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Altered Thyroid and Adrenal Function in Children Born at Term and Preterm, Small for Gestational Age

Department of Paediatrics, Regional Hospital of Bolzano, 39100 Bolzano, Italy

Address all correspondence and requests for reprints to: Dr. Giorgio Radetti, Department of Paediatrics, Regional Hospital, via L. Boehler 5, 39100 Bolzano, Italy. E-mail: giorgio.radetti{at}asbz.it.

	Abstract

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Intrauterine growth retardation may permanently influence the endocrine system by affecting its programming during development. The aim of this study was to evaluate thyroid and adrenal function together with insulin sensitivity in a group of children born small for gestational age (SGA). Forty SGA children (mean age, 6.7 ± 1.7 yr) and 35 children born appropriate for gestational age (mean age, 6.5 ± 2.2 yr) were selected for the study. TSH, free T₄, free T₃ (fT₃), rT₃, antithyroid antibodies, cortisol, and dehydroepiandrosterone sulfate (DHEAS) were assessed. Insulin sensitivity was evaluated with the quantitative insulin sensitivity check index (QUICKI). A thyroid ultrasound was also performed in the SGA children. We found that TSH was significantly higher in SGA than in children born appropriate for gestational age [2.9 ± 1.1 vs. 1.7 ± 0.7 µU/ml (mIU/liter); P < 0.001]; furthermore, eight SGA children (20%), seven born preterm and one at term, had TSH levels above the upper limit of normality. fT₃ was also higher in SGA children (4.2 ± 0.4 vs. 3.6 ± 0.6 pg/ml; 6.4 ± 0.6 vs. 5.5 ± 0.9 pmol/liter; P < 0.0001), whereas no difference was found for free T₄, rT₃, and the fT₃/rT₃ ratio. Urinary iodine was normal, and antithyroid antibodies were absent. Thyroid ultrasound showed a normal echographic pattern with a normal volume in SGA children. Serum cortisol was similar in both groups, whereas DHEAS was significantly lower in SGA subjects (43 ± 18 vs. 65 ± 50 µg/dl; 1.1 ± 0.4 vs. 1.7 ± 1.3 µmol/liter; P < 0.05). There was no difference in insulin sensitivity between the two groups. Birth length and birth weight were the main determinants of TSH and DHEAS serum levels, respectively.

In conclusion, functional thyroid and adrenal changes have been found in children who suffered from intrauterine growth retardation. A larger survey with an appropriate follow-up is, however, required to confirm these findings and to assess their natural evolution.

	Introduction

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RECENT STUDIES HAVE provided unequivocal evidence of the role played by events occurring in prenatal life in modulating the future development of adult diseases. Intrauterine growth retardation is frequently associated with a higher systolic blood pressure (1, 2), increased cardiovascular mortality (3), elevated plasma cortisol (4), glucose intolerance, hyperinsulinism, type 2 diabetes (5, 6), premature pubarche, and ovarian hyperandrogenism (7, 8, 9). Given the significant alterations that thyroid and adrenal glands show in case of severe illness (10, 11, 12, 13, 14, 15) or metabolic derangement (16, 17), we decided to study a group of children born small for gestational age (SGA) to investigate whether fetal growth restriction could induce permanent changes in thyroid and adrenal function.

	Subjects and Methods

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We studied 40 children (29 female, 11 male) born SGA who, at the time of the investigation, were 6.7 ± 1.7 (2.2–11.5) years old. SGA was defined as weight and length at birth below the 10th centile, according to Lubchenko et al. (18). These children were part of a group of 194 SGA children born at our hospital in the period between 1995 and 2000, who were regularly followed up in our Pediatric Department. They represent the first 40 consecutive patients whose parents gave their consent to participate to the study. Twenty-six of them were preterm (gestational age < 37 wk), and 14 were full-term newborns. Gestational age was 35 ± 2 wk (31–40 wk), weight 1740 ± 500 g (935–2470 g), length 41 ± 3 cm (36–47 cm), and head circumference 29 ± 2 cm (25–34 cm). The length of the newborns was assessed by the use of a neonatal infantometer.

