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Longitudinal Study of Thyroid Function in Children with Mild Hyperthyrotropinemia at Neonatal Screening for Congenital Hypothyroidism

Endocrinologia, Dipartimento di Medicina Interna e Medicina Specialistica, Università di Catania, Ospedale Garibaldi-Nesima, 95122 Catania, Italy

Address all correspondence and requests for reprints to: Professor Riccardo Vigneri, Endocrinologia–Università di Catania, Ospedale Garibaldi-Nesima, Via Palermo 636, 95122 Catania, Italy. E-mail: vigneri{at}unict.it.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Objective: Long-term outcome of thyroid function in children with very short-lasting neonatal hyperthyrotropinemia ("false positive" at neonatal screening) was studied in an observational, prospective study. Thyroid function and morphology were evaluated in 44 "false positive" children up to advanced childhood (8.0 ± 0.7 yr of age). In these children a high prevalence (50%) of subclinical hypothyroidism in early childhood (2.8 ± 0.5 yr) had already been described.

Results: At an average of 5.3 yr, subclinical hypothyroidism persisted in 19 of 44 (43.2%) children and, more specifically, in two of three of those who had increased TSH in early childhood. Euthyroidism was present in all cases that were euthyroid in early childhood, although they had TSH and free T₃ values significantly higher than control children with a normal TSH at birth (TSH = 2.6 ± 0.7 vs. 1.5 ± 0.6 mU/liter, P < 0.001; free T₃ = 4.9 ± 0.8 vs. 3.9 ± 0.9 pmol/liter, P < 0.01). Thyroid morphology alterations were frequent in the group of children with subclinical hypothyroidism. At an average of 8.0 yr, subclinical hypothyroidism persisted in 14 of 44 (31.8%) children. In all other children, TSH and thyroid hormones were confirmed within the normal range.

Conclusions: This prospective longitudinal study confirms that newborns "false positive" at neonatal screening have a high risk to develop persistent subclinical hypothyroidism. The prevalence of hypothyroidism decreases with increasing age, but it is still high (>30%) in late childhood. Even those "false positive" children that maintain euthyroidism in late childhood have an average TSH value that, although within the normal range, is higher than in normal controls, a possible marker of minor congenital thyroid function abnormalities.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Congenital hypothyroidism (CH) is one of the most common causes of mental retardation, preventable if treated early. Screening programs have been successful in the early detection and treatment of infants with CH and, in addition, have helped to identify a wide spectrum of neonatal thyroid dysfunctions (1, 2, 3). Most (60–70%) newborns suspected of CH because of elevated neonatal TSH levels have normal or nearly normal TSH and normal free T₄ (FT4) after a few days, at the recall examination. Therefore, these newborns have very short-lasting hyperthyrotropinemia and are usually classified as "false positive" at CH screening because the early neonatal abnormalities are attributed to a variety of transient causes that have no relevant adverse clinical consequences (4, 5). Some of these children have been reported to have hyperthyrotropinemia during childhood (6, 7).

Studying the thyroid function in a group of 56 "false positive" children at 16–44 months of age, we previously reported a high prevalence (50%) of subclinical hypothyroidism (8). Several different thyroid abnormalities were identified in these children, including genetic abnormalities and thyroid gland malformations. Therefore, transient neonatal hyperthyrotropinemia in many cases was the consequence of documented and persistent, although minor, thyroid abnormalities and represented an abnormal condition of minor severity, which often caused mild (subclinical) hypothyroidism that could either persist or reappear later in life, after the neonatal period.

To investigate the natural history of this condition, we have now performed a prospective, longitudinal study by examining the thyroid function up to 8.0 ± 0.7 yr of age in 44 of the previously studied cohort of 56 "false positive" children.

Data indicate that in more advanced childhood subclinical hypothyroidism, although decreasing as prevalence in studied cases, persisted in many of these children, especially those with a more severe thyroid function deficiency. Therefore, "false positivity" at screening should be considered a marker of high risk for subsequent subclinical hypothyroidism.

