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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 9 5309-5312
Copyright © 2005 by The Endocrine Society

BRIEF REPORT

Parity and the Risk of Autoimmune Thyroid Disease: A Community-Based Study

John P. Walsh, Alexandra P. Bremner, Max K. Bulsara, Peter O’Leary, Peter J. Leedman, Peter Feddema and Valdo Michelangeli

Department of Endocrinology and Diabetes (J.P.W.), Sir Charles Gairdner Hospital, Perth, Western Australia 6009, Australia; Schools of Medicine and Pharmacology (J.P.W., P.J.L.), Population Health (A.P.B., M.K.B.), and Women’s and Infants’ Health (P.O.), University of Western Australia, Western Australia 6009, Australia; Genomics Directorate (P.O.), Department of Health, Western Australia 6009, Australia; Laboratory for Cancer Medicine (P.J.L.), University of Western Australia Centre for Medical Research, Western Australian Institute for Medical Research, Perth, Western Australia 6000, Australia; Department of Endocrinology and Diabetes (P.J.L.), Royal Perth Hospital, Perth, Western Australia 6000, Australia; and Biomediq-DPC (P.F., V.M.), Doncaster, Victoria 3108, Australia

Address all correspondence and requests for reprints to: Dr. John P. Walsh, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia. E-mail: john.walsh{at}health.wa.gov.au.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Recent studies have suggested that fetal microchimerism (transplacental passage of fetal cells followed by engraftment into maternal tissues) may play a role in the pathogenesis of autoimmune thyroid disease. If that is true, then parity should be a risk factor for autoimmune thyroid disease.

Objective: The objective of this study was to examine parity as a risk factor for autoimmune thyroid disease.

Design, Setting, and Participants: TSH, thyroid peroxidase antibody, and thyroglobulin antibody concentrations were measured on archived sera from 1045 female participants in a 1981 community health survey in Busselton, Western Australia.

Outcome Measures: Odds ratios (ORs) for positive thyroid antibodies (increased concentration of either antibody) or thyroid dysfunction (abnormal serum TSH) were used.

Results: After adjustment for age, women who had previously been pregnant did not have a significantly increased risk of positive thyroid antibodies [OR, 1.20; 95% confidence interval (CI), 0.74–1.97; P = 0.46], raised TSH (OR, 0.93; 95% CI, 0.46–1.87; P = 0.84), or reduced TSH (OR, 0.87; 95% CI, 0.33–2.30; P = 0.79) compared with women who had never been pregnant. For each additional pregnancy, the OR was 1.02 (95% CI, 0.94–1.11; P = 0.57) for positive antibodies, 1.02 (95% CI, 0.91–1.14; P = 0.67) for raised TSH, and 1.03 (95% CI, 0.87–1.22; P = 0.73) for reduced TSH. Analysis using number of live births gave similar results. The results were similar in younger and older women.

Conclusions: Parity is not a risk factor for thyroid autoimmunity or thyroid dysfunction. These data do not support a key pathogenic role for fetal microchimerism in chronic autoimmune thyroid disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DESPITE RECENT ADVANCES (1, 2, 3), many aspects of the pathogenesis of autoimmune thyroid disease are poorly understood, including the female preponderance of the disorder. Several recent studies have examined the possible pathogenic role of fetal microchimerism. This term refers to the presence in maternal tissues of cells of fetal origin that are presumed to have crossed the placenta during pregnancy. The cells involved include fetal mesenchymal stem cells with the potential to differentiate into a range of cell types, depending on the tissue environment where engraftment occurs (4, 5).

Studies of microchimerism rely on the detection of cells with antigens or DNA foreign to the host, such as male-specific markers in the tissues of female subjects. Using these techniques, fetal microchimerism has been shown to be more common in the thyroids of women with autoimmune thyroid disease than controls (6, 7, 8, 9). Similar results have been found in an animal model of autoimmune thyroid disease (10). It has been hypothesized that, within the thyroid, the presence of cells of fetal origin may initiate an immune response resulting in autoimmune thyroid disease (3, 11). Direct evidence for such an effect is lacking, however, and it remains possible that fetal microchimerism is an incidental remnant of pregnancy with no pathological significance (12), or a feature of the tissue response to inflammation, rather than its cause (4).

