This study showed that the prevalence of overt hypothyroidism and subclinical hyperthyroidism is significantly associated with parity. After adjustment for age, smoking status, BMI, and TPOAb positivity, the prevalence of overt hyperthyroidism is associated with multiple abortions. Moreover, the hazard ratios indicated that parity is significantly associated with higher subclinical and overt hypothyroidism incidence. Conversely, history of abortion is significantly associated with a lower incidence of overt hypothyroidism. No significant association between menopause and thyroid dysfunctions was observed.
These observations indicate that the female reproductive system has close interactions with thyroid function. Our findings indicated that the hazard ratio for subclinical and clinical hypothyroidism significantly increases for each pregnancy. A cross-sectional study by Pederson et al. also found that the odds ratio for hypothyroidism non-statistically significant increases with the number of pregnancies [16]. In a study conducted in Greece, TSH in mothers with one pregnancy was significantly higher than mothers with no pregnancy or more than one pregnancy [17]. Furthermore, in our investigation, it was observed that more than four parities were significantly associated with higher rates of clinical and subclinical hypothyroidism incidence. This observation could not be reported in many previous studies due to the small sample size. Wickham survey indicated no significant increase in incidence ratio of thyroid dysfunctions after parity, and post-pregnancy thyroiditis did not result in an increase in thyroid disorders, findings in contrast with our results [1].
To evaluate the true impact of reproductive status on thyroid dysfunctions, we adjusted our results for TPOAb positivity as well as age, smoking status, and BMI since several previous reports suggested that autoimmune thyroid dysfunction can be associated with the number of pregnancies [18]. Our earlier study concluded that parity does not significantly affect the incidence of TPOAb positivity [11]. Its results were in line with reports from Walsh et al., Sgarbi et al., and Bjegevred et al. [4, 19, 20] while contradicting the report from Friedreich et al. [18]. It was also observed that an increase in the incidence of hypothyroidism could not be necessarily aligned with an increase in autoimmune thyroid dysfunctions [21]. Nevertheless, it is also essential to consider that autoimmune thyroid dysfunctions have a complex signaling pathway, and herein, we only adjusted our results for Anti-TPO positivity. Although Anti-TPO antibodies are the most common antithyroid antibodies found in patients with Hashimoto thyroiditis or Graves, various other antibodies such as activating and blocking TSH receptor antibodies, Anti-thyroglobulin antibodies, and Anti-Na+/I − symporter antibodies have been found in patients with autoimmune thyroiditis. Currently, many aspects of autoimmune thyroid dysfunctions remain unclear. Recently signs of expression of thyroid peroxidase have been found in the endometrium and placenta, which indicates a more complex relationship between the female reproductive system and thyroid dysfunctions [22]. Many of the studies that researched the effect of pregnancies on thyroid function did not consider the effect of other immune autoantibodies or immune system malfunctions and mainly focused and based their results on Anti-TPO antibodies [22]. Thus, this led to inconsistencies in the literature. However, our results can indicate other autoimmune mechanisms other than mere Anti-TPO can be responsible for the long-term effect of reproductive cycles on pregnancies.
In addition, iodine deficiency and socioeconomic status can also contribute to thyroid dysfunctions, including hypothyroidism [23]. However, iodine deficiency is not a common finding in Tehran district 13, and our study participants have almost similar socioeconomic status, which means other unknown factors can contribute to these observations.
The relationship between pregnancy and the occurrence of hyperthyroidism is still debatable. Transient hyperthyroidism episode is not an uncommon occurrence during pregnancy [24]. Early studies from the eighties with a relatively small sample size of 93 women pointed out that pregnancy can be associated with a higher incidence of Graves’ disease [25]. Moreover, some studies also indicated that hyperthyroidism is significantly higher in early pregnancy and 7–9 months after pregnancy [26]. However, many other reports indicated that the association between Graves’ disease and pregnancy is not as influential as previously believed [27]. The result of our study also demonstrates that parity is not associated with a higher risk of subclinical and overt hyperthyroidism incidence. The higher incidence rate of postpartum hyperthyroidism in previous studies can be attributed to the immunological and hormonal changes during the pregnancy, which can temporarily influence the course of disorders [28].
Our previous study suggested that abortion is not associated with the hazard ratio for TPOAb positivity [11]. However, in a study conducted by Chauhan et al., abortion could increase the incidence of TPOAb positivity, supporting the hypothesis of the effect of microchimerism during pregnancy on autoimmune dysfunctions. Therefore, we adjusted the results of our study for TPOAb positivity to achieve a much clearer view of the factors contributing to thyroid dysfunctions. In an interesting observation, we found that abortion decreases the risk of developing subclinical and overt hypothyroidism. Imbalances in feminine hormones in mothers with abortion could be an explanation. Combined with other observations of our study, which indicated that parity is associated with a higher hazard ratio for subclinical and overt hypothyroidism, we can hypothesize the changes at cellular and molecular levels during the third trimester can be responsible for these observations. Changes in endocrine and paracrine signaling in the third trimester have been associated with alterations in protein production and the immune system that can potentially influence thyroid functions [29, 30]. For instance, various studies are indicating that a normal thyroid function is necessary for the survival of the fetus in the first and second trimesters. Furthermore, thyroid peroxidase mRNA is expressed in various tissue, including the breast, endometrium, and placenta. However, the role of the ectopic TPO on thyroid function is not yet fully understood. To our knowledge, no studies have been conducted on the alteration of thyroid peroxidase expression in the gestational period. Furthermore, the role of other antithyroid autoantibodies on the placenta and endometrium is not investigated [22]. It can also be hypothesized that abortion can alter the expression or function of thyroid peroxidase in the endometrium or other associated antithyroid antibody targets and their interaction with the immune system before 20 weeks of pregnancy in a way that can modulate immune system response in long-term. Further evaluations of the local endometrial expression of thyroid peroxidase, the endometrial targets of antithyroid antibodies, and the effects of abortion on the endometrium and immune system are crucial for devising a proper hypothesis. In another point of view, different trends of chorionic gonadotropin hormone and upregulation of thyroxine-binding globulin in pregnancy have been discussed to be responsible for different reference values for TSH and fT4 in different trimesters [31].
Our results documented no association between menopause and the prevalence and incidence of thyroid dysfunctions. The previous observation of the positive association of autoimmune hypothyroidism with older ages recommended that this result could be related to menopausal status [32, 33]. Although the menopause term is inevitably aligned with age, the existent studies have not clarified the independent role of menopause in thyroid dysfunctions. Our results after adjustment for TPOAb positivity and age, suggest that the positive association between age and thyroid dysfunctions can result from age-related TPOAb conversion and other autoimmune alterations, and changes in female reproductive hormones cycles have less contribution in this matter.
This study has several limitations that prevent us from coming up with a decisive explanation. Although the population’s socioeconomic status was generally similar, certain behaviors and socioeconomic status, including diet, physical activity, and educational status, might be associated with mothers with more pregnancies. These factors could influence the results of this study, which could not specifically be evaluated. Furthermore, the number of participants with subclinical hyperthyroidism was not high enough to reach decisive conclusions. The result of this study showed that we lack enough evidence on a molecular level to come up with a hypothesis surrounding the incidence rate of thyroid dysfunctions and its association with pregnancy. To further improve our knowledge of pregnancy and its association with thyroid dysfunctions, we have to improve our understanding of paracrine and endocrine signaling in pregnancy.