Thyroid function in early childhood, but not at birth or at recall examination, had a strong predictive value. When thyroid function was normal in early childhood, it was always normal also in more advanced childhood, allowing to assign these children to a less strict follow-up protocol.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In the recruitment period, there were 132 recalled newborns (with normal FT4 at recall). To identify children with an unknown cause of transient hyperthyrotropinemia, we excluded children with prematurity, small for gestational age, Down’s syndrome, newborns from thyroid autoimmunity positive mothers, and those with TSH at recall more than 12.0 mU/liter. Of the remaining newborns (no = 88), 56 (= 63.6%) gave informed consent and entered the study (8). We assume that these infants do represent all newborns with mild hyperthyrotropinemia at screening for CH (once referred to as "false positive") because in terms of residence, birth weight, gestational age, and TSH levels at recall, they had no difference with those who "dropped out" before age 2–3 yr.

We now studied 44 children of this cohort of 56 infants with elevated TSH values at screening (blood spot TSH > 20 mU/liter or 40 mU/liter serum for a hematocrit of 50%) because 12, all with normal TSH at 2–3 yr, dropped out from the study because of different reasons.

At a second measurement (recall or confirmatory examination, at d 22.6 ± 6 of life), all 44 newborns included in the present study had a normal serum FT4; 23 of 44 had also a normal TSH (<5.0 mU/liter), whereas 21 of 44 had slightly elevated TSH (5.0–12.0 mU/liter) (9, 10). When thyroid function was examined again at 2–3 yr of age, all 44 children had a normal serum FT4, but both their serum TSH mean value (4.8 ± 2.2 mU/liter) and free T₃ (FT3) levels (5.1 ± 0.7 pmol/liter) were significantly higher (P < 0.001) in respect to values observed in a control group of 65 children matched for age and sex but with a normal TSH at screening. At age 2–3 yr, among these 44 children, we identified two groups: 16 of 44 with a normal serum TSH level (<4.0 mU/liter, 99.7th percentile of the values obtained in control children of the same age) (group 1, 11 of 16 with TSH at recall < 5.0 mU/liter); and 28 of 44 with a slightly elevated serum TSH (4.0–10.1 mU/liter, group 2, 12 of 28 with TSH at recall < 5.0 mU/liter). L-T₄ treatment, at a dosage able to reduce TSH within the normal range, was given to 20 of 28 children in group 2. Only eight of 20 L-T₄ treated patients continued therapy through 7.2–9.5 yr.

At the mean age of 5.3 ± 0.6 yr (median 5.1, range 4.1–6.6), thyroid function (TSH, FT4, and FT3) and morphology (ultrasound) were evaluated again in these 44 children. Antithyroperoxidase (anti-TPO) and antithyroglobulin (anti-Tg) antibodies were also measured, and the auxological data recorded. In children receiving L-T₄, treatment was withdrawn 2–3 months before evaluation. Results were compared with those obtained in a group of 17 children of the same age (4.5–6.3 yr) living in the same area and with a normal TSH at birth.

Thyroid function was evaluated again in all these children at a prepubertal age (mean age 8.0 ± 0.7 yr, median 8.0, range 7.2–9.5). All examined and control children were living in areas with normal iodine intake (8). The study was performed in accordance with the guidelines of the Helsinki Declaration. In all cases parents gave informed consent for the child to enter the study, which was approved by the local research ethic committee.

Thyroid function and morphology

TSH, FT4, FT3, anti-Tg, and anti-TPO antibodies were measured using commercially available methods. TSH was measured by an ultrasensitive method (TSH Axsym; Abbott Laboratories, Inc., Rome, Italy), which in our hands has a coefficient of variation within-assay of 6.1 and 3.7% at TSH concentrations of 0.25 and 5.5 mU/liter, respectively. Between-assay variability, at the same TSH concentrations, was 1.1 and 2.2%, respectively. This method is the same that we used in the study performed in the same children at 2–3 yr of age.

