Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 6375

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Neonatal TSH screening: is it a sensitive and reliable tool for

monitoring iodine status in populations?
Mu Li, PhD, Senior Lecturer a, *, Creswell J. Eastman, MD, Clinical Professor,
Vice Chairman of ICCIDD and Regional Coordinator Asia Pacic Region b,1
a
b

School of Public Health, the University of Sydney, Sydney, NSW 2006, Australia
Sydney Medical School, the University of Sydney, Sydney, NSW 2006, Australia

Keywords:
newborns
thyroid stimulating hormone (or thyrotropin)
monitoring
iodine deciency

Iodine deciency is the most common cause of preventable brain

damage in the newborn. The indicators for assessing iodine
nutritional status include urinary iodine excretion, thyroid size,
thyroid stimulating hormone (TSH) and thyroglobulin (Tg)
concentrations in the blood. Neonatal TSH concentration is
increased when the supply of thyroid hormone and iodine from
the maternal circulation to the foetus has been compromised. The
World Health Organization (WHO) has suggested that when
a sensitive assay is used on samples collected 34 days after birth,
a <3% frequency of TSH concentrations >5 mIU l1 indicates iodine
sufciency in a population. However, many studies have attempted
to apply the frequency of neonatal TSH values >5 mIU l1 in
determining population iodine status and monitoring intervention
programmes, and although some have proven to be successful,
most have provided conicting or uncertain data. This is due to the
many technical issues that remain unresolved on the use of
neonatal TSH screening for monitoring iodine status, making it
doubtful as a sensitive and reliable quantitative tool. More research
is required to resolve these issues. In the interim, WHO should
consider withdrawing its current guidelines for neonatal TSH
screening for monitoring iodine deciency in populations.
Crown Copyright 2009 Published by Elsevier Ltd. All rights
reserved.

* Tel.: 61 2 9351 5996; Fax: 61 2 9351 5049.

E-mail addresses: muli@health.usyd.edu.au (M. Li), ceastman@med.usyd.edu.au (C.J. Eastman).
1
Tel.: 61 2 9439 9396; Fax: 61 2 9436 1505.
1521-690X/$ see front matter Crown Copyright 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.beem.2009.08.007

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M. Li, C.J. Eastman / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 6375