As a control group, we selected 35 children matched for gender and chronological age (6.5 ± 2.2 yr; range, 2.0–10.5), all born at our hospital at term and appropriate for gestational age (AGA), who were examined at our department because of short stature. They all underwent a thorough clinical investigation for short stature. Organic disorders such as celiac disease, intestinal malabsorption, renal impairment, cardiac abnormalities, bone diseases, and chromosomal anomalies were all ruled out. A full blood count, urine analysis, and biochemical profile were also normal. Thyroid and adrenal function was normal. GH deficiency was excluded by the finding of a GH peak of more than 10 ng/ml (10 µg/liter) after two pharmacological stimuli (arginine stimulation test and insulin-induced hypoglycemia) and by a normal nocturnal GH secretion: blood samples were taken every 30 min from 2000 to 0800 h. A mean GH value above 3 ng/ml (3 µg/liter) was considered normal. Children were considered affected by growth retardation when bone age was retarded by more than 1 yr compared with chronological age; otherwise, a diagnosis of familial short stature was made. There were no pubertal children in either group, and none of them had precocious pubarche. The clinical characteristics of both groups of children at the time of the study are reported in Table 1. An informed consent for the study was obtained from all parents of the SGA and AGA children, and the study protocol was approved by the Ethical Committee of our hospital.

The children were admitted to the hospital between 0800 and 0900 h after an overnight fast for evaluation of thyroid function, TSH serum levels, adrenal function, insulin sensitivity, and auxological parameters; moreover, they all underwent a thyroid ultrasound.

Weight, length, and head circumference at birth were converted, for statistical purposes, to SD scores (SDSs), according to Usher and McLean (19), whereas the actual height was expressed as SDS according to Tanner et al. (20). Nutritional status at birth was assessed with the ponderal index (PI) (g/cm³ x 100) (21), whereas at the time of the study it was expressed as body mass index (BMI) (kg/m²) SDS (22).

Insulin sensitivity was evaluated with the quantitative insulin sensitivity check index (QUICKI) = 1/[log(I₀) + log(G₀)], where I₀ is the fasting insulin and G₀ the fasting glucose (23).

The atherogenic index [total/high-density-lipoprotein (HDL) cholesterol], which is considered an index of severe cardiovascular risk (24), was also calculated.

Thyroid ultrasound was performed by the same observer using a 7.5-MHz transducer. The findings were then compared with the normal ones for the same population (25).

Assays

TSH was measured by RIA (DiaSorin, Dietzenbach, Germany); the intra- and interassay coefficients of variation (CV) were 2.5 and 5.7%, and the sensitivity limit was 0.02 mIU/ml. fT₃ was measured by RIA (DiaSorin); the intra- and interassay CV were 4.6 and 6.5%, and the sensitivity limit was 0.35 pg/ml. Free T₄ (fT₄) was measured by RIA (DiaSorin); the intra- and interassay CV were 2.4 and 6.8%, and the sensitivity limit was 1 pg/ml. rT₃ was measured by RIA (Adaltis, Casalecchio di Reno, Italy) with an intra- and interassay CV of 7 and 8.5% and a sensitivity limit of 0.01 ng/ml. Thyroglobulin antibodies were measured by immunoradiometric assay (DiaSorin) with an intra- and interassay CV of 4.1 and 5.2% and a sensitivity limit of 2 U/ml; thyroid peroxidase antibodies were measured by RIA (Biocode, Liege, Belgium) with an intra- and interassay CV of 4.8 and 6.2% and a sensitivity limit of 1 U/ml. Iodine urinary excretion was measured on a morning urine spot by inductively coupled mass spectrography (Perkin-Elmer, Montreal, Quebec, Canada). Cortisol was measured by chemiluminescence (Diagnostic Products Corp.-Medical Systems, Los Angeles, CA) with an intra- and interassay CV of 6 and 7.8% and a sensitivity limit of 10 ng/ml. Dehydroepiandrosterone sulfate (DHEAS) was measured by chemiluminescence (Diagnostic Products Corp.-Medical Systems) with an intra- and interassay CV of 6.5 and 9.3% and a sensitivity limit of 30 µg/dl. Serum glucose level was measured with automatic analyzers, using a hexokinase-catalyzed glucose oxidase method. Serum insulin was measured with an immunoradiometric assay (Immulite 2000 insulin, Diagnostic Products Corp.-Medical Systems) which has an intra- and interassay CV of 8.3 and 8.6%, respectively, and a sensitivity limit of 2 µIU/ml. Total and HDL cholesterol and triglycerides were measured enzymatically by an automatic photometric method (Olympus Diagnostica Gmbh, Lismeehan, O’Callaghan’s Mills, County Clare, Ireland).