Thyroid morphology was evaluated by ultrasound, and thyroid volume was measured and compared with reference values obtained from the literature (11). Hypoplasia was defined as a thyroid lobe volume at least 50% smaller than the reference volume for body surface.

Auxological evaluation

Standing height was measured with a Harpenden Stadiometer (CSM Weighing Equipment LTD., London, UK). To allow the comparison between different ages and genders, height was expressed as SD score (SDS) according to the method of Tanner et al. (12). SDS was obtained by calculating the ratio between measured individual height minus mean normal height value for age and gender and SD of normal mean height. Bone age was evaluated by the Tanner-Whitehouse method (13).

Statistical analysis

Results are expressed as mean and median values; variability is indicated by SD and/or value range. Data were analyzed by the Student’s t test and one-way ANOVA test for comparison between groups.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Thyroid function

In more advanced childhood (4.1–6.6 yr age range), average serum TSH in the 44 studied children that were "false positive" at neonatal screening was significantly higher than in the control group (4.0 ± 2.0 vs. 1.5 ± 0.6 mU/liter, respectively; P < 0.001). Individual TSH serum values were within the normal range in all 16 children who had a normal TSH in early childhood (group 1) and also in nine of the 28 children who had an increased TSH in early childhood (group 2) (Fig. 1). However, when the 25 children with normal serum TSH at 4.1–6.6 yr were compared with the control group, their average TSH value was significantly higher (Table 1). In the remaining 19 of 28 (67.8%) children in group 2 (with TSH increased in early childhood), serum TSH persisted elevated at the evaluation at a more advanced age (values > 3.9 mU/liter or the 99.7th percentile of values obtained in control children of the same age). At this age mean TSH value was 5.9 ± 1.6, range 4.0–9.2 mU/liter.

View larger version (14K): [in this window] [in a new window]   FIG. 1. Basal serum TSH values in early (16–44 months) and more advanced childhood (4.1–6.6 yr) and in prepubertal age (7.2–9.5 yr) in 44 children "false positive" at birth screening for CH. Serum TSH was always within the normal range in children with normal TSH in early childhood (group 1). At 4.1–6.6 yr, subclinical hypothyroidism persisted in 19 of 28 children in group 2. At 7.2–9.5 yr, subclinical hypothyroidism was present in 14 of 28 children in group 2.

When thyroid function was evaluated again at the mean age of 8 yr, TSH serum values were within the normal range in all 16 children in group 1 (2.5 ± 0.7 mU/liter) and also in the nine children of group 2 who had normalized thyroid function at 4.1–6.6 yr. In the 19 children in group 2 who had elevated TSH at 4.1–6.6 yr, serum TSH was above normal (>3.9 mU/liter) in 14 and within the normal range in the other five of 19 children (2.95 ± 0.4 mU/liter, range 2.4–3.3) (Fig. 1).

Of eight children treated with L-T₄, up to 7.2–9.5 yr, at L-T₄ withdrawal, seven of eight had persistent elevated TSH. Of these seven children, six had genetic and/or morphological abnormalities of the thyroid as the possible cause of their mild hypothyroidism (8).

Serum FT3 and FT4 were normal in all children (Tables 2 and 3). Antithyroid antibodies (anti-TPO and anti-Tg) were negative in all children, including the one with slight positivity at 5.9 yr.

At ultrasound evaluation, performed during more advanced childhood, thyroid morphology abnormalities were frequent. Hemiagenesis found at 2–3 yr of age was confirmed, but an unexpected elevated number (13 of 44) of thyroid hypoplasia of one lobe was also found (five in group 1 and eight in group 2) (Table 4). In addition, three small goiters and three cases of generalized hypoplasia of the whole gland (a possible consequence of L-T₄ treatment) were observed. These thyroid morphology abnormalities were present in both groups of studied children but were more frequent in group 2 (15 of 28 = 53% vs. six of 16 = 37% in group 1) (Table 4). Abnormalities were very frequent among the 14 children with persistently elevated TSH at average 8.0 yr age: four had hemiagenesis, six hypoplasia of one lobe, and two had a goiter.

