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Screening for congenital hypothyroidism: The value of retesting after four

weeks in neonates with low and very low birth weight

Article  in  Journal of Medical Screening · December 2005

DOI: 10.1258/096914105775220697 · Source: PubMed

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ORIGINAL ARTICLE

Screening for congenital hypothyroidism: the value of

retesting after four weeks in neonates with low and very
low birth weight
Dorota Tylek-LemanŁska, Ma$gorzata Kumorowicz-Kopiec and Jerzy Starzyk
..................................................................................................

J Med Screen 2005;12:166–169

See end of article for
authors’ affiliations
...............
Correspondence to:
Dr Dorota Tylek-Lemańska,
Department of Pediatric and
Adolescent Endocrinology,
Polish-American Children’s
Hospital, Collegium
Medicum, Jagiellonian
University, 265 Wielicka
St., 30-663 Krakow,
Poland;
d.lemanska@chello.pl
Accepted for publication
11 August 2005
...............
Objectives Thyroid-stimulating hormone (TSH), normally a reliable screening test for congenital
hypothyroidism (CH), may fail to detect cases among infants who have low and very low birth weight.
The purpose of this study was to identify neonates with false-negative screening results.
Setting A province in Poland in which 3854 neonates had body weight p2500 g, between 1999
and 2001.
Methods TSH levels in blood on filter paper were measured in all neonates between the third and
sixth days after birth, but were repeated in low and very low birth weight infants after four weeks of
age.
Results The repeat test showed TSH levels X10 mIU/L in 19 of the 3854 low birth weight neonates.
The final diagnosis in these neonates was permanent CH in two, transient CH in five, possible
compensated CH in six and transient high TSH in six. Of the 19, 16 (84%) required iodine and/or
thyroxine replacement therapy.
Conclusions In neonates with low and very low birth weight, normal TSH levels measured between
the third and sixth day of life do not exclude thyroid dysfunction, but a repeat TSH measurement after
the fourth week of life identifies the false-negative results. In our data, the prevalence of primary and
secondary hypothyroidism (both permanent and transient) was about 0.5%.

INTRODUCTION
In Poland, a pilot screening study for congenital hypothyr-
oidism (CH) was initiated in the Warsaw district in 1972.
The programme was extended to include the Krakow district
in 1985, and the whole country in 1994. In Poland (as in
other European countries), such screening is based on
thyroid-stimulating hormone (TSH) concentrations in blood
measured between the third and sixth days after birth.
Elevated TSH (X15 mIU/L) indicates primary CH (though
not secondary hypothyroidism, in which TSH concentra-
tions are normal or low). A well-documented phenomenon
is the immaturity of the hypothalamic–hypophyseal–
thyroid axis and inadequate synthesis of thyroid hor-
mones observed in the first weeks of life in infants with
low and very low birth weight.1–3 This may result in
false-negative TSH screening results and thus failure to
detect late-onset forms of CH, which become manifest
somewhat later in low and very low birth weight infants
than in those born at term with normal birth weight.4 It is
therefore necessary to repeat TSH measurements in low
and very low birth weight infants 2–4 weeks after birth.
The thyroid dysfunction usually resolves spontaneously
within several weeks, but this is not the case for permanent
or transient CH, which require thyroxine replacement
therapy to ensure normal development of the central
nervous system. To date, no uniform management policy
has been developed. Discussion is ongoing on the need for
iodine and thyroxine supplementation and on the effect of
transient thyroid dysfunction on the future intellectual
development of neonates with low and very low birth
weight.5–8
METHODS
The subjects were neonates with birth weight p2500 g,
who were born in the Ma"opolska province of southeast
Poland between 1 January 1999 and 31 December 2001.
TSH was measured in blood on filter paper between the
third and sixth days after birth (Test 1). Neonates with low
(1500–2500 g) and very low birth weight (o1500 g) were
identified, and those with a TSH concentration o15 mIU/L
were retested four weeks after birth (Test 2). If the TSH
value exceeded 10 mIU/L in Test 2, TSH and free thyroxine
concentrations were measured at the age of five or six
weeks. Based on these values, preliminary diagnoses were
made. This rescreening included 3854 neonates (2929 with
low birth weight and 925 with very low birth weight); this
group accounted for approximately 5% of all live births.
In infants with suspected CH or hyperthyrotropinaemia
(that is, elevated TSH with normal thyroxine) (Table 1), iodine
and/or thyroxine therapy was instituted. The final diagnosis
was made at the age of two years, following discontinuation
of thyroxine and/or iodine treatment for at least four weeks.
The diagnosis was based on medical history data, serum TSH,
free thyroxine levels, thyroid ultrasound and scintiscan.
Laboratory data
In the blood from heel prick tests, collected on filter paper,
measurements of TSH were made using the immuno-
luminometric method and reagent kits (Byk Sangtec
Diagnostica, Germany). The normal TSH value was defined
as o15 mIU/L between the third and sixth days after birth
(Test 1) and o10 mIU/L at four weeks of age (Test 2).