Statistical analysis

Data are expressed as mean ± SD. Differences between means were assessed by using an unpaired Student’s t test. The correlation between variables was sought by calculating the Pearson coefficient, after ascertaining that the values were normally distributed. Forward stepwise regression analysis was used in the selection of predictors of TSH and DHEAS serum levels. A P value of less than 0.05 indicates statistical significance. A computer program was used for all statistical calculations (Statgraphics Plus, Manugistics Inc, Rockville, MD).

	Results

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Auxology

At birth, length SDS in the SGA group was –2.3 ± 1.12, weight SDS –2.2 ± 0.7, and head circumference SDS –1.4 ± 1.2. PI was 31 ± 4. Normal PI values, calculated for a group of 30 babies of the same gestational age and born with appropriate weight and length, were 34 ± 4 (P < 0.001); the babies, all born in our hospital, were admitted either to the nursery or to the neonatal intensive care unit. At the time of the study (Table 1), height SDS was normal in SGA, and in particular none had a height SDS of less than –1.2, showing that all children had a full catch-up growth. Height among SGA children was even greater than that of the control group (P < 0.001), which was, however, preselected on the basis of short stature. BMI SDS was also normal, suggesting that the nutritional status of the children was good.

Furthermore, SGA children were subdivided according to their TSH level (normal or elevated); their auxological data, at birth and at the time of the study, are shown in Table 2. A statistically significant difference was found only for the birth length (P < 0.05); i.e. the shorter the newborn, the higher the TSH level.

TSH was significantly higher in SGA children (P < 0.0001) (Table 3), and in particular eight of them (20%), seven born preterm and one at term, had a TSH serum level above the upper limit of normality [3.5 µU/ml (mIU/liter)], with values ranging from 3.6 to 5.6 µU/ml (mIU/liter) (Fig. 1). fT₃ was also higher, but rT₃ and fT₄ were similar to those of controls as well as the fT₃/rT₃ ratio. Thyroid autoimmunity in those with elevated TSH levels was excluded by the absence of thyroid antibodies and by the normal echographic pattern. Furthermore, the thyroid volume was within the normal reference range (25). Iodine deficiency was also excluded because all SGA children had a normal urinary iodine concentration (range, 106 to 259 µg/liter; normal value, >100 µg/liter).

View larger version (17K): [in this window] [in a new window]   FIG. 1. TSH serum levels in the SGA and AGA groups.

Cortisol serum level was similar in both SGA and AGA children, whereas DHEAS was significantly lower in the SGA subjects (43 ± 18 vs. 65 ± 50 µg/dl; 1.1 ± 0.4 vs. 1.7 ± 1.3 µmol/liter; P < 0.05) (Table 4).

Lipids

No differences were found between SGA and AGA children concerning triglyceride values (64 ± 35 vs. 73 ± 40 mg/dl; 0.64 ± 0.35 vs. 0.73 ± 0.40 g/liter), total cholesterol (169 ± 30 vs. 156 ± 24 mg/dl; 4.37 ± 0.77 vs. 4.04 ± 0.62 mmol/liter), HDL cholesterol (55 ± 12 vs. 53 ± 10 mg/dl; 1.42 ± 0.31 vs. 1.37 ± 0.25 mmol/liter), and the atherogenic index (3.2 ± 0.7 vs. 3.0 ± 0.7).

Correlations

The actual height was positively correlated with gestational age (r = 0.32; P < 0.05), with height gain (r = 0.65; P < 0.00001), and with PI (r = 0.41; 0.01). Furthermore, height gain was negatively correlated with birth length (r = –0.65; P < 0.0001) and positively with gestational age (r = 0.33; P < 0.05). TSH was negatively correlated with birth length (r = –0.34; P < 0.05); no correlation was found, however, between TSH, weight, and head circumference at birth. DHEAS was also positively correlated with birth length (r = 0.31; P = 0.05) and birth weight (r = 0.38; P < 0.05). Forward stepwise regression analysis with TSH as the dependent variable showed that birth length was the main determinant of TSH serum level (adjusted r² = 0.09; P < 0.05), whereas birth weight was the main determinant of DHEAS serum level (adjusted r² = 0.12; P < 0.05).

