Sofie Bliddal

Do Thyroid Disrupting Chemicals Influence Foetal Development during Pregnancy

Maternal euthyroidism during pregnancy is crucial for normal development and, in particular, neurodevelopment of the foetus. Up to 3.5 percent of pregnant women suffer from hypothyroidism. Industrial use of various chemicals—endocrine disrupting chemicals (EDCs)—has been shown to cause almost constant exposure of humans with possible harmful influence on health and hormone regulation. EDCs may affect thyroid hormone homeostasis by different mechanisms, and though the effect of each chemical seems scarce, the added effects may cause inappropriate consequences on, for example, foetal neurodevelopment. This paper focuses on thyroid hormone influence on foetal development in relation to the chemicals suspected of thyroid disrupting properties with possible interactions with maternal thyroid homeostasis. Knowledge of the effects is expected to impact the general debate on the use of these chemicals. However, more studies are needed to elucidate the issue, since human studies are scarce.

Gestational age-specific reference ranges from different laboratories misclassify pregnant women's thyroid status: comparison of two longitudinal prospective cohort studies

OBJECTIVES Correct interpretation of thyroid status during pregnancy is vital to secure fetal development. Pregnancy-related changes in maternal thyroid status necessitate the use of gestational age-specific reference ranges. In this study, we investigated between-laboratory reproducibility of thyroid reference ranges in pregnant women. DESIGN Comparison of two longitudinal prospective cohort studies including 255 (cohort 1) and 101 (cohort 2) healthy antibody-negative Danish pregnant women attending prenatal care at Copenhagen University Hospital. METHODS Different immunoassays were used to measure thyroid hormone levels in the two cohorts. Thyroid hormone reference ranges were established for every 5 weeks of gestation. Differences between cohorts were explored through mixed-model repeated measures regression analyses. By applying reference ranges from one cohort to the other, the proportion of women who would be misclassified by doing so was investigated. RESULTS TSH increased and free thyroxine (FT4) decreased as pregnancy progressed. Results indicated highly significant differences between cohorts in free triiodothyronine (F=21.3, P<0.001) and FT4 (F=941, P<0.001). TSH levels were comparable (P=0.09). Up to 90.3% of the women had FT4 levels outside their laboratorys nonpregnant reference range, and up to 100% outside the other cohorts gestational-age-specific reference ranges. Z-score-based reference ranges markedly improved comparison between cohorts. CONCLUSION Even in the same region, the use of gestational-age-specific reference ranges from different laboratories led to misclassification. Up to 100% of maternal FT4 levels fell outside the other cohorts reference range despite similar TSH levels. In clinical practice, thyroid testing of pregnant women without adding method specificity to gestational age-dependent reference ranges will compromise patient safety.

Antithyroid drug-induced fetal goitrous hypothyroidism

Maternal overtreatment with antithyroid drugs can induce fetal goitrous hypothyroidism. This condition can have a critical effect on pregnancy outcome, as well as on fetal growth and neurological development. The purpose of this Review is to clarify if and how fetal goitrous hypothyroidism can be prevented, and how to react when prevention has failed. Understanding the importance of pregnancy-related changes in maternal thyroid status when treating a pregnant woman is crucial to preventing fetal goitrous hypothyroidism. Maternal levels of free T4 are the most consistent indication of maternal and fetal thyroid status. In patients with fetal goitrous hypothyroidism, intra-amniotic levothyroxine injections improve fetal outcome. The best way to avoid maternal overtreatment with antithyroid drugs is to monitor closely the maternal thyroid status, especially estimates of free T4 levels.

