. This study, performed on 2,238 infants
(with repeat testing in 2,039) born over a period of 2 years
(April 2005March 2007), evaluated results in four groups
of babies whose first tests were conducted usually on days
58; 98.5% of infants had a TSH less than 6 mIU/L on both
occasions (true negatives). Nineteen infants had false
positive results, showing a TSH value greater than 6 mIU/L
on the first occasion and <6 mIU/L on the second. Three
infants had a true elevation of TSH on both occasions. Five
infants had a delayed rise in TSH but four of the five infants in
this category had a normal TSH level on a subsequent sample,
and in the other, TSH was only marginally elevated.The
authors reported that by keeping a low threshold for TSH with
the initial screen (TSH of 6 or even 10 mIU/L), it would be
possible to detect nearly all cases of congenital hypothyroid-
ism. This studys results are not comparable to ours, nor to
other reported studies, because of the systematically later
collection of the first blood sample, at days 58, compared
with 4872 h.
Our study raises several issues. Firstly, categorisation of
hypothyroidism in VLBW babies has proved difficult. It is
not clear that the age-related reference ranges for TSH
which were used are appropriate to VLBW babies, some of
whom may have TSH levels above 7 mIU/LWB at 4 weeks,
without having significant hypothyroidism (Tylek-
Lemaska et al. 2005). However, only one of the treated
babies in our study had plasma TSH level before treatment
of less than 12 mIU/L. Several of the babies in our cohort
have not yet had a documented trial withdrawal of
treatment, so it is not clear how many will need permanent
treatment, although it seems likely that at least three others
will. We found two babies with thyroid hemiagenesis,
which has a population prevalence of around 1:2,000 to
1:2,500. There have been very few reports of hemiagenesis
being associated with hypothyroidism, but Mikosch and
colleagues in a survey of adults in an iodine-deficient area
found 16 cases of hemiagenesis, 50% of whom did have
mild hypothyroidism (Mikosch et al. 1999). There was also

a baby with Down syndrome who was treated. There is
evidence that most babies with Down syndrome have
slightly abnormal thyroid function and may benefit from
treatment with thyroxine (van Trotsenburg 2006). The
second issue is that we know of only two VLBW babies
(twins with ectopic thyroid glands) with permanent hypo-
thyroidism missed by our screening programme over a
period of 22 years. VLBW babies are under considerable
clinical scrutiny during their first years of life, so that
hypothyroidism would be likely to be diagnosed readily
and would be likely to be reported to the programme. This
accords with experience elsewhere (Rapaport 2000; Vincent
et al. 2002). Thus it is most puzzling that such a large group
of VLBW babies needed treatment. All the babies still able
to be followed have been deemed by paediatric endocrinol-
ogists to need treatment for at least 2 years. Do these babies
represent those who without re-screening would later be
found to have juvenile hypothyroidism? It seems unlikely
that such a problem for VLBW babies would have gone
unnoticed for such a long period. Alternatively most might
have had mild subclinical hypothyroidism, uncovered only
by the repeat testing. This scenario was found (but not in
VLBW babies however) in the interesting retrospective
study in Sweden (Alm et al. 1984).
In our study, there were only 2,117 repeat samples from
2,275 babies, and thus there is a possibility that some cases
were missed. However, even in this small cohort 16 of 18
positive cases showed a delayed rise in TSH. Among the 16
babies, 13 had TSH below 6 on initial testing and would
still have been missed using a lower threshold. By reducing
the threshold TSH level on retesting to 6 mIU/L as
recommended (Korada et al. 2008) the false positive rate
would increase from 0.1 to 2.8% of the population, but
would still miss most cases showing a delayed rise in TSH.
Our initial testing was done earlier than in the UK babies of
Koradas study and this may have influenced results.
Forty-three babies in our study had transient hypothyroid-
ism, with thyroid function which normalised before 2 months
of age, and most of these were not treated at all. This number
suggests that transient hyperthyrotropinaemia may be more
common in infants with VLBW, and it is not known how this
might affect developmental outcome. Pollitt suggests that
additional cases of hypothyroidism are being found because
of better analytical performance in screening laboratories, and
that identifying and treating either mild or transient hypothy-
roidism does not accord with currently accepted criteria for
screening (Pollitt and Wales 2010). Long-term neurodeve-
lopmental studies in a large number of infants and children
are needed to evaluate the effects of subtle thyroid function
abnormalities in neonates (Rapaport 2000), and this might
need to be a retrospective study similar to the instructive
study of Alm and colleagues (Alm et al. 1984) as suggested
(Pollitt and Wales 2010).
J Inherit Metab Dis
In conclusion, our study confirms that a delayed rise in TSH
is a distinct entity amongst infants with VLBW, with cases of
permanent and transient hypothyroidism being missed unless a
second screening protocol is used. Almost 1% of VLBW
babies were deemed by paediatric endocrinologists to need
treatment with thyroxine for a substantial period if not
permanently. A strategy involving a second screen needs to
be pursued if all VLBW babies currently deemed to need
treatment for a period are to be detected. This of course begs
the question of whether some of the treatment was unneces-
sary, but as the long-treated babies remained euthyroid on
usual replacement doses of thyroxine, this seems unlikely. Our
study is one of the few that has follow-up data relating to trial
of withdrawal of treatment. Routine second screening of all
infants, not just VLBW babies, does detect extra cases of
hypothyroidism, and there is an urgent need for studies that
will guide us on the benefit or otherwise of treating mild cases.
At present treatment is directed to numbers, without clear
evidence of benefit (Krude and Blankenstein 2011).
Acknowledgements We are very grateful to the paediatric endo-
crinologists who kindly supplied us with follow-up data, and to the
staff of the NSW Newborn Screening Programme who of course did
most of the work.
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