As a result of these investigations, we identified a thyroid morphological and/or genetic abnormality in 13 of 14 children with persistent subclinical hypothyroidism at prepubertal age.

Auxological parameters

Auxological data in the 44 children with elevated TSH at birth indicate a normal growth in all cases, as judged by the height SDS. SDSs ranged from –0.92 to +0.90 in group 1 and –1.34 to + 1.64 in group 2. L-T₄ treatment, administered to 20 of 28 children of group 2, may have affected these results. The average height SDS was 0.10 ± 0.8 (range –1.3 to +1.6) in L-T₄ treated children and –0.12 ± 0.7 (range –0.9 to + 1.1) in the untreated group (P = not significant). Bone age was within the normal range in all children studied. The ratio bone age to chronological age was 1.0 ± 0.2 in children treated with L-T₄ vs. 1.1 ± 0.2 in the untreated group (P = not significant).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study is aimed at elucidating the natural history of thyroid function during childhood in newborns with elevated TSH at neonatal screening for CH and normal thyroid function at recall examination ("false positive" for CH) (8). This is a heterogeneous group as far as thyroid function is concerned because of the influence of both exogenous and endogenous causes. However, 50% of these newborns had subclinical hypothyroidism in early childhood (16–44 months of age), associated and probably caused by a variety of thyroid abnormalities (thyroid gland malformations, genetic abnormalities). The same factors causing CH, when less severe, may cause milder forms of hypothyroidism, including subclinical or compensated hypothyroidism. Therefore, a continuous spectrum of thyroid impairment severity can occur because of either genetic or environmental factors, or both. We can distinguish newborns that are "false positive" at CH screening because of transiently impaired thyroid function due to environmental (i.e. iodine deficiency, goitrogens, etc.) or mother-derived causes (i.e. treatment with antithyroid drugs, antibodies, treatment with iodine at high concentration). These newborns have a normal thyroid and will recover a normal function as soon as the causes are removed. However, newborns that are "false positive" at screening may also have genetic abnormalities (intrinsic alteration) of thyroid structure and function. These newborns have a high risk of subclinical hypothyroidism during childhood and later in life. Because of the different etiology of neonatal transient hyperthyrotropinemia, future evolution of thyroid function cannot be predicted by TSH level at screening evaluation or at recall examination. Instead, reevaluation in early childhood will differentiate children with persistent subclinical hypothyroidism (most likely due to intrinsic abnormalities of the child thyroid) from children with normalized thyroid function. The transient, external causes of thyroid impairment will no longer be present, and these children will have a normal thyroid function.

The long-term thyroid function outcome in children "false positive" at CH screening has not yet been studied (2). The present longitudinal study, by evaluating the same cohort of children up to prepubertal age, provides some information in this regard.

First of all, children "false positive" at CH screening that have persistent elevated TSH in early childhood (2–3 yr of age) are at very high risk for persistent (subclinical) hypothyroidism also in advanced childhood. In fact, 50% of these children have an elevated TSH up to prepubertal age. Evidence indicates that genetic and/or morphological abnormalities, although mild, cause in these children a persistent condition of subclinical hypothyroidism. TSH value at recall examination is poorly predictive of thyroid function outcome at older age in this group of patients with mild hyperthyrotropinemia. Mild hypothyroidism at prepubertal age was observed in five of 23 (22%) children with recall TSH less than 5.0 mU/liter and in nine of 21 (43%) children with recall TSH in the range of 5.0–12.0 mU/liter. In contrast, normal TSH value in early childhood is strongly predictive of normal thyroid function outcome. All children with normal TSH at that age had normal thyroid function up to prepubertal age. However, children with elevated TSH in early childhood may subsequently normalize TSH value.