Iodine nutrition in pregnant women and newborns

Iodine requirement in pregnancy
Iodine of maternal origin is essential for foetal and neonatal brain development. At a population and
global level, iodine deciency is the leading cause of preventable mental handicap. At an individual level,
the developing brain is extremely vulnerable to even minor degrees of maternal hypothyroxinaemia
secondary to iodine deciency or maternal thyroid disease. Even mild, clinically unrecognisable,
hypothyroxinaemia can cause serious irreversible neuromotor decits rendering a child handicapped
for life.1 The invisibility of the deciency during pregnancy and neonatal development makes it all the
more dangerous in both developing and developed societies. Despite enormous efforts to conquer
iodine deciency, it remains a serious public health problem. The World Health Organisation (WHO)
estimates that almost 2 billion people worldwide, comprising over 300 million children in 54 countries,
still have inadequate iodine intake.2 The United Nations Childrens Fund (UNICEF) estimates that
presently over 38 million newborns annually are not protected from iodine deciency.3
Pregnancy demands a large increase in iodine requirements principally to keep pace with the increased
maternal thyroidal production of thyroxine (T4). The maternal thyroid hormone pool (chiey T4) increases
on average by 50% due to the need to saturate the increased thyroxine-binding globulin produced by the
liver and maintain a normal free T4 concentration. Increased T4 production is facilitated by enhanced
thyroidal stimulation from human chorionic gonadotropin during early pregnancy.4 Additional demands
on the thyroid come from passage of T4 from mother to foetus and increased degradation of T4 by the
placenta.4 Enhanced renal clearance of iodine during pregnancy results in maternal wastage of iodine and
contributes to the demand for increased iodine intake. While the foetal thyroid commences synthesis of
thyroid hormone at the end of the rst or early second trimester, most of the T4 in the foetal circulation is
derived from maternal passage until very late in pregnancy. In addition to maternal transfer of T4 to the
foetus, there is also transfer of iodine in the latter weeks of gestation. Although the precise quantity of this
transfer has yet to be established, it is estimated to be in the range of 5075 mg per day, based on the known
requirement of 90 mg per day in the neonates and infants (012 months).6
The recommended daily intake (RDI) of iodine in the non-pregnant state is 150 mg, increasing to
250 mg during pregnancy.5,6 The infant will require around 90100 mg iodine per day, mandating
a requirement of approximately 250 mg iodine daily in the breastfeeding mother.5,6 The iodine content
of human breast milk varies with maternal iodine intake, emphasising the need to ensure iodine intake
is boosted during lactation to protect the infant from hypothyroxinaemia.
Monitoring of iodine intake and use during pregnancy and lactation in mothers remains a controversial and poorly researched issue. Urinary iodine excretion, serum concentrations of free T4, TSH and
thyroglobulin (Tg) provide direct or indirect indices of thyroid function and iodine intake during
pregnancy. Each of these tests is prone to methodological problems and artefactual interference during
pregnancy. The simplest test at a population level, but not in an individual, is the urinary iodine
excretion concentration (UIC). Most of the iodine absorbed through the gut is eventually excreted in
the urine. One can calculate iodine intake using the simple assumption that 90% of intake is excreted
within the next 24 h. The current convention of judging UIC measurements in pregnant women against
non-pregnant adults is misleading. If the RDI for iodine during pregnancy is 250 mg per day, then this
intake would correspond to a UIC of 150 mg l1.4
Physiology and pathophysiology of use of iodine in the foetus and neonate
An adequate iodine intake in the mother is essential for the normal synthesis of maternal and foetal
thyroid hormones important for foetal brain development.7,8 Insufcient iodine supply from the
mother can result in a decreased synthesis of both T4 and 30 ,3,5-triiodothyronine (T3), with an
increased concentration of TSH in the newborn. In most cases, the impaired thyroid function due to
iodine deciency is transient.9 Infants, especially if born prematurely, are susceptible to transient
hypothyroxinaemia10, a condition characterised by a transient elevation of newborn TSH level in
conjunction with a normal T4 concentration. It occurs at higher frequency in mild-to-moderate iodinedecient environments.11

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65

Neonatal TSH screening

Neonatal screening for Congenital Hypothyroidism
The incidence of sporadic congenital hypothyroidism (CH) is around 1 in 3000 to 1 in 4000 live
births.11,12 The symptoms and signs of sporadic congenital hypothyroidism are often non-specic and,
unless tested for biochemically, CH will be frequently overlooked, resulting in irreparable neurological
damage from thyroid hormone deciency during this crucial period of brain development. To address
this problem and permit early detection and implementation of thyroid hormone therapy, systematic
screening programmes for thyroid function were introduced in many countries in the early 1970s.11,13
The initial screening method was measurement of T4 in heel-prick blood samples. This has been
superseded by measurement of thyrotropin (TSH) in most programmes around the world. Convincing
arguments can be made for the superiority of either one of these tests as the primary screening
method. The major disadvantage of using TSH is that it will not detect central (hypothalamic or
pituitary) hypothyroidism, a rare disorder occurring in approximately 1 in 20 000 neonates, that can be
picked up by T4 testing. TSH testing does detect subclinical or transient primary hypothyroidism that
will be missed by T4 screening and may cause brain damage.12
TSH testing results in neonates born in iodine-decient environments
The newborn thyroid has limited iodine stores, and even mild deciency during pregnancy will
compromise neonatal thyroidal secretion of T4 causing increased pituitary TSH secretion. It follows
that an elevated TSH in the neonate is a sensitive indicator of an inadequate supply of thyroid hormone
to the developing brain. This principle underpins the application of newborn TSH screening as an
indicator of maternal and hence population iodine nutrition. Thus, neonatal TSH screening may be
a powerful and underused tool in monitoring iodine nutrition in mothers and babies. However,
multiple factors other than maternal iodine status can inuence measurement of newborn TSH,
including prematurity, the timing of the heel-prick collection, maternal or newborn exposure to
iodine-containing antiseptics (povidone), the collection paper employed for the bloodspot and the TSH
assay methodology. Consequently, the original recommendations of categorising the severity of iodine
deciency using measurement of neonatal TSH promulgated by WHO in 199414 (Table 1) have not been
included in the more recent recommendations.6,15 The Swiss experience showed neonatal TSH was
sensitive to even marginal improvement of iodine nutrition status of pregnant women, following the
increase of iodine concentration in iodised salt. This was demonstrated in the reduction of the
frequency of newborn TSH values >5 mIU l1 from 2.9% to 1.7%.16
Newborn TSH screening as a tool for assessing iodine deciency
Monitoring tool in iodine-decient environments
In contrast to sporadic CH, elevated TSH levels, accompanied by either normal or low T4 levels occur
much more commonly in neonates born in iodine-decient environments. Studies performed in the
1980s in Zaire and India, where iodine deciency is endemic, conrmed neonatal TSH concentrations
were grossly elevated in the cord blood of the offspring of mothers suffering from moderate-to-severe
Table 1
WHO/ICCIDD/UNICEF Indicators for Assessing Iodine Deciency Disorders.
Indicator