Epidemiology offers a means to address this uncertainty because, if fetal microchimerism does indeed initiate autoimmune disease in the thyroid, it is to be expected that autoimmune thyroid disease should be more common in women who have been pregnant than those who have not. There are only limited data on whether parity is a risk factor for thyroid autoimmunity or disease. Parity was not associated with Hashimoto’s disease in a case control study of 89 affected women (13), a study of 51 females with type 1 diabetes and Hashimoto’s disease (14), or in a study of relatives of subjects with autoimmune thyroid disease, including 44 subjects with thyroid disease (15). Each of these studies had relatively small numbers of subjects with thyroid disease, and none was community-based. To address this uncertainty, we studied parity as a risk factor for autoimmune thyroid disease in a cross-sectional, community-based study.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The Busselton Health Study (http://bsn.uwa.edu.au) includes a series of cross-sectional health surveys of adults on the electoral roll of Busselton, a rural town in Western Australia with a predominantly white population. (Registration to vote is compulsory in Australia.) There is no systematic monitoring of iodine status in Western Australia, but it is thought to be an iodine-sufficient region. We used data from the 1981 survey, in which the response rate was 64%, comprising 3447 subjects (2142 females). Detailed descriptions of the surveys have been published previously (16). Participants completed a health and lifestyle questionnaire, which included items regarding the number of pregnancies and live births and a single question regarding history of thyroid disease or goiter (yes/no) and had a venous blood sample collected in the fasting state.

Archived serum samples which had been stored at –70 C were available for 1045 of the 2142 female participants (49%) in the 1981 survey (for the remainder, no sera was available, or storage conditions were suboptimal). The age, prevalence of self-reported thyroid disease/goiter, number of pregnancies, and number of live births did not differ significantly between subjects with and without available sera. Serum TSH, free T4, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) concentrations were measured on an Immulite 2000 chemiluminescent analyzer (Diagnostic Products Corporation, Los Angeles, CA) in 2001. For the TSH assay, functional sensitivity was 0.02 mU/liter. Interassay imprecision (expressed as coefficient of variation) for each analyte was as follows: TSH, 7.6%; free T4, 9.6%; TPOAb, 7.2%; and TgAb, 8.5%. Reference ranges [based on 95% confidence intervals (CIs) after excluding gross outliers and subjects with self-reported thyroid disease/goiter] were as follows: TSH, 0.4–4.0 mU/liter; free T4, 9–23 pmol/liter; TPOAb, less than 35 kIU/liter; and TgAb, less than 55 kIU/liter. Euthyroidism was defined as normal serum TSH (regardless of free T4 concentration), hyperthyroidism as TSH less than 0.1 mU/liter with increased free T4 concentration, subclinical hyperthyroidism as TSH less than 0.4 mU/liter with normal free T4 (17), subclinical hypothyroidism as TSH more than 4.0 mU/liter with normal free T4, and hypothyroidism as TSH more than 4.0 mU/liter with reduced free T4.

The definitions of thyroid disease used in the study were self-reported thyroid disease or goiter, positive thyroid antibodies (defined as increased concentration of either TPOAb or TgAb), raised serum TSH (>4.0 mU/liter), and reduced serum TSH (<0.4 mU/liter). We also used two composite endpoints: positive antibodies or raised TSH (as an indicator of probable chronic autoimmune thyroiditis) and positive thyroid antibodies or serum TSH outside the reference range (as a composite marker of thyroid disease). Parity was analyzed using number of pregnancies (as reported in the 1981 survey) both as a binary variable (0, ≥1) and a continuous variable, and a similar analysis was conducted using number of live births. Logistic regression models, adjusted for age, were used to assess the association of each definition of thyroid disease with each measure of parity, and odds ratios (ORs) and 95% CIs were calculated. Statistical analyses were performed using R 1.8.1. Significance was set at P < 0.05. The study was approved by the Royal Perth Hospital Ethics Committee.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The mean age of the 1045 study subjects was 49.5 yr (range, 18.0–88.5), the mean number of pregnancies was 2.9 (range, 0–10), and the mean number of live births was 2.5 (range, 0–10). Positive TPOAbs were present in 186 women (18%), positive TgAbs in 90 women (9%), and either positive TPOAbs or TgAbs in 210 (20%). Serum TSH was increased in 91 women (9%), of whom 82 subjects had subclinical hypothyroidism, and nine had overt hypothyroidism. Serum TSH was less than 0.4 mU/liter in 40 women (4%), including 21 women with subclinical hyperthyroidism and nine with overt hyperthyroidism. Sixty-three subjects (6%) had a history of thyroid disease or goiter. Of these, 33 subjects had positive antibodies, seven had overt hyperthyroidism biochemically, three had subclinical hyperthyroidism, 11 had subclinical hypothyroidism, and one had overt hypothyroidism.