A certain number of "false positive" children with confirmed subclinical hypothyroidism in early childhood reverse to a normal thyroid function in more advanced childhood. The reason for this normalization with increasing age is not known. A possible explanation is that thyroid function normalization reflects the progressively decreasing requirement for thyroid hormones with advancing age. In children with permanent CH, the substitutive L-T₄ dose requirement progressively decreases with age (15, 16), paralleling the decreasing growth velocity. When the thyroid defect is minor and environmental factors are favorable, even partially impaired thyroid function may provide sufficient thyroid hormones, and the child will reach euthyroid TSH values. However, also in these euthyroid children, TSH and FT3 serum levels, although in the normal range, will be higher than average values in control children of the same age, indicating that thyroid function background is not fully normal (17). In some of these children, the thyroid impairment is minimal, and serum TSH levels may be found sometimes normal and sometimes slightly elevated, confirming a borderline deficiency of thyroid function.

Increased serum FT3 levels suggest that these children are able to compensate the (mild) thyroid deficiency with increased FT3 production (16). These children might be prone to develop hypothyroidism if environmental conditions will become less favorable later in life. In fact, they have a variable degree of mild or compensated life-long hypothyroidism. Each time the thyroid hormone requirement will be increased or the environmental conditions will be less favorable (puberty, pregnancy, iodine deficiency, goitrogens, autoimmune or other thyroid diseases), a biochemically measurable thyroid function deficiency will reappear. The marker of their thyroid condition will be a serum TSH in the high-normal range or mildly elevated.

Among possible causes of childhood subclinical hypothyroidism, an intriguing observation is the high prevalence of thyroid autoantibody positivity in early childhood and a clear decrease of positivity during follow-up. This observation has already been reported by others (18). No data are available on the subsequent development of hypothyroidism in children with positive antithyroid antibodies.

The clinical relevance of long-term subclinical (compensated) hypothyroidism starting during childhood is not clear. Subclinical hypothyroidism may cause minimal end-organ abnormalities that, although not detectable, may produce clinically significant problems over the course of many years (i.e. abnormalities of lipid metabolism, heart function, linear growth, and, more important, cognitive development) (19, 20). Whether this condition needs to be treated is still a matter of debate (2). We believe that, after discussing the problem with parents and carefully avoiding overtreatment, children with a serum TSH above the normal range should be treated with L-T₄ to normalize their TSH (21, 22). Treatment is easy, inexpensive, and requires minimal control. It avoids potentially relevant unfavorable consequences.

In conclusion, "false positivity" at the CH screening allows to identify subjects at risk for subsequent subclinical hypothyroidism. As suggested by the recent guidelines of the American Academy of Pediatrics for transient TSH elevation (23), also in these "false positive" children may be useful to determine at some later time whether the (mild) thyroid defect is permanent. TSH values during early childhood, but not at recall examination, are good predictors of thyroid function in later childhood. When serum TSH is higher than normal during early childhood, a high risk (50%) of persistent subclinical hypothyroidism is present and requires prolonged monitoring. Therefore, it might be considered whether L-T₄ treatment should be started in these children when TSH levels are higher than normal, even if only slightly (24).

	Acknowledgments

 
We thank Dr. G. Parrinello and A. Mirone for their accurate and continuous technical support.

	Footnotes

 
The present research was supported by grants from the University of Catania (Progetti d’Ateneo, 2002; to L.S.) and from Health Ministry Project 2000, no. OAH/F Molecular Basis of Congenital Hypothyroidism.

Disclosure Information: The authors have nothing to declare.

First Published Online April 29, 2008

Abbreviations: CH, Congenital hypothyroidism; FT4, free T₄; FT3, free T₃; SDS, SD score; Tg, thyroglobulin; TPO, thyroperoxidase.

Received November 27, 2007.

Accepted April 21, 2008.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Leonardi, D. Articles by Calaciura, F. Search for Related Content PubMed PubMed Citation Articles by Leonardi, D. Articles by Calaciura, F. Related Collections Pediatric Endocrinology Thyroid