Target
population

Severity of public health problem (prevalence)

Mild

Moderate

Severe

Thyroid volume >97 centile by ultrasound

Median urinary iodine level (mg/L)
TSH >5 mIU/l whole blood

SACa
SAC
Newborns

5.019.9%
5099
3.019.9%

20.029.9%
2049
20.039.9%

30%
<20
40%

Adapted from WHO/NUT/94.6, 1994 (14).

a
School aged children

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M. Li, C.J. Eastman / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 6375

iodine deciency.1719 From these studies, neonatal TSH screening was put forward as a populationmonitoring tool for iodine deciency, in addition to its role as a case-detection tool for diagnosing
individual neonates with congenital hypothyroidism.20
Delange advocated neonatal thyroid screening as an indicator of the degree of iodine deciency at
a population level and as a monitoring tool in programmes of iodine supplementation.20,21 In his
reviews, Delange concluded that neonatal TSH screening is the only indicator that allows prediction of
a possible impairment of mental development.20,21 However, in the context of declining urinary iodine
concentration reported from several countries, where the frequency of TSH >5 mIU l1 is often below
3%, it is uncertain whether neonatal TSH screening results can truly reect the current iodine intake
trend in these populations.22,23
Published reports of neonatal TSH screening for monitoring population iodine nutrition
Table 2 is a summary of published reports using TSH screening for assessment of iodine-deciency
status or monitoring the outcome of iodine prophylaxis programmes in countries or sub-national regions,
with reference to the WHO criteria.6,14,15 One good example is in southeast Poland, where TylekLemanska24 and colleagues were able to demonstrate that, from the CH screening programme, with the
reintroduction of iodised kitchen salt in 1992, the prevalence of neonatal TSH results 5 mIU l1 dropped
from above 20% in 1991 to just over 5% between 1995 and 2000. There have been other examples of using
newborn TSH screening to assess iodine-deciency status.16,2537 In Thailand, with the application of
a geographic information system to their neonatal TSH screening programme, which covers 760 000 live
births annually (94% of total), it is possible to identify iodine deciency down to the sub-district level.37
In Table 2, reported studies are listed under three categories, according to the timing and nature of
the blood samples. Majority of the published reports have employed dried blood spot samples
collected >48 h after birth, as recommended for neonatal screening for CH. Greater than 3% of TSH
>5 mIU l1 is the arbitrary indicator for iodine deciency in a population.6,15 Some studies have used
dried cord blood spots, particularly the two multi-nation studies by Sullivan30 and Copeland,34 which
also used TSH >5 mIU l1 as the cut off. Other studies used cord blood serum samples. In addition,
multiple methods, and the same technique by different assay manufacturers, have been used. In the
following, we look at these issues closely to see how they may impact on the TSH test results.
Inuencing factors of newborn TSH measurements
Maternal iodine status
Maternal iodine nutrition and thyroid function status can have signicant impact on foetal and
newborns TSH levels.38 In a study comparing maternal and neonatal thyroid status in Nigeria,39 it was
found that women from a known iodine-decient area (Saki) had signicantly lower UIC levels and
higher goitre rates compared with women from the control area. Their plasma total T3 (TT3) and total
T4 (TT4) were lower and TSH was higher than the values of the controls, although they did not reach
the statistically signicant level. The mean plasma neonatal TSH of babies from Saki, however, was
signicantly higher than the control value.
Data from newborn screening in Europe have shown that the frequency of serum TSH >50 mU ml1
(mIU l1) for recall was inversely related to maternal urinary iodine level.9 This was further evidenced
by the Costante study,31 which showed a negative relationship between the frequency of TSH
>11 mU ml1 (mIU l1), the 97% cut off of neonatal TSH and the median UIC of schoolchildren living in
the same area (r2 0.86, P 0.007). A study conducted in the West Black Sea area of Turkey showed
that the maternal median UIC was different for mothers living in three different cities (from 31 mg l1 to
75 mg l1). The proportion of neonatal heel blood TSH >5 mIU l1 and the median neonatal Tg
concentration correlated inversely with the maternal UIC.36 A study of a cohort of 253 healthy pregnant
women in Hong Kong has clearly demonstrated that mothers had lower urinary iodine levels giving
birth to infants with higher TSH level, compared with mothers with normal urinary iodine excretion
levels. Furthermore, women, who had given birth to infants with cord blood serum TSH >16 mIU l1,
had signicantly lower urinary iodine concentrations and serum FT4 levels compared with mothers
who had given birth to newborns with normal TSH levels.40 A recent study from three districts of

