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Low Birth Weight Is Not Associated with Thyroid Autoimmunity: A Population-Based Twin Study

Department of Endocrinology and Metabolism (T.H.B., P.S.H., A.B.R., J.B.H., L.H.), Odense University Hospital, 5000 Odense C, Denmark; and The Danish Twin Registry (P.S.H., A.S., K.O.K.), University of Southern Denmark, 5230 Odense M, Denmark

Address all correspondence and requests for reprints to: Thomas Heiberg Brix, M.D., Ph.D., Department of Endocrinology and Metabolism, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark. E-mail: thomas.brix{at}ouh.fyns-amt.dk.

	Abstract

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Context: Low birth weight has been proposed as a risk factor for the development of antibodies toward thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) in adult life. However, the association could also be due to genetic or environmental factors affecting both birth weight and the development of thyroid autoantibodies. The effect of these confounders can be minimized through investigation of twin pairs.

Objective and Design: To examine the impact of low birth weight on the development of thyroid autoimmunity, we studied whether within-twin-cohort and within-twin-pair differences in birth weight are associated with differences in the serum concentration of TPOAb and TgAb in adult life.

Participants: We studied 1024 euthyroid twin individuals who were distributed in 512 same-sex twin pairs.

Methods: Original midwife protocols were traced manually through the Provincial Archives of Denmark. TPOAb and TgAb were measured using solid-phase time-resolved fluoroimmunometric assays.

Results: There were no statistically significant associations between birth weight and serum concentrations of TPOAb [regression coefficient (ß) = 0.003 (95% confidence interval, –0.010 to 0.015); P = 0.67] or TgAb [ß = 0.002 (–0.010 to 0.014); P = 0.77]. When restricting the analysis to twin pairs with a within-pair difference in birth weight of 500 g or greater or to twin pairs born 4 wk or more before term, the regression coefficients were almost unchanged. Controlling for potential confounders (sex, zygosity, gestational age, TSH, and smoking) did not change the findings of nonsignificant regression coefficients.

Conclusion: Low birth weight per se has no evident role in the etiology of thyroid autoimmunity.

	Introduction

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CLINICALLY OVERT AUTOIMMUNE thyroid diseases (AITD) affect around 2% of women and 0.2% of men, whereas subclinical disease, reflected by the presence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) in euthyroid individuals, is up to 10-fold higher (1, 2). Although common, the etiology of these diseases is still incompletely understood. However, it is generally assumed that the development of overt as well as subclinical AITD is the net result of environmental triggers operating in genetically predisposed individuals (3, 4, 5).

During the last two decades, low birth weight has repeatedly been associated with an increased propensity to a number of adverse health outcomes in adult life, including cardiovascular disease and insulin resistance (6). These observations have led to the hypothesis that poor nutrition in utero (reflected by a low birth weight) programs to impaired function of particular organs, with consequent clinical disease in later life (6).

This could theoretically have implications for the pathogenesis of thyroid autoimmunity. Indeed, two previous studies have suggested a link between low birth weight and the development of TPOAb and TgAb in later life (7, 8). However, both studies had a relatively small number of individuals, and no effort was made to adjust for potentially important confounding factors, such as smoking habits and TSH, hampering any conclusions. In the present study, the impact of birth weight on the presence of thyroid autoantibodies was investigated by comparing differences in birth weight and serum concentrations of TPOAb and TgAb within 512 euthyroid twin pairs.

	Subjects and Methods

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Subjects

This study is part of a nationwide project (GEMINAKAR) investigating the relative influence of genetic and environmental factors on a variety of different traits among Danish twins. A detailed description of the ascertainment procedure in the GEMINAKAR project has been published elsewhere (4, 9). In brief, in 1997, a representative sample of self-reported healthy twin pairs born between 1931 and 1982 was recruited from the Danish Twin Register on the basis of nationwide questionnaire surveys concerning health and health-related behavior performed in 1994 and 1996. In all, 1512 individuals (756 twin pairs) were examined during 1997–2000. Blood samples were available from 736 twin pairs. Twin pairs with self-reported thyroid disease (32 subjects in 28 twin pairs), overt biochemical thyroid disease (19 subjects in 18 pairs), or a missing midwife protocol (116 subjects in 58 pairs) were excluded. Moreover, because sex is a potential confounder, the opposite sex pairs (240 subjects in 120 pairs) were also excluded, leaving 1024 subjects [512 twin pairs, distributed in 260 monozygotic (MZ) and 252 dizygotic (DZ) pairs] available for the data analysis.