Journal of Medical Screening 2005 Volume 12 Number 4 www.jmedscreen.com

Rescreening for congenital hypothyroidism in low and very low birth weight neonates 167

Table1 Criteria of thyroid dysfunction adopted by the authors

Test 1 Test 2 5th–6th week of life Two years of age

Diagnosis TSH (whole blood) TSH (whole blood) TSH (serum) fT4 (serum) TSH (serum) fT4 (serum)
Permanent CH N m m k m k
Transient CH N m m k N N
Compensated CH N m m N m N
Transient N m N N N N
hyperthyrotropinaemia
rectified by the
age of 5–6 weeks
Transient N m m N N N
hyperthyrotropinaemia
rectified by the
age of 2 years
Elevated TSH, normal fT4, no evidence of a thyroid disorder CH, congenital hypothyroidism; fT4, free thyroxine; TSH, thyroid-stimulating hormone (m above normal range, k below normal
range, N – within normal range)

Table 2 Laboratory data and diagnosis in neonates with very low birth weight
Test 1
(3rd–6th Test 2 5th–6th
day) (4th week) week of life

Birth TSH (mIU/L) TSH (mIU/L) TSH (mIU/L) fT4 (pmol/L) Thyroid condition Final diagnosis and
No. weight (g) whole blood whole blood serum serum (5th–6th week of life) aetiology (two years of age)
1 710 3.1 96 73 11.5 CH suspected Transient CH
Iodine-containing agents
2 750 2.6 18 16 14.3 High Transient
hyperthyrotropinaemia hyperthyrotropinaemia
up to 2 years of age
Possible iodine deficiency
3 880 0.4 109 45 4.2 CH Transient CH
Iodine-containing agents
4 890 7.5 91 194 0.5 CH CH Hypoplasia
5 935 4.0 39 26 10 CH suspected Transient
hyperthyrotropinaemia
up to 2 years of age
Possible iodine deficiency
6 970 2.5 16 24 9.4 CH suspected Transient CH
Iodine-containing agents
7 980 4.5 28 22 4.3 CH Transient CH
Possible iodine deficiency
8 1000 5.3 52 55 10 CH suspected Possible compensated CH
Possible iodine deficiency
9 1190 4.9 20 29 15.4 Hyperthyrotropinaemia Possible compensated CH
Possible iodine deficiency
10 1250 3.0 14 7 14.5 Hyperthyrotropinaemia Possible compensated CH
Possible iodine deficiency
11 1300 12.9 11 8 12.3 Hyperthyrotropinaemia Possible compensated CH
Possible iodine deficiency
CH, congenital hypothyroidism; fT4, free thyroxine; TSH, thyroid-stimulating hormone