Table 2
Reported Neonatal TSH with Reference to Iodine Deciency.
Country/Region

Settings

Sample size

Turkey/West Black
Sea Area
Switzerland

Neonatal screening
program
Neonatal screening
program

Ireland

Neonatal screening
program
Neonatal screening
program

Thailand

Australia/Sydney

Teaching Hospital

USA/Atlanta

Hospital

Australia/NSW

Public hospitals
and local community
health centres
District hospitals

Thailand/Songkhla

18,606
259,035
218,665

73,019
550,927
543,121
639,583
766,392
1,316
1,457

Method

UIE (mg/L)

Goitre
prevalence (%)

Reference

14.4

Fluroimmunoassay
(DELFIA neonatal TSH kit Wallac, Finland)

65.6 (SCa)

37 (SC)

31

4.5
17.7

20

30.0
26.7

Fluroimmunoassay
(DELFIA neonatal TSH kit)
Fluroimmunoassay (FIA) and
Luminoimmunoassay (LIA)
Immuno-urometric assay
(IFMA, DELFIA neonatal
TSH kit Wallac)
IRMA (DPC)
RIA (DPC, USA)

2.9 (199298)
1.7 (19992004)

Time-resolved
Fluroimmunoassay

3.642.35
(19952006)
13.54 (2003)
15.28 (2004)
21.55 (2005)
19.56 (2006)
8.1, 5.4

Dissociation-enhanced
uroimmunoassay (DELFIA)
ELISA

205.7
2.7

28

42.9

815

2.2

236

8.9

65b (SC)

33
24

143 (SC)

4.5 (SC)

Mothers 40,
neonates 85
Mothers 138 (1999),
249 (2004)
SC
115 (1999)
141 (2004)
4568a
(pregnant women)

61

36
16

23
37

Dissociation-enhanced
uroimmunoassay
(DELFIA Wallac, Finland)
ELISA (Enzaplate N-TSH, Ciba
Corning Japan)
Fluroimmunoassay
(Auto DELFIA Wallac)

109 (mothers)

Mothers 85

42

Immunoradiometric assay

Gestation1216 weeks
75.5
2830 weeks 87.6
3436 weeks
72.1

41

282

43

34

67

(continued on next page)

M. Li, C.J. Eastman / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 6375

Dried blood spot collected >48 hours after birth (>5 mIU/L)
Italy/Calabria
Neonatal screening
22,384
program
Belgium/Brussels
Neonatal screening
308,614
program
Estonia
Neonatal screening
20,021
program
Poland/Cracow
Neonatal screening
634,179
program
Argentina/Buenos Aires Neonatal screening
1,500
program

Frequency (%)

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Table 2 (continued)
Country/Region

Settings

Sample size

Frequency (%)