	Discussion

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The results of our study show that intrauterine growth restriction is associated with some endocrine disturbances later on in life, because slight alterations of the pituitary-thyroid axis and of the adrenal steroidogenesis were found. We did not find, however, in the SGA population any evidence of insulin resistance, which is at variance with previous studies (26, 27) but in accordance with another one (28), suggesting that an impaired insulin sensitivity, a hallmark of the metabolic syndrome, might not be an obligatory feature of children born SGA.

Our findings on thyroid function confirm and expand the data of Cianfarani et al. (28), who also found a significantly higher TSH level in SGA subjects; our group of SGA children were, however, more affected, because about 20% of them had a TSH serum level above the upper limit of normality. All but one were premature babies; however, prematurity per se, to our knowledge, has never been reported to cause thyroid dysfunction later on in life. Thyroid autoimmunity could be excluded by the absence of thyroid autoantibodies together with a normal echographic pattern and iodine deficiency by a normal urinary iodine excretion. Thyroid morphology and volume were also normal on ultrasound examination, thus potentially excluding factors interfering with gland growth and differentiation. Other possible explanations for these findings, such as polymorphisms of the TSH receptors, are currently under investigation. As an alternative hypothesis, the raised TSH might not be the result of a thyroid impairment but rather of an altered feedback at the hypothalamic-pituitary level. Recently, in fact, a significant reduction of the expression of thyroid receptor isoforms in the fetal nervous system of children with intrauterine growth restriction has been described (29), which could explain the resetting of TSH sensitivity at the hypothalamic-pituitary level. This interpretation would also explain the modestly elevated fT₃ concentration in the SGA patients, as a consequence of the chronic thyroid stimulation.

With regard to the adrenal function, we found normal cortisol levels, in accordance with some (4, 28) but not other studies (31, 32); surprisingly, a small but significant decrease in DHEAS levels was detected. Although some papers have reported high DHEAS levels (7, 33), others could not confirm these findings (32). Maybe differences in patient selection could account for these discrepancies.

A dissociated secretion of adrenal steroids has been already reported in severe illnesses (14, 15), in cases of metabolic derangement (16, 17), and in chronic inflammatory diseases (12, 13) but not yet in a healthy population such as children born SGA. The reasons for the low DHEAS levels are not yet completely understood, although, at least in the case of chronic inflammatory diseases, it has been suggested that some soluble immune mediators such as IL-1 and TGFß1 could inhibit the adrenal 17–20 lyase (34, 35), thus explaining the preferential cortisol secretion in relation to DHEAS. We wonder whether the decreased DHEAS secretion should also be considered a marker of an in utero reprogrammed adrenal function. The results, however, are preliminary, with small differences between groups, and as a consequence, a definitive conclusion is not allowed. These findings deserve, however, further investigation.

All of our patients had a full catch-up growth, being all above –1.2 height SDS at the last examination. Factors affecting actual height were birth length, birth weight, and gestational age. A pronounced postnatal catch-up growth has been linked to insulin resistance in adulthood (30). We could not find, however, in our patients any signs of insulin resistance, not even in those who had the greatest postnatal catch-up growth. SGA children with appropriate catch-up growth are therefore not necessarily destined to have a permanent derangement in glycemic homeostasis, as previously reported by Cianfarani et al. (28).

The findings of this study seem to suggest a strong link between intrauterine growth restriction and some functional alterations of the thyroid and adrenal function. In particular, stepwise regression analysis identified birth length as the main determinant of serum TSH (Fig. 2) and birth weight as that of serum DHEAS, suggesting that the shortest and lightest SGA newborns, i.e. those who suffered more in utero, are those at greater risk of developing future endocrine dysfunctions. This seems to be further supported by the fact that the children who were the shortest at birth were also those who showed raised TSH serum levels (Table 2).

View larger version (17K): [in this window] [in a new window]   FIG. 2. Relationship between TSH serum levels and birth length SDS in the SGA group.

	Footnotes

 
Abbreviations: AGA, Appropriate for gestational age; BMI, body mass index; CV, coefficient(s) of variation; DHEAS, dehydroepiandrosterone sulfate; fT₄, free T₄; HDL, high-density lipoprotein; PI, ponderal index; SDS, SD score; SGA, small for gestational age.

Received December 22, 2003.

Accepted August 4, 2004.

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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 Radetti, G. Articles by Messner, H. Search for Related Content PubMed PubMed Citation Articles by Radetti, G. Articles by Messner, H.