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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-Leman´ska, Department of Pediatric and Adolescent Endocrinology, Polish-American Children’s Hospital, Collegium Medicum, Jagiellonian University, 265 Wielicka St., 30-663 Krakow, Poland;
[email protected] 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
METHODS
In Poland, a pilot screening study for congenital hypothyroidism (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 concentrations are normal or low). A well-documented phenomenon is the immaturity of the hypothalamic–hypophyseal– thyroid axis and inadequate synthesis of thyroid hormones 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
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.
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Laboratory data In the blood from heel prick tests, collected on filter paper, measurements of TSH were made using the immunoluminometric 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). www.jmedscreen.com
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Table1 Criteria of thyroid dysfunction adopted by the authors Test 2
Test 1
5th–6th week of life fT4 (serum)
Two years of age
Diagnosis
TSH (whole blood)
TSH (whole blood)
TSH (serum)
Permanent CH Transient CH Compensated CH Transient hyperthyrotropinaemia rectified by the age of 5–6 weeks Transient hyperthyrotropinaemia rectified by the age of 2 years
N N N N
m m m m
m m m N
k k N N
m N m N
TSH (serum)
k N N N
fT4 (serum)
N
m
m
N
N
N
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 day) No.
Birth weight (g)
Test 2 (4th week)
5th–6th week of life
TSH (mIU/L) TSH (mIU/L) TSH (mIU/L) whole blood whole blood serum
fT4 (pmol/L) serum
Thyroid condition (5th–6th week of life)
Final diagnosis and aetiology (two years of age) Transient CH Iodine-containing agents Transient hyperthyrotropinaemia up to 2 years of age Possible iodine deficiency Transient CH Iodine-containing agents CH Hypoplasia Transient hyperthyrotropinaemia up to 2 years of age Possible iodine deficiency Transient CH Iodine-containing agents Transient CH Possible iodine deficiency Possible compensated CH Possible iodine deficiency Possible compensated CH Possible iodine deficiency Possible compensated CH Possible iodine deficiency Possible compensated CH Possible iodine deficiency
1
710
3.1
96
73
11.5
CH suspected
2
750
2.6
18
16
14.3
High hyperthyrotropinaemia
3
880
0.4
109
45
4.2
4 5
890 935
7.5 4.0
91 39
194 26
0.5 10
CH CH suspected
6
970
2.5
16
24
9.4
CH suspected
7
980
4.5
28
22
4.3
CH
8
1000
5.3
52
55
10
CH suspected
9
1190
4.9
20
29
15.4
Hyperthyrotropinaemia
10
1250
3.0
14
7
14.5
Hyperthyrotropinaemia
11
1300
12.9
11
8
12.3
Hyperthyrotropinaemia
CH
CH, congenital hypothyroidism; fT4, free thyroxine; TSH, thyroid-stimulating hormone
In blood samples, measurements of TSH and free thyroxine 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, administered 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. www.jmedscreen.com
RESULTS 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 prophylaxis during pregnancy, iodine-containing disinfectants used Journal of Medical Screening
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Table 3 Laboratory data and diagnosis in neonates with low birth weight Test 1 (3rd–6th day)
Test 2 (4th week)
5th–6th week of life
No
Birth weight (g)
TSH (mIU/L) TSH (mIU/L) TSH (mIU/L) whole blood whole blood serum
fT4 (pmol/L) Serum
1
1600
4.8
34
26
4.2
2
1650
1.4
11
5
10.3
3
1700
4.7
22
14
14.4
4 5
1820 1900
13.3 2.0
182 16
101 15
8.6 12.4
6
1950
8.3
17
5
11.2
7
2050
5.4
19
3
10.4
8
2450
9.9
42
25
12.3
Thyroid disorder (5th–6th week of life)
Final diagnosis and aetiology (two years of age)
CH
Transient CH Possible iodine deficiency Unknown
Transient hyperthyrotropinaemia up to 5–6 weeks of age Hyperthyrotropinaemia Possible compensated CH Possible iodine deficiency CH CH hypoplasia Hyperthyrotropinaemia Possible compensated CH Possible iodine deficiency Transient Unknown hyperthyrotropinaemia up to 5–6 weeks of age Transient Unknown hyperthyrotropinaemia up to 5–6 weeks of age 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 ultrasound 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 hyperthyrotropinaemia 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 numbers 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 Journal of Medical Screening
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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 hypothyroidism 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 maternal 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 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 substitution 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.