Philippines/Manila

Major hospitals

750

32

Pakistan/Islamabad
Quetta
Lahore
Karachi
Kyrgyzstan
Bishkek
Osh
Bangladesh

Major hospitals

201
279
256
148
90
92

76
65
80
69
74
47

Local hospitals

208

84

Guatemala

Local hospitals

141

58

USA

Local hospitals

243

82

Argentina/Buenos Aires

Neonatal screening
program

186

11.3

Major hospitals

Cord blood serum collected at delivery (>10 mIU/L unless specied)

Thailand/Chiangmai
Provincial and
10,150
20.0
Nan
district hospitals
8,603
15.3
Bangkok
Teaching hospital
7,688
7.2
(Bangkok)
Hong Kong
Teaching hospital
253
22

Sudan/Omdurman
Turkey/Kayseri
India/West Bengal
Thailand/Bangkok
a
b
c
d
e

Local hospital
Teaching hospital
Local hospital
Neonatal screening
programs

School aged children.

Indirectly quoted data.
and from personal communication.
TSH > 5 mIU/L.
TSH > 11.2 mIU/L.

76
70
267
5,114

70d
27.1
2.9d
31e

UIE (mg/L)

ELISA (Spectra-Screen TSH,

IEM Diagnostics, USA)
ELISA (Spectra-Screen TSH,
IEM Diagnostics, USA)
ELISA (Spectra-Screen TSH,
IEM Diagnostics, USA)

33 (mothers)

ELISA (Spectra-Screen TSH,

IEM Diagnostics, USA)

30 (SC)

49 (SC)

30

ELISA (Enzaplate N-TSH,

Ciba Corning Japan)
ELISA ((Enzaplate N-TSH,
Ciba Corning Japan)
ELISA (Enzaplate N-TSH,
Ciba Corning Japan)
Immuno-uorometric assay
(DELFIA Wallac, Finland)

96 (mothers)
73 (SC)
120 (mothers)
181 (SC)
105 (mothers)
282 (SC)
143 (SC)

27 (SC)

34

15 (SC)

34

34

4.5 (SC)

61

Immunoradiometric assay
(Department of Health
Science, Thailand)

64b

15.7b
36.4b
6.2b

29

Immunochemilumino-metric
assay (ACS Ciba Corning
Diagnostic Corp, USA)
TR-FIA (DELFIA Wallac, Finland)
IRMA (Amersham, UK)
ELISA (Pathozyme Diagnostics, India)
Electro-chemiluminescence immunoassay
(Roche Diagnostics, Germany)

z122 (0.98 mmol/l)

40

30.2 (mothers)
144 (mothers)
85

50
35
70
22

40b (SC)

Goitre
prevalence (%)

Reference

30
2b (SC)

30
30

M. Li, C.J. Eastman / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 6375

Dried cord blood spot sample collected at delivery (>5 mIU/L)

