The Danish investigation on iodine intake and thyroid disease (DanThyr): history and implications.

Due to mild-to-moderate iodine deficiency in Denmark, health authorities initiated a voluntary iodine fortification (IF) program in 1998, which became mandatory in 2000. In line with recommendations from the World Health Organization, the Danish investigation on iodine intake and thyroid disease (DanThyr) was established to monitor the effect on thyroid health and disease. The program involved different study designs and followed two Danish sub-populations in the years before IF and up till 20 years after. Results showed that the IF was successfully implemented and increased the level of iodine intake from mild-moderate iodine deficiency to low adequacy. The level of thyroglobulin and thyroid volume decreased following IF, and there was an indication of fewer thyroid nodules. The incidence of hyperthyroidism increased transiently following IF but subsequently decreased below the pre-fortification level. Conversely, thyroid-stimulating hormone levels and the prevalence of thyroid autoimmunity increased along with an increase in the incidence of hypothyroidism. These trends were mirrored in the trends in treatments for thyroid disease. Most differences in thyroid health and disease between regions with different iodine intake levels before IF attenuated. This review illustrates the importance of a monitoring program to detect both beneficial and adverse effects and exemplifies how a monitoring program can be conducted when a nationwide health promotion program - as IF - is initiated.

Hyperthyroidism in pregnancy: design and methodology of a Danish multicenter study.

BACKGROUND: Graves' disease (GD) is the main cause of hyperthyroidism in women of the fertile age. In pregnant women, the disease should be carefully managed and controlled to prevent maternal and fetal complications. Observational studies provide evidence of the adverse effects of untreated hyperthyroidism in pregnancy and have in more recent years substantiated a risk of teratogenic side effects with the use of antithyroid drugs (ATDs). These findings have challenged the clinical recommendations regarding the choice of treatment when patients become pregnant. To extend observational findings and support future clinical practice, a systematic collection of detailed clinical data in and around pregnancy is needed. METHODS: With the aim of collecting clinical and biochemical data, a Danish multicenter study entitled 'Pregnancy Investigations on Thyroid Disease' (PRETHYR) was initiated in 2021. We here describe the design and methodology of the first study part of PRETHYR. This part focuses on maternal hyperthyroidism and recruits female patients in Denmark with a past or present diagnosis of GD, who become pregnant, as well as women who are treated with ATDs in the pregnancy, irrespective of the underlying etiology. The women are included during clinical management from endocrine hospital departments in Denmark, and study participation includes patient questionnaires in pregnancy and postpartum as well as review of medical records from the mother and the child. RESULTS: Data collection was initiated on November 1, 2021 and covered all five Danish Regions from March 1, 2022. Consecutive study inclusion will continue, and we here report the first status of inclusion. As of November 1, 2022, a total of 62 women have been included in median pregnancy week 19 (interquartile range (IQR): 10-27) with a median maternal age of 31.4 years (IQR: 28.5-35.1). At inclusion, 26 women (41.9%) reported current use of thyroid medication; ATDs (n = 14), Levothyroxine (n = 12). CONCLUSION: This report describes a newly established systematic and nationwide collection of detailed clinical data on pregnant women with hyperthyroidism and their offspring. Considering the course and relatively low prevalence of GD in pregnant women, such nationwide design is essential to establish a sufficiently large cohort.

Determinants of TSH change in a community-based cohort.

INTRODUCTION: Thyroid disorders are common with occurrence primarily determined by the availability of dietary iodine. Iodine fortification programmes are internationally recommended to ensure sufficient iodine intake in populations. An understanding of the role of thyroid hormone levels within the normal range, set points and etiological factors related to thyroid disease development is important for optimal prevention and treatment. Limited data, however, exist regarding the impact of iodine fortification on thyroid function development. Additionally, the relation between body weight and thyrotropin (TSH) within the normal range and the role of female reproductive factors in the etiology of thyroid autoimmunity is debated. OBJECTIVE: The aim of this PhD project was to analyse the effect of a nationwide iodine fortification programme on individual development in thyroid function and to identify concurrent determinants for the possible changes. Furthermore, we aimed to investigate the association between weight and serum TSH change as well as the association between female reproductive factors and change in TSH and thyroid peroxidase antibody (TPO-Ab) status.    METHODS: A longitudinal population-based study of the DanThyr C1 cohort examined before (1997-1998) and after (2008-2010) the introduction of mandatory iodine fortification of salt on July 1 2000. A total of 2,465 individuals participated in the follow-up examination. The main outcome measure was change in serum TSH. Change in TPO-Ab status was additionally used in Paper III.  RESULTS: Urinary iodine excretion levels increased significantly during follow-up. Serum TSH also increased significantly, most pronounced in the region with the highest iodine intake, whereas the increase was not significant in the low-iodine-intake region. The presence of TPO-Ab at baseline and absence of goitre and multiple nodules were identified as determinants of TSH increase. Moreover, a low-normal TSH at baseline was a determinant of future decreased serum TSH, while likewise a high-normal baseline TSH values determined a TSH above normal reference range at follow-up. A positive association between 11-year serum TSH change and weight change was found, but without baseline body mass index being a determinant of future weight change and without baseline TSH being a determinant of future weight change. An inverse association between the time on HRT treatment and the risk of increased TPO-Ab status during follow-up was found, but the association was not significant when applying the Bonferroni adjusted significance level and not associated with TSH change. Parity, OCP use, abortions, age at menarche and menopausal status were associated neither with TSH change nor with increased TPO-Ab status during follow-up. CONCLUSION: TSH increased significantly, and the difference be-tween regions with different iodine intakes could indicate that iodine, at least partly, explains the TSH increase. The identified determinants of TSH change may indicate that susceptible individuals were subject to well-known adverse effects of iodine fortification. The predictive value of TSH on future TSH levels suggests a gradual development of thyroid disease. Whether body weight and TSH are causally connected remains to be proven. These results are an important contribution to the discussion of the role of thyroid hormones level within the normal range, set points and the association with body weight. A minor role, if any, is suggested for the studied female reproductive factors in development of thyroid autoimmunity. The longitudinal study neither solves the problem of causality nor is of the optimal design to measure the impact of iodization of salt, but can be informative in the study of determinants.