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Spontaneous Hypothyroidism in Adult Women Is Predicted by Small Body Size at Birth and during Childhood

National Public Health Institute (E.K., T.F., J.G.E.), Department of Epidemiology and Health Promotion, 00300 Helsinki, Finland; Hospital for Children and Adolescents (E.K.), Helsinki University Central Hospital, 00029 HUS, Helsinki, Finland; Medical Research Council Epidemiology Resource Centre, and Developmental Origins of Health and Disease Centre (D.I.W.P., C.O., D.J.P.B.), University of Southampton, Southampton SO16 6YD, United Kingdom; and Department of Public Health (J.G.E.), University of Helsinki, 00014 Helsinki, Finland

Address all correspondence and requests for reprints to: Eero Kajantie, M.D., National Public Health Institute, Department of Epidemiology and Health Promotion, Mannerheimintie 166, 00300 Helsinki, Finland. E-mail: eero.kajantie{at}helsinki.fi.

	Abstract

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Background: The relationships of early growth with coronary heart disease and type 2 diabetes have received considerable attention. It is not known whether fetal or childhood growth is linked with autoimmune disorders.

Objective: Our objective was to assess whether the risk of adult-onset spontaneous hypothyroidism is predicted by body size at birth and during childhood.

Design and Setting: We conducted a birth cohort study in Helsinki, Finland.

Participants: A total of 293 women who were born between 1934 and 1944 and had their heights and weights recorded at birth and during childhood participated in the study.

Measurements: We measured spontaneous hypothyroidism, defined as: 1) a disease history confirmed from medical records, or 2) previously undiagnosed hypothyroidism (TSH > 10 mU/liter).

Results: Twenty women (6.8%) had spontaneous hypothyroidism; 18 had been diagnosed previously, between 43 and 65 yr of age, and two had undiagnosed subclinical hypothyroidism. In addition, 59 women were thyroid peroxidase antibody positive. Compared with the 214 thyroid peroxidase antibody-negative women with no thyroid disorder, those with spontaneous hypothyroidism had on average 252 g [95% confidence interval (CI), 61 to 443 g; P = 0.01] lower birth weight and 1.2 cm (95% CI, 0.5 to 2.0 cm; P = 0.002) shorter length at birth. The odds of developing hypothyroidism increased 4.4-fold per kilogram decrease in birth weight (95% CI, 1.4 to 14.1). Hypothyroid subjects had been shorter in early childhood and had lower body mass index during later childhood.

Conclusions: Small body size at birth and during childhood increases the risk of spontaneous hypothyroidism in adult women.

	Introduction

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OBSERVATIONS LINKING small size at birth and during infancy with adult diseases such as coronary heart disease (1, 2, 3) and type 2 diabetes (4) have enhanced our understanding of the early life origin of these disorders. By contrast, not much is known about early life origins of autoimmune disorders that become manifest during adult life. Autoimmune thyroid disease is the most common form of spontaneous hypothyroidism. It occurs predominantly in women, in whom the prevalence reaches 5 to 10% by the seventh decade of life (5). A study of women from a birth cohort in Hertfordshire, United Kingdom, has shown that small size at birth is related to an increased prevalence of thyroid autoantibodies to thyroglobulin and thyroid peroxidase (TPO), serological markers of thyroid autoimmuity (6). More recently, a twin study has shown that this association is observed within monozygous twin pairs, suggesting that this is not solely due to genetic factors (7). It is not known, however, whether the birthweight association extends to individuals with overt hypothyroidism or whether the disease is linked with the trajectory of growth during infancy and childhood. We have therefore evaluated the prevalence of spontaneous hypothyroidism in the Helsinki Birth Cohort Study, a unique study incorporating measurements of weight, length, and gestational age at birth with repeated height and weight measurements during childhood.

	Subjects and Methods

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Using random-number tables, we selected 304 women from among the participants of a clinical study of 2003 individuals (1075 women and 928 men) born as singletons in Helsinki University Central Hospital between 1934 and 1944, who had detailed birth records (including weight and length at birth and date of the last menstrual period) and serial measurements of height and weight obtained between birth and 12 yr of age at child welfare and school health care centers. These records and the original cohort have been described in detail elsewhere (2, 3). We restricted the study to women because of the much lower prevalence of spontaneous hypothyroidism in men (5). After an overnight fast, the women attended a clinic between 0800 and 1000 h. A blood sample was obtained for determination of free T4 (fT4), TSH, and TPO antibodies; a medical history was taken; and height and weight were measured. We asked about a previous diagnosis of hypothyroidism or hyperthyroidism and a history of the use of thyroid drugs, thyroid surgery, or treatment with radioiodine. For patients with thyroid disorders, medical records including laboratory results were obtained to confirm the diagnoses. We excluded five subjects with a history of thyroid surgery (three of whom had hyperthyroidism), two with conservatively treated hyperthyroidism, one patient with hypothyroidism secondary to lithium treatment, and one with Sjögren’s syndrome. Two subjects had unavailable medical records, leaving 293 subjects.