Written informed consent was obtained from all participants, and the study was approved by all the Regional Scientific Ethical Committees in Denmark.

Birth weight and smoking history

Midwife protocols were traced manually through the four Provincial Archives of Denmark. The protocols contain data on birth weight, birth length, birth order, and whether the birth was at term and, if not, how many weeks early or late it was.

Smoking status was based on self-reported information. We defined smokers as former or current smokers.

Assays

Serum concentrations of TSH, TPOAb, and TgAb were measured using solid-phase time-resolved fluoroimmunometric assays (AutoDelfia; PerkinElmer/Wallac, Turku, Finland).

The reference interval for TSH is 0.58–4.07 mU/liter. The analytical coefficient of variation at TSH concentrations between 0.23–6.1 mU/liter is 8.1% (10). The reference intervals are 2–10 kIU/liter for TPOAb and 3–19 kIU/liter for TgAb, and the coefficient of variation analytical is 9.3 and 9.0% for TPOAb and TgAb, respectively (11, 12). All serum samples were analyzed at the same laboratory, and twin individuals from the same pair were analyzed within the same run.

Zygosity was established by DNA fingerprinting using a PE Applied Biosystems (Foster City, CA) AmpFISTER Profiles Plus Kit.

Confounding variables

Sex, TSH, and zygosity (proxy for genetic confounding) were considered as potential confounding variables. Clearly, sex is related to both birth weight (13) and to the liability to develop thyroid autoimmunity (1, 2). Also TSH might be related to both birth weight and thyroid autoimmunity, because a link between fetal growth and serum TSH in adult life has been suggested (14). Additionally, serum TSH is related to the concentration of thyroid autoantibodies, especially TPOAb (10). Moreover, both birth weight (15) and thyroid autoimmunity (4, 16) are under genetic influence, suggesting the possibility of genetic confounding. In other words, the genotype responsible for thyroid autoimmunity may itself cause low birth weight. Because MZ pairs share 100% of their genes and DZ pairs share 50%, the twin approach allows, by stratifying according to zygosity, to control for this phenomenon.

The effect of smoking was considered in the analysis because smoking is one of the few known lifestyle determinants of the concentration of thyroid autoantibodies (17).

Statistical methods

Group frequencies were compared with the Pearson ² test, whereas group medians were compared with a modified Wilcoxon test (18). Because of deviation from normality, logarithmic transformation of serum TSH, TPOAb, and TgAb concentration values was carried out.

The relationship between birth weight and the logged serum concentrations of TPOAb and TgAb (within-cohort analysis, n = 1024) as well as the relationship between within-twin-pair differences in birth weight and within-pair differences in TPOAb and TgAb concentrations (within-twin-pair analysis, n = 512) were assessed by linear regression.

In the within-cohort analysis, the paired nature of the twin data was taken into account by using the cluster option in STATA (StataCorp, College Station, TX). Subsequently, the data were analyzed with the logged concentration of autoantibodies as the response variable and birth weight, sex, zygosity, TSH, smoking, and gestational age as the explanatory variables.

In the within-twin-pair analysis, the regression line was constrained to pass through the origin so that the results were independent of the labeling of the twin as the first or second born. Subsequently, we stratified according to zygosity and sex and adjusted for serum TSH and smoking habits by using the within-pair differences of these variables as explanatory variables in the regression model. In this analysis, pairs with a within-pair difference 5 SD values or more from the logged within-pair mean were considered to be outliers (n = 3 pairs) and were excluded.

Significant differences were defined as a P value less than 0.05 using two-tailed tests. All analyses were carried out using version 7 of the STATA statistical package.