Malaysia/Kuching
Major hospitals
195
52

Method

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69

Songkhla, southern Thailand has revealed a negative correlation between neonatal TSH concentrations
and urinary iodine concentrations in their mothers, although it failed to reach a statistical signicant
level (r 0.10, P 0.068).41 Studies from Australia and Denmark with mild-to-borderline iodine
deciency, however, could not nd the expected negative correlation between neonatal whole blood
TSH and maternal UIC.4244
Although WHO recommends that the iodine intake in pregnancy should be increased to 250 mg per
day to ensure a corresponding urinary iodine level of 150 mg l1,6 this has been challenged by a recent
Thai study that found a decrease in the median urinary iodine concentration in pregnant women did
not directly impact on the median newborn TSH concentration. Despite that median maternal UIC level
has more than halved in the Dan Sai district, northern Thailand in 2003 compared with 1998
(106 mg l1 from 249 mg l1) and the median maternal UIC in Bangkok was as low as 85 mg l1, there was
no substantial difference in cord blood serum TSH concentrations in the corresponding newborns.22
A number of studies have used measurement of Tg as part of the assessment of neonatal thyroid
function in relation to iodine status. Kungs study in Hong Kong40 showed there were signicant
differences in both neonatal TSH and Tg of babies born to mothers who had UIC <0.44 mmol l1
(50 mg l1) or >0.79 mmol l1 (100 mg l1). Furthermore, in neonates with TSH >16 mIU l1 their Tg
levels were signicantly higher than those with TSH levels <16 mIU l1 (32.0 vs. 25.6, P < 0.05). The
study in the West Black Sea area of Turkey showed a positive relationship between percentage neonatal
TSH >5 mIU l1 and median Tg (r 0.51, P < 0.01).36
Mode of delivery
Many studies have explored the impact of delivery characteristics on neonatal TSH levels, particularly in cord blood. This is most relevant in countries where cord blood, either serum or dried blood
spot, is used for the neonatal thyroid screening. The reports are still controversial. Neonates born with
assisted vaginal delivery, including vacuum or forceps extraction, were reported to have higher TSH
values than those of normal vaginal delivery.4547 Furthermore, newborns by vaginal delivery had
higher TSH levels compared with babies delivered by caesarean section.4548 This may relate to stress
associated with vaginal delivery.47 Studies in Japan and Sudan, however, found no difference in
newborn TSH levels in relation to vaginal delivery, assisted or non-assisted, or caesarean section, and
they claimed that the TSH was less inuenced by perinatal factors.49,50
An interesting study from Sydney, Australia, described a phenomenon that newborns delivered by
caesarean section were more likely to have TSH levels >5 mIU l1 on day 3 after birth than those born
by vaginal delivery.51 There could be a number of implications of this nding. First, more babies
delivered by caesarean section were born before 37 weeks gestation, so their thyroid glands might be
less mature in handling topical iodine used to prepare for the caesarean section.51 Second, Sydney is
a mild iodine-decient area.43,52,53 As discussed further in this article, iodine deciency might exacerbate the ability of the thyroid to handle excessive iodine in preterm babies. Third, based on the
guidelines, most reported heel blood samples were collected between day 2 and 4; this phenomenon
could, therefore, have an impact on the results of TSH screening and IDD monitoring. Last, the number
of babies delivered by caesarean section is increasing in many countries, suggesting this should be
taken into consideration in interpreting neonatal TSH results.
Time of sampling: cord blood vs. heel blood taken in the rst few days of life
The recommended time of sampling for screening of CH is before day 5 of life. It is most highly
desirable at 48 h to 4 days due to the neonatal TSH surge in the rst 24 h after birth.12,54,55 Some
neonatal screening programmes use cord blood samples collected at delivery for convenience or for
better acceptance of the test by parents.40,56 In some countries, both cord blood and heel blood samples
are used to achieve higher coverage.29,57 Another issue has been the early discharge of mothers and
babies within 48 h of birth for various reasons, including cultural practices in some countries where
women return home within 24 h after giving birth.58,59 Samples collected at different times have
presented a major challenge for setting the appropriate cut-off points for neonatal screening. Evidence
shows that the mean TSH level sampled less than 24 h after birth was signicantly higher than the mean
TSH level of neonates after the rst 24 h.59,60 This poses an even bigger challenge for monitoring IDD
programmes, as we are looking at a narrowly dened level, that is, <3% of neonates TSH >5 mIU l1.

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M. Li, C.J. Eastman / Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 6375