fT4, TSH, and TPO antibody concentrations were determined by an Abbott AxSYM automated analyzer (Abbott Diagnostics, Abbott Park, IL). The TPO antibody microparticle enzyme immunoassay is standardized against National Institute for Biological Standards and Control 66/387 reference serum and is considered positive when above 12 IU/ml, which is the cutoff point recommended by the manufacturer. The assay and the cutoff point were in addition validated against another widely used automated assay (AutoDelfia, PerkinElmer, Inc., Wellesley, MA; cutoff limit, 35 IU/ml) by use of 107 samples submitted for TPO antibody, TSH, and fT4 testing (32 males; median age, 56 yr; range, 3 to 88 yr). Of these samples, 19 were considered positive by both assays, four by the Abbott assay only and one by the AutoDelfia assay only, indicating 95% concordance. The reference ranges are 9–19 pmol/liter for fT4 and 0.4–4.0 mU/liter for TSH. These reference ranges are based on a recommendation by the assay manufacturer and confirmation in the hospital laboratory by the use of approximately 50 samples from adult subjects of both sexes submitted for thyroid testing. For fT4, the intra- and interassay coefficients of variation were 4.0 and 5.8% (at a mean concentration of 13.8 pmol/liter), and for TSH, 2.8 and 4.2% (at a mean concentration of 4.8 mU/liter), respectively. For TPO antibodies, the intra- and interassay coefficients of variation at a mean concentration of 2.9 IU/ml were 11 and 12%, respectively; corresponding numbers at a mean concentration of 70.7 IU/ml being 7 and 10%.

t-Tests were used to compare groups. Weight, length, and ponderal index [weight (kilograms)/length (meters)³] at birth were adjusted for gestational age by use of linear regression. Logistic regression was used to determine odds ratios for developing spontaneous hypothyroidism. The study was performed according to the Declaration of Helsinki, with its protocol approved by the Ethics Committee of the National Public Health Institute. All subjects gave written informed consent.

	Results

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A total of 18 (6.1%) women reported a history of spontaneous hypothyroidism, were taking T₄, and had their diagnosis confirmed by review of medical records. The mean age at diagnosis was 54.1 (range, 43 to 65) yr. The subjects who had reported no history of thyroid disorder had a fT4 concentration ranging from 9.2 to 19.6 pmol/liter (mean, 14.1 pmol/liter), but two of them had undiagnosed subclinical hypothyroidism (TSH, 17.3 and 16.7 mU/liter; both were TPO antibody positive), giving a total number of 20 (6.8%) women with spontaneous hypothyroidism. Sixteen (80%) of these women were TPO antibody positive compared with 59 (22%) of the 273 women with normal TSH and no history of a thyroid disorder. The 214 TPO antibody-negative women with normal TSH and no history of a thyroid disorder served as a control group.

Measurements at birth, during childhood, and at clinical examination are shown in Table 1. Women who had developed spontaneous hypothyroidism were on average 252 g [95% confidence interval (CI), 61 to 443 g; P = 0.01] lighter at birth than subjects with no thyroid disorder. Women with hypothyroidism were also shorter at birth (mean difference, 1.2 cm; 95% CI, 0.5 to 2.0 cm; P = 0.002) but did not differ in head circumference or ponderal index. They were, however, born at a later gestational age (mean difference, 5.6 d; 95% CI, 0.7 to 10.6 d; P = 0.03). The odds of developing spontaneous hypothyroidism increased 4.4-fold per kilogram decrease in birth weight (95% CI, 1.4 to 14.1). There was no difference in the mother’s age, height, body mass index (BMI), or parity. Figure 1 shows that women who developed spontaneous hypothyroidism had lower weight during childhood. Their small size was characterized by shortness during infancy and early childhood and a lower BMI during later childhood. Ages at menarche and menopause were similar. On examination at 61 yr, they were shorter but had a similar BMI.

View larger version (20K): [in this window] [in a new window]   FIG. 1. Mean weight, height, and BMI (in SD units) in the first 12 yr after birth in women who developed spontaneous hypothyroidism in adulthood. The mean rank of all hypothyroid and control subjects is set at zero, with deviations from the mean indicated by the SD score.