	Results

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Twin characteristics (Table 1)

Descriptive characteristics and distribution of thyroid autoantibody measurements in the twin cohort, as a whole and stratified by zygosity and sex, are given in Table 1. A statistically significant difference between MZ and DZ twins was observed for smoking (MZ vs. DZ; 46 vs. 53%, P = 0.025) and birth weight (MZ vs. DZ; 2520 vs. 2700 g, P = 0.0004). As for gender, significant differences were seen for birth weight (males vs. females; 2650 vs. 2535 g, P = 0.002) and the concentration of serum TSH (males vs. females; 1.47 vs. 1.62 mU/liter, P = 0.03). There was no statistically significant difference in the concentration of TPOAb and TgAb across zygosity and gender. However, significantly more females than males had values of TPOAb (11.2 vs. 4.9%, P < 0.001) and TgAb (8.0 vs. 2.4%, P < 0.001) above the cutoff limit for being autoantibody positive.

Twin analysis (Fig. 1)

In the overall study population (within cohort), no significant associations were found between birth weight and the logged concentrations of TPOAb [regression coefficient (ß) = 0.003 (95% confidence interval, –0.010 to 0.015), P = 0.67] and TgAb [ß = 0.002 (–0.010 to 0.014), P = 0.77]. Controlling for potential confounders (sex, zygosity, TSH, smoking, gestational age) did not change the findings of nonsignificant regression coefficients (data not shown).

View larger version (32K): [in this window] [in a new window]   FIG. 1. Within-twin-pair differences in the logarithmically transformed concentration of TPOAb (lnTPOAb) and TgAb (lnTgAb) for every 100 g within-twin-pair difference in birth weight. Ninety-five percent confidence intervals are given in parentheses.

Looking at pairs with a within-pair difference in the serum concentration of TPOAb (n = 73) and TgAb (n = 85) of 20 kIU/liter or more did not change the findings: TPOAb, ß = –0.029 (–0.088 to 0.030), P = 0.33; TgAb, ß = 0.020 (–0.048 to 0.087), P = 0.57.

	Discussion

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Despite conflicting results (7, 8, 19), a link between low birth weight and the development of thyroid autoimmunity has been suggested (5). In contrast to the studies by Phillips et al. (7, 8), we could find no indication of a low birth weight conferring an increased risk of harboring TPOAb or TgAb, extending our previous findings in overt AITD (19). At variance with others (7, 8), we looked at both within-twin-cohort and within-twin-pair differences in antibody concentrations and birth weights in a large cohort of euthyroid twins ascertained from a population-based twin registry. Moreover, our study is very robust, because the twin design allows optimal control for genetic, environmental, and maternal factors affecting both birth weight and the development of thyroid autoantibodies (20).

Whether our results, obtained in twins, can be generalized to the background population depends on whether twins can be considered to be no different from non-twin individuals with respect to the implications of low birth weight and the etiology of thyroid autoimmunity. Because the birth weight of twins is, on average, 1000 g less than the birth weight of singletons, it has been argued that low birth weight in twins does not have the same implication as low birth weight in singletons (20). In our study, we have tried to overcome this potential limitation by looking at twin pairs with a within-pair difference in birth weight of 500 g or greater and pairs born 4 wk or more before term. The findings in these subsamples of highly growth-impaired twin pairs were almost unchanged, indicating that this is unlikely to be a major concern. Moreover, if low birth weight per se were associated with thyroid autoimmunity, one would expect a higher prevalence of thyroid autoantibodies among twins than in the non-twin population, which is not the case (2, 4), indicating that there are no major differences between twins and non-twin individuals with respect to the etiology of thyroid autoimmunity.

In conclusion, low birth weight per se has no evident role in the etiology of thyroid autoimmunity.

	Footnotes

 
Disclosure statement: The authors have nothing to disclose.

First Published Online July 5, 2006

Abbreviations: AITD, Autoimmune thyroid disease; DZ, dizygotic; MZ, monozygotic; TgAb, thyroglobulin antibodies; TPOAb, thyroid peroxidase antibodies.

Received June 22, 2006.

Accepted June 28, 2006.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 91/9/3499    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart 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 Google Scholar Google Scholar Articles by Brix, T. H. Articles by Hegedüs, L. Search for Related Content PubMed PubMed Citation Articles by Brix, T. H. Articles by Hegedüs, L. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Thyroid Diseases Related Collections Pediatric Endocrinology Autoimmunity