In blood samples, measurements of TSH and free thyroxine RESULTS

were performed using the immunoradiometric method and
reagent kits manufactured by BRAHMS Diagnostica
GmbH, Germany. Normal ranges for TSH were 0.8–9.1 mIU/L
(2 weeks–2 years old) and 0.3–4.0 mIU/L (>2 years old).
Normal ranges for free thyroxine were 10–25 pmol/L.
Imaging studies
Thyroid gland ultrasound was performed using a 7.5 MHz
head and a LOGIQ 500 unit. Thyroid scintiscans were
performed using a 99mTc marker (pertechnetate, adminis-
tered intravenously). The assessment of marker distribution
and uptake intensity was performed 15–20 min after
intravenous administration. The standard dose in infants
under three months was 0.2 mCi. Table 1 summarizes the
criteria of thyroid dysfunction used.
In Test 1, TSH values were within the normal range in
all 3854 neonates included in the study. Test 2 showed that
TSH levels were below the cut-off value (10 mIU/L) in 3835
infants (99.5% of the entire group), and above the cut-off
value in 19 infants (0.5%). Table 2 shows the results in the
11 very low birth weight infants with TSH>10 mIU/L. In the
fifth and sixth weeks of life, primary hypothyroidism was
suspected in seven infants and hyperthyrotropinaemia
in four. Table 3 shows the results in the eight low birth
weight infants with TSH >10 mIU/L. In the fifth and sixth
weeks of life, primary hypothyroidism was suspected in two
infants and hyperthyrotropinaemia in six (transient in three
of these).
The diagnosis was re-assessed at the age of two years (final
diagnosis), based on medical history data (iodine prophy-
laxis during pregnancy, iodine-containing disinfectants used

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168 Tylek-Lemańska et al.

Table 3 Laboratory data and diagnosis in neonates with low birth weight
Test 1
(3rd–6th Test 2 5th–6th
day) (4th week) week of life

Birth TSH (mIU/L) TSH (mIU/L) TSH (mIU/L) fT4 (pmol/L) Thyroid disorder Final diagnosis and
No weight (g) whole blood whole blood serum Serum (5th–6th week of life) aetiology (two years of age)
1 1600 4.8 34 26 4.2 CH Transient CH
Possible iodine deficiency
2 1650 1.4 11 5 10.3 Transient Unknown
hyperthyrotropinaemia
up to 5–6 weeks of age
3 1700 4.7 22 14 14.4 Hyperthyrotropinaemia Possible compensated CH
Possible iodine deficiency
4 1820 13.3 182 101 8.6 CH CH hypoplasia
5 1900 2.0 16 15 12.4 Hyperthyrotropinaemia Possible compensated CH
Possible iodine deficiency
6 1950 8.3 17 5 11.2 Transient Unknown
hyperthyrotropinaemia
up to 5–6 weeks of age
7 2050 5.4 19 3 10.4 Transient Unknown
hyperthyrotropinaemia
up to 5–6 weeks of age
8 2450 9.9 42 25 12.3 Hyperthyrotropinaemia Transient
hyperthyrotropinaemia
up to 2 years of age
Possible iodine deficiency
CH, congenital hypothyroidism; fT4, free thyroxine; TSH, thyroid-stimulating hormone