After adjustment for age, the prevalence of self-reported thyroid disease or goiter, positive thyroid antibodies, raised serum TSH concentrations, reduced TSH and composite endpoints incorporating positive antibodies and abnormal serum TSH did not differ significantly between women who had previously been pregnant and those who had never been pregnant (Table 1Go). In the analysis using number of pregnancies as a continuous variable, there was no evidence of increased risk of thyroid antibodies or abnormal TSH with increasing number of reported pregnancies (after adjustment for age) (Table 2Go). There was, however, a significantly increased risk of self-reported thyroid disease or goiter with each additional pregnancy (age-adjusted OR, 1.18; 95% CI, 1.04–1.35; P = 0.01).


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  		TABLE 1. Prevalence of positive thyroid antibodies and thyroid dysfunction in women with and without previous pregnancy

 

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  		TABLE 2. Prevalence of positive thyroid antibodies and thyroid dysfunction in women by number of pregnancies

 
The analysis was repeated using number of live births instead of pregnancies, and the results were essentially unchanged. We repeated both analyses after excluding subjects with self-reported thyroid disease (n = 63) and using more rigorous cutoffs for defining abnormal serum TSH (<0.1 or >6.0 mU/liter) and positive thyroid antibodies (TPOAb > 100 kIU/liter or TgAb > 100 kIU/liter). In each case, the results were essentially unchanged. In case an association with parity was limited to younger women of childbearing age, we performed subgroup analyses based on age [<50 and ≥50 yr and quartiles of age (18–35, 35–50, 50–63, and 63–89 yr)]. In each case, the results were similar to those for the whole group.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this large, community-based study, we found no association between parity and thyroid autoimmunity (defined by positive TPOAb or TgAb), thyroid dysfunction, or composite markers of thyroid disease. Our results confirm those of smaller studies of selected subjects in which parity was not a risk factor for Hashimoto’s disease (13, 14, 15). Our data do not rule out an association between parity and Graves’ disease, because the number of hyperthyroid subjects in our study was small, TSH receptor antibody concentrations were not measured, and the survey questionnaire did not ask specifically about a history of Graves’ disease.

We did find a significant association between parity and a self-reported history of thyroid disease or goiter in the analyses using number of pregnancies as a continuous variable. This result is difficult to interpret for three reasons. Firstly, there was no significant association when pregnancy was analyzed as a binary variable; secondly, details of the diagnosis of thyroid disease or goiter were not recorded in the survey; and thirdly, the diagnosis of thyroid disease was not verified by access to medical records. A self-reported diagnosis of thyroid disease may be unreliable; in one large study, such a diagnosis was verified in only 23% of cases (18). It is, however, possible that the result reflects the presence in the sample of women with previous postpartum thyroiditis, postpartum Graves’ disease, or subjects with physiological goiter detected during pregnancy.

The lack of association between parity and objective markers of thyroid disease such as thyroid antibodies and abnormal serum TSH may seem surprising, given the well-established changes in immune function during pregnancy and the postpartum period, the high community prevalence of postpartum thyroiditis, and the increased long-term risk of hypothyroidism in subjects with postpartum thyroiditis (19). This paradox is resolved by the observation that most (and in some series all) cases of postpartum thyroiditis occur in women with preexisting thyroid antibodies (19, 20). In most cases, therefore, the immunological changes of the postpartum period precipitate thyroid disease in predisposed women rather than initiate the autoimmune process. The same is probably true of women who develop new-onset Graves’ disease in the postpartum period, although we are not aware of any studies specifically addressing that question.

The strengths of our study include its large sample size and its community-based design, which make it less prone to bias than previous studies that were smaller and of selected subjects. A weakness of our study is that details of diagnosis and treatment of previous thyroid disease were not recorded in the survey. This is unlikely to be a significant confounder in the analyses of positive thyroid antibodies and TSH because excluding subjects with self-reported thyroid disease or goiter did not affect the results, but it does hamper interpretation of the association found between parity and self-reported thyroid disease. Participants were not asked about previous miscarriage, which, if more common in subjects with thyroid autoimmunity, might mask an association between parity and autoimmune thyroid disease.

In conclusion, the lack of association between parity and objective markers of autoimmune thyroid disease (thyroid antibodies and thyroid dysfunction) in this community-based study does not support the hypothesis that fetal microchimerism plays a key role in the pathogenesis of chronic autoimmune thyroid disease. It remains possible that fetal microchimerism is a pathogenic factor in specific thyroid diseases, such as postpartum thyroiditis and postpartum Graves’ disease. Further studies are required to address that question.


   Acknowledgments
 
We thank the Busselton Population Medical Research Foundation for permission to access the survey data and stored sera and Helen Bartholomew for data extraction and advice.


   Footnotes
 
First Published Online June 14, 2005

Abbreviations: CI, Confidence interval; OR, odds ratio; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody.

Received April 8, 2005.

Accepted June 2, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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