We further assessed whether early life measurements predict the presence of TPO autoantibodies per se by comparing the 59 TPO antibody-positive euthyroid women with the remaining 214 women with no thyroid disorder and negative TPO antibodies. This is also shown in Table 1. Although there was no difference in any measurement at birth or at examination, during childhood subjects who had developed TPO autoantibodies had lower weight (P < 0.05 between 8 and 12 yr; mean difference ranging from 0.30 to 0.38 SD) and BMI (P < 0.05 between 5 and 12 yr; mean difference, 0.31 to 0.51 SD). These subjects also had a later age at menopause (mean difference, 1.8 yr; 95% CI, 0.4 to 3.3 yr), whereas their age at menarche was similar.

	Discussion

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This study demonstrates that women who develop spontaneous hypothyroidism in adult life are characterized by small body size at birth, partial catch-up in height during childhood, and shortness in adulthood. The differences we found in birth and childhood measurements were of considerable magnitude, approximately 0.5 SD. For comparison, the well-established relationship between early growth and coronary heart disease is associated with a 0.2 SD lower mean weight at birth and during infancy (3). These findings reinforce previous reports of the prevalence of thyroid autoantibodies to TPO and thyroglobulin in singleton births (6), although attempts of replication in small-scale twin studies have given discrepant results; birthweight was similar in 14 Danish twin pairs discordant for Hashimoto’s thyroiditis (8), whereas a study of 15 monozygous twin pairs discordant in birth size suggested that the smaller twin had a higher prevalence of TPO antibody (7). The present study included women who were born as singletons in Helsinki and lived there during their childhood. The region was known to have mild to moderate iodine deficiency, which was eradicated by iodization of salt in the late 1950s. The prevalence of women with spontaneous hypothyroidism in this study (7%) is within the range of the reported prevalence in northern Europe (5).

There are a number of possible explanations for our findings. The early environment is known to alter permanently the settings of a number of major hormonal axes during adult life. These hormonal changes in turn predispose to the development of autoimmunity. Low birth weight is associated with lifelong alterations in the secretion of glucocorticoids, which have potent immunomodulatory effects (9). The secretion of sex steroids is also known to be programmable (10). Sex steroids may play an important role in the pathophysiology of the disorder, perhaps explaining its female predominance and related observations, for example the link between thyroid autoimmunity and a longer reproductive span (the time between menarche and menopause) (11). Our findings are also consistent with a role for gonadal steroids. TPO antibody-positive women reported a later age at menopause, and although we found no relationship with age at menarche, the pattern of childhood growth we observed—shorter length in early childhood, this difference attenuating in later childhood, followed by reduced adult height—is consistent with an earlier timing of puberty, which has been shown to be more frequent in girls with low birth weight (12).

We found thinness in late childhood to be predictive of not only overt hypothyroidism but also the presence of TPO antibodies. Although it has been shown that prenatal undernutrition and poor prenatal and infancy growth are associated with reduced thymic size and function (13, 14), less is known about the effects of growth and nutrition before and during puberty. The absolute size of thymus peaks at puberty (15), and it is thus possible that our finding reflects poor nutrition during this period, reducing the potential for immune regulation and permitting the emergence of autoimmunity.

Our data do not allow us to explore the potential role of a family history of thyroid disease. There is a clear genetic predisposition to spontaneous hypothyroidism (16), and some of the mothers may have had thyroid dysfunction during pregnancy. Some (17) although not all (18) studies have shown that mild, even apparently treated maternal hypothyroidism is associated with lower birth weight of the child. Mild maternal hypothyroidism has well-established long-term effects on neurocognitive development (18), which could be associated with broader long-term effects on growth or thyroid function, although we are unaware of any studies that have assessed this directly.

In conclusion, women who develop spontaneous hypothyroidism in adult life are characterized by low birth weight and short length at birth, short height during early childhood, and low BMI during late childhood. The differences are considerable (approximately 0.5 SD) and suggest that spontaneous hypothyroidism should be included among those adult disorders whose development is initiated during early life. Studies of the pathways linking early life events with adult disease have had a considerable impact on our understanding of adult disorders such as coronary heart disease and type 2 diabetes. Therefore, it would be important to extend our observations in other birth cohort studies, which will have a similar potential in increasing our understanding of the development of thyroid disorders and autoimmunity.

	Footnotes

 
This work was supported by Academy of Finland, British Heart Foundation, Finnish Foundation for Cardiovascular Research, Finnish Foundation for Pediatric Research, Finnish Diabetes Foundation, Finnish Medical Society Duodecim, Novo Nordisk Foundation, Päivikki and Sakari Sohlberg Foundation, Signe and Ane Gyllenberg Foundation, and Yrjö Jahnsson Foundation.

Disclosure statement: The authors have nothing to disclose.

First Published Online September 19, 2006

Abbreviations: BMI, Body mass index; CI, confidence interval; fT4, free T₄; TPO, thyroid peroxidase.

Received May 22, 2006.

Accepted September 13, 2006.

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