at birth), serum TSH, free thyroxine levels, thyroid ultra-
sound and scintiscan (determined at least four weeks after
discontinuation of thyroxine and/or iodine treatment). In
the 11 infants with very low birth weight, permanent CH
was diagnosed in one infant, transient CH in four, possible
compensated CH in four, and transient hyperthyrotropinae-
mia up to two years of age in two. The causes of thyroid
dysfunction included possible iodine deficiency in seven
infants, iodine-containing postoperative disinfectants in
three (who had had surgery prior to collecting material for
Test 2) and hypoplasia in one (Table 2). In the eight with low
birth weight, permanent CH was diagnosed in one child,
transient CH in one, possible compensated CH in two, and
hyperthyrotropinaemia up to 2 years of age in one. In three
with transient hyperthyrotropinaemia up to the fifth or
sixth week of life, no treatment or further testing was
carried out. Sixteen of the 19 infants (84%) required iodine
and/or thyroxine replacement therapy. The causes of
thyroid dysfunction included possible iodine deficiency in
four infants and hypoplasia in one. The aetiology was
unknown in three infants.
DISCUSSION
Over the last decade, there has been interest in thyroid
function in neonates with low and very low birth weight.
With continuous progress in neonatology, increasing num-
bers of such infants are surviving, and this is reflected in an
increased number of infants with thyroid dysfunction,
usually transient in character, in the first weeks of life.6,9–11
Low and very low birth weight neonates tend to have an
immature hypothalamic–hypophyseal–thyroid axis, which is
manifested in low thyroxine levels and normal or decreased
serum TSH values. Although this secondary type of thyroid
dysfunction is generally much less common than the
primary form, it is relatively common in low and very low
birth weight infants.6 It is therefore useful to repeat the TSH
measurement and to measure free thyroxine about four
weeks after birth in this group. Based on the tests performed
between the fifth and sixth weeks of life, no secondary
hypothyroidism was noted in our patients.
Functional immaturity of the thyroid in low and very low
birth weight neonates is responsible for the high incidence
of transient primary hypothyroidism and compensated
hypothyroidism.6,11 In our study, a repeat TSH test detected
19 low or very low birth weight infants with TSH levels
>10mIU/L, among whom permanent or transient hypo-
thyroidism was subsequently detected in five. Similar results
were obtained by Mandel et al.12 Our observations are also
in agreement with data reported by Fisher et al.,6 which
showed a prevalence of primary thyroid dysfunction of
about 0.5%.
Our cut-off value of 10 mIU/L for the repeated TSH test
performed in the fourth week of life is supported by the
Larson et al.13 study, which showed that TSH levels increase
after a mean period of 30 days in very low birth weight
children, while the TSH value in the repeated screening test
should not exceed 15 mIU/L.
The transient thyroid dysfunction found in low and very
low birth weight neonates is caused by factors such as
prematurity, exposure to iodine-containing antiseptics,
maternal iodine prophylaxis during pregnancy, and mater-
nal exposure to medications and antiseptics that contain
organic iodine and affect the thyroid function of the fetus
and the neonate.13,14
Some reports question the benefits of retesting low and
very low birth weight infants. Vincent et al.15 presented a
group of 465 very low birth weight infants in whom
permanent CH was diagnosed in four on the first TSH test,
and no additional cases were diagnosed on rescreening. It
should be emphasized, however, that the group was small
and, in addition, in two of the four neonates with
permanent primary CH the first TSH test was greatly
delayed (performed at 2–3 months of age instead of the
3–6 days after birth in routine screening programmes). The
result is therefore inconclusive.16
While thyroid dysfunction usually resolves spontaneously
in the first few weeks of life, this is not the case for
permanent or transient CH, which requires substitution

Journal of Medical Screening 2005 Volume 12 Number 4 www.jmedscreen.com

Rescreening for congenital hypothyroidism in low and very low birth weight neonates
therapy to ensure normal development of the central
nervous system. A 30–60-day course of thyroxine treatment
improves the intelligence quotient measured at two years of
age.6,8,17 Studies to establish an optimal dose of thyroxine
and confirm the benefits of such treatment are in
progress.5–7 Therapeutic management in low and very low
birth weight infants depends on the type of disorder they
manifest. All neonates with hyperthyrotropinaemia on the
first test who are born in an iodine-deficient area, especially
those with low and very low birth weight, require iodine
supplementation.5,18 On the other hand, infants with
suspected transient CH should receive thyroxine substitu-
tion up until the time the diagnosis is verified at 2–3 years of
age. To date, observations indicate a beneficial therapeutic
effect of early treatment.19–21
Studies on this early treatment in neonates are planned
for the area serviced by the screening programme in
Krakow. The assessment of the psychophysical status of
the group at risk should resolve the issue of the validity of
introducing rescreening in neonates with low and very low
birth weight.
CONCLUSIONS
(1) In neonates with low and very low birth weight,
normal TSH levels between the third and sixth days
after birth do not exclude the presence of thyroid
dysfunction.
(2) Measuring TSH again after four weeks avoids false-
negative results and identifies infants who require
diagnostic management for primary permanent or
transient hypothyroidism and hyperthyrotropinaemia
(which might result in compensated hypothyroidism).
................
Authors’ affiliations
Dorota Tylek-Lemańska, Head of Neonatal Screening Laboratory,
Department of Pediatric and Adolescent Endocrinology, Polish-
American Children’s Hospital, Collegium Medicum, Jagiellonian
University, Krakow, Poland, and Division of Screening and Metabolic
Diseases, University Children’s Hospital of Krakow, Poland
Ma$gorzata Kumorowicz-Kopiec, Paediatrician, Department of
Pediatric and Adolescent Endocrinology, Polish-American Children’s
Hospital, Collegium Medicum, Jagiellonian University, Krakow,
Poland
Jerzy Starzyk, Head of Department of Pediatric and Adolescent
Endocrinology, Polish-American Children’s Hospital, Collegium
Medicum, Jagiellonian University, Krakow, Poland
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169
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