In a study from the United States, Lott and colleagues60 analysed results from 161 44 newborn blood
samples collected between <24 h and >95 h of life in 24-h intervals and found that the mean TSH levels
progressively reduced from 15.20 mIU l1 to 3.24 mIU l1, highlighting the necessity of establishing the
age-dependent cut-off values. Other studies also showed the median TSH levels of samples collected in
the days beyond 48 h after birth were signicantly lower than the level in cord blood,34,61 suggested that
it was inappropriate to apply the same cut-off point for samples collected at different time points. This is
particularly important in assessing the iodine-deciency status when cord blood spot samples are used,
but the same criteria still apply as for blood spot samples collected >48 h after birth. This could lead to
overestimation of the problem if the results were looked at in isolation from other indicators. Using TSH
>5 mIUl1 as the cut-off, Copeland34 found the proportion of TSH concentrations above this cut-off in
dried cord blood varied between 58% in Guatemala and 84% in Bangladesh, which is much higher than
the reported results using dried heel-prick blood spots collected >48 h throughout the world.
Furthermore, there was a marked discrepancy between neonatal TSH and other iodine-deciency
indicators, namely urinary iodine excretion level and total goitre rates in schoolchildren. For instance, in
Bangladesh, 84% neonates had TSH >5 mIU l1, while median UIC in schoolchildren was 73 mg l1 and
26% of children had enlarged thyroids by ultrasound, indicating mild-to-moderate iodine deciency. In
Guatemala, the UIC of schoolchildren was in the normal range (181 mg l1) and 15% children had
palpable goitre, but the proportion of neonatal TSH values >5 mIU l1, however, was as high as 58%.
Maternal or neonatal exposure to iodine-containing antiseptics
Maternal or neonatal exposure to iodine-containing antiseptics is a common cause of transient
hyperthyrotropinaemia and/or hypothyroidism in newborns.11,6266 Only a few newborn TSH screening
programmes, however, have reported information on maternal or neonatal exposure to iodine-containing antiseptics before or during delivery.24,34,36,67 Copeland34 reported that a very high percentage
(82%) of newborns at the Crawford Long Hospital in Atlanta, Georgia, in the United States, had cord
blood TSH levels above 5 mIU l1. This was partially attributed to maternal exposure to beta-iodinecontaining antiseptics prior to birth, including intravenous infusion, epidural insertion and catheterisation. Simsek conrmed that all hospitals in the area of their study used povidone as a local skin
antiseptic in mothers or in newborns.36 Telek-Lemanska24 commented that information on the use of
iodine-containing disinfectants was not available. This is likely to be the case for many screening
programmes where the information was either not collected or not well managed and reported.
One study from Poland, in particular, is of interest as it highlights the strong inuence of using
iodine-containing antiseptics in obstetric practice on the results of TSH screening.67 Based on a survey,
there were 71% of obstetric clinics in 1998 and 58% in year 2000 in Poland using iodine as a skin
disinfectant. When the neonatal TSH data was examined for the iodine-free hospitals and those using
iodine-containing antiseptics separately, the authors found more than a threefold increase in TSH
levels greater than the cut-off (15 mIU l1) in the hospitals using iodine. Many reported cases of
transient perinatal hyperthyrotropinaemia resulting from iodine exposure occurred in countries where
there was mild-to-moderate iodine deciency.65 A recent study in an iodine-replete area of Iran has
showed that povidone disinfection at delivery did not affect TSH measurement from cord dried blood
spot or the rate of hyperthyrotropinaemia among mature and normal-birth-weight neonates.48
Instead of exposure to iodine-containing antiseptic products, a study from Denmark44 found 41% of
the neonates whose mothers were exposed to regular daily iodine-containing supplements during
pregnancy had cord blood serum TSH level greater than 10 mIU l1, compared with 31% in the noniodine-supplemented control group. The median urinary iodine excretion of mothers (60 mg l1 in I
group vs. 34.5 mg l1 in non-I group) and babies (63 mg l1 in I group vs. 31 mg l1 in non-I group), clearly
indicating that the iodine supplement was inadequate and both mothers and babies in the supplemented group were still mildly iodine decient. The authors have postulated that iodine deciency
might predispose the foetal and neonatal thyroid gland to the inhibitory effect of an excessive iodine
load on thyroid hormone synthesis, leading to elevated neonatal TSH concentrations.
Type of samples: dried cord blood spot vs. cord blood serum vs. dried heel blood spot
In a small study in Japan, Fuse and colleagues49 found that there was a signicant linear correlation of
the TSH concentration in dried cord blood spots and cord venous blood samples in the same neonate,