REFERENCES 1 2 3 4 5 6 7 8 9 10 11
CONCLUSIONS 12
(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 falsenegative results and identifies infants who require diagnostic management for primary permanent or transient hypothyroidism and hyperthyrotropinaemia (which might result in compensated hypothyroidism).
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Authors’ affiliations ´ ska, Head of Neonatal Screening Laboratory, Dorota Tylek-Leman Department of Pediatric and Adolescent Endocrinology, PolishAmerican 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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13 14 15 16 17 18 19 20
21
Frank JE, Faix JE, Hermos RJ, et al. Thyroid function in very low birth weight infants: effects on neonatal hypothyroidism screening. J Pediatr 1996;128:548–55 Paul DA, Leef KH, Stefano JL, Bartoshesky L. Thyroid function in very lowbirth-weight infants with intraventricular hemorrhage. Clin Pediatr 2000; 39:651–6 Van-Wasseraer AG, Kok JH, Dekker FW, De-Vijlder JJ. Thyroid function in very preterm infants: influences of gestational age and disease. Pediatr Res 1997;42:604–9 Asami T, Otabe N, Wakabayashi M, et al. Congenital hypothyroidism with delayed rise in serum TSH missed on newborn screening. Acta Paediatr 1995;37:634–7 Ares S, Escobar-Morreale HF, Quero J, et al. Neonatal hypothyroxinemia: effects of iodine intake and premature birth. J Clin Endocrinol Metab 1997;82:1704–12 Fisher DA. Hypothyroxinemia in premature infants: is thyroxine treatment necessary? Thyroid 1999;9:715–20 Karna P. Developmental follow-up of very low birth weight premature infants with low free thyroxine. Am J Perinatol 1991;8:288–91 Van-Wassenaer AG, Kok JH, Briet JM, et al. Thyroid function in preterm newborns; is T4 treatment required in infantso27 weeks’ gestational age? Exp Clin Endocrinol Diabetes 1997;105:12–18 Delange F, Dalhem A, Bourdoux P, et al. Increased risk of primary hypothyroidism in preterm infants. J Pediatr 1984;105:462–9 Hsu CH, Chang JH, Lee YJ, et al. Thyroid function in the sick very low-birthweight infants. Acta Paediatr 1999;40:237–42 Waller DK, Anderson JL, Lorey F, Cunningham GC. Risk factors for congenital hypothyroidism: an investigation of infant’s birth weight, ethnicity, and gender in California, 1990–1998. Teratology 2000;62: 36–41 Mandel SJ, Hermos RJ, Larson CA, et al. Atypical hypothyroidism and the very low birthweight infant. Thyroid 2000;10:693–5 Larson C, Hermos R, Delaney A, et al. Risk factors associated with delayed thyrotropin elevations in congenital hypothyroidism. J Pediatr 2003;143: 587–91 Rapaport R. Evaluation of thyroid status of infants in intensive care settings: recommended an extension of newborn screening. J Pediatr 2003;143: 556–8 Vincent MA, Rodd C, Dussault JH, et al. Very low birth weight newborns do not need repeat screening for congenital hypothyroidism. J Pediatr 2002; 140:311–14 Rapaport R. Thyroid function in the very low birth weight newborn: rescreen or reevaluate? J Pediatr 2002;140:287–9 Van Wassenaer AG, Briet JM, van Baar A, et al. Free thyroxine levels during the first weeks of life and neurodevelopmental outcome until the age of 5 years in very preterm infants. Pediatr 2002;109:534–9 Mikelsaar RV, Viikmaa M. Neonatal thyroid-stimulating hormone screening as an indirect method for the assessment of iodine deficiency in Estonia. Hormone Res 1999;52:284–6 Calaciura F, Mendrola G, Distefano S, et al. Childhood IQ measurements in infants with transient congenital hypothyroidism. Clin Endocrinol 1995; 43:473–7 Czapin´ska E, Z˙ukowicz-S"abowska B, Rybakowa M, et al. Diagnostyka rozwojowo-czynnos´ciowa metoda˛ Hellbru¨ge u niemowla˛t z dysfunkcja˛ tarczycy. (Developmental–functional diagnostic management after the Hellbru¨ge method in infants with thyroid dysfunction). Przeg Lek 1991;48: 4344–6 Rybakowa M, Zygmunt A, Rzon´ca A. Niedobo´r jodu a rozwo´j psychomotoryczny dziecka w pierwszym roku z’ ycia. (Iodine deficiency vs. psychomotor development of a child in the first year of life). Ann Acad Med Siles 1995;Suppl. 20:19–27
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