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suggesting that the cord blood collected on lter paper might be a feasible alternative for a TSH screening
programme using cord blood. This was supported by a study in southwest China, an iodine-decient
endemic area.45 The study showed that there was not only a good correlation of TSH levels between the
dried cord blood spots and the cord venous blood samples (r 0.84, P < 0.01) but also a good correlation
between the dried cord blood and dried heel blood obtained 35 days after birth (r 0.67, P < 0.01).
In a larger-scale study involving seven provinces in China, it was shown that while the median
urinary iodine excretion level in pregnant women was within the optimal range (246 mg l1), signicant variations were found in dried cord blood spot TSH levels. Furthermore, the TSH levels were also
signicantly affected by the type of delivery.68 The authors concluded that the neonatal dried cord
blood TSH was inuenced by many factors; therefore, it was not a suitable indicator for IDDs
surveillance in areas where iodine nutrition was adequate.68 In Thailand, both dried blood spot
collected from 48 h (national programme)37 and cord blood serum (in Ramathibodi Hospital,
Bangkok)22 are used for the neonatal TSH screening. Comparing data from the two programmes, it has
been concluded that the whole blood collected from a heel prick on day 3 was not sensitive enough to
assess the status of iodine nutrition in neonates.22
TSH assay methodology
Table 2 reveals that there is a large range of assay methodologies used for measuring neonatal TSH.
In a study from Buenos Aires, Argentina, 1500 samples collected more than 48 h after birth were tested
by the standard immunouorometric assay (IFMA, DELFIA Wallac). A proportion of the samples
(n 238) were also measured by an immunoradiometric assay method (IRMA, Diagnostic Products
Corp). The median TSH value measured by the immunouorometric assay was 1.28 mIU l1, with 2.7%
of TSH levels greater than 5 mIU l1 dried whole blood. This was in keeping with other indicators, that
is, goitre rate (4.5%) and median urinary iodine level (146 mg l1) in schoolchildren, indicating that
Buenos Aires was iodine sufcient. However, in the 238 samples tested by the IRMA, the frequency of
samples with TSH level >5 mIU l1 was as high as 30%, representing a more than 10-fold increase.61 In
the current CDC Newborn Screening Quality Assurance Program, there are no less than 13 assay
methodologies accepted in the programme.69 The variation of the assays performance can be as broad
as 15%. This highlights the difculties in interpreting and comparing data, particularly when
attempting to determine if the proportion >5 mIU l1 is below or above the 3% cut-off.43 As illustrated

Fig. 1. TSH Measurement Variation by Methods (Quarter 3, 2008).

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in Fig. 1, there is a wide range of variation among the assays. More importantly, these assay are
designed to detect CH, which are usually optimised at higher cut-off values (1020 mIU l1) than
needed for assessing iodine nutritional status (5 mIU l1). This has been demonstrated by Elnagar32
that there was a poor correlation of the TSH levels obtained from serum and dried blood spot below
5 mIU l1 in the DELFIA TSH ultra assay.
In conclusion, despite what is recommended in the WHO/UNICEF/ICCIDD guidelines and some
encouraging successes in countries such as Belgium and Switzerland, there are still some serious
technical issues in relation to using the frequency of neonatal TSH values greater than 5 mIU l1 as
a tool for assessing population iodine nutrition status and monitoring iodine deciency control programmes condently. To establish valid guidelines for neonatal TSH screening in these situations, more
research is required with adherence to standardised protocols to minimise the large number of
variables that can inuence the neonatal TSH concentration.
Practice points
 The neonatal TSH should only be used as one of the indicators for assessing the status of
iodine nutrition in a population if the screening system is robust, adheres to a strict protocol
with strict quality assurance and the data is routinely collected for the primary purpose of
screening for CH.
 Neonatal TSH should not be used as the sole indicator for monitoring iodine deciency
control programs, especially when samples are collected less than 48 hours after birth, as
there are no established reference intervals.
 The current WHO/UNICEF/ICCIDD criteria for iodine deciency, i.e. >3% of neonatal TSH
greater than 5 mIU/L, does not specify assay methods when this should be an essential
requirement. Marked variation in assay results question the validity of these data. It is
important to bear this in mind when interpreting or comparing neonatal TSH results by
different methods.
 The continuing decline of iodine intake in many developed countries warrants closer
monitoring of the subtle increases in neonatal TSH levels, even when the proportion of TSH
>5 mIU/L that may be less than 3%.
 It appears that the neonatal TSH measurement may not be a reliable monitoring tool for
iodine deciency control programs due to the many potential confounding factors which may
discredit the data and its interpretation. WHO should reconsider their published guidelines
until these issues have been resolved.

Research agenda
 Continuing research is necessary to explore sensitive and reliable indicators for assessing
mild to moderate iodine deciency conditions and monitoring intervention programs.
 Further research is required to establish the recommended cut off levels for using mixed
dried cord blood spot samples, as they are used in many countries where heel prick blood
sample collection is not possible.
 Research is needed to quantify the variations among different assay methods in order to
guide the interpretation and comparison of the neonatal TSH data.

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