Thyroid function and autoimmunity in Danish pregnant women after an iodine fortification program and associations with obstetric outcomes

OBJECTIVE Aberrations in maternal thyroid function and autoimmunity during pregnancy have been associated with negative obstetric outcome. In Denmark, a national iodine fortification program was implemented in the year 2000 with the aim to alleviate the mild-moderate iodine deficiency. Following the iodine implementation, there has been an increase in thyroid autoimmunity in the background population. This study investigates the thyroid status of pregnant Danish women following the iodine fortification program, and a possible association with preterm delivery. DESIGN Historical cohort study of 1278 randomly selected pregnant Danish women attending the national Downs syndrome screening program. METHODS The main outcome measures were thyroid status according to laboratory- and gestational-age-specific reference intervals, and association with risk of abnormal obstetric outcome. Antibody-positivity was defined as an antibody-level (thyroid peroxidase and/or thyroglobulin antibodies) above 60 U/ml. RESULTS Establishing laboratory-specific gestational-age-dependent reference intervals, we found a prevalence of maternal thyroid dysfunction of 10%-15.8% by use of the cut-off suggested by the American Thyroid Association. Thyroid dysfunction was significantly associated with antibody-positivity (P<0.05). No associations were found between preterm delivery and thyroid dysfunction (adjusted OR 0.6, 95% CI: 0.1-2.3) or autoimmunity (adjusted OR 1.1, 95% CI: 0.4-2.7). CONCLUSIONS After the implementation of the Danish iodine fortification program, the prevalence of thyroid dysfunction and autoimmunity in Danish pregnant women is high - even higher by use of pre-established reference intervals from international consensus guidelines. However, no associations were found with abnormal obstetric outcome. Large randomized controlled trials are needed to clarify the benefit of treating slight aberrations in pregnant womens thyroid function.

Recent advances in understanding autoimmune thyroid disease: the tallest tree in the forest of polyautoimmunity

Autoimmune thyroid disease (AITD) is often observed together with other autoimmune diseases. The coexistence of two or more autoimmune diseases in the same patient is referred to as polyautoimmunity, and AITD is the autoimmune disease most frequently involved. The occurrence of polyautoimmunity has led to the hypothesis that the affected patients suffer from a generalized dysregulation of their immune system. The present review summarizes recent discoveries unravelling the immunological mechanisms involved in autoimmunity, ranging from natural autoimmunity to disease-specific autoimmunity. Furthermore, the clinical grounds for considering AITD in a setting of polyautoimmunity are explored. A better understanding of these may pave the way for designing new treatment modalities targeting the underlying immune dysregulation when AITD appears in the context of polyautoimmunity.

Thyroid Autoimmunity and Function after Treatment with Biological Antirheumatic Agents in Rheumatoid Arthritis

With the increased pro-inflammatory response in both rheumatoid arthritis and thyroid autoimmune diseases, treatment with biological antirheumatic agents (BAAs) of the former may affect the course of the latter. In hepatitis C and cancer patients, treatment with biological agents substantially increases the risk of developing thyroid autoimmunity. As the use of BAAs in the treatment of rheumatoid arthritis is increasing, this review aimed to investigate if such use affected thyroid status in rheumatoid arthritis patients. We conducted a systematic literature search and included six studies with a total of 311 patients as well as three case reports. The patients were treated with tumor necrosis factor-α inhibitors (infliximab, etanercept, or adalimumab) or the monoclonal CD20-antibody rituximab. There was a non-significant trend of slight improvement of both thyroid function and autoantibody status: a reduction of thyroid peroxidase and thyroglobulin antibody concentrations, and a reduction of thyrotropin levels in hypothyroid patients. Despite the small number of studies, they presented compliant data. The BAAs used in rheumatoid arthritis thus did not seem to negatively affect thyroid status in patients with rheumatoid arthritis and can be considered safe with regard to thyroid autoimmunity. However, the well-established association between rheumatic diseases and thyroid autoimmunity necessitates continued monitoring of thyroid function in patients with rheumatoid arthritis. Each new BAA should be scrutinized for its effect on thyroid as well as other autoimmune diseases in order to establish concise recommendations for patient follow-up for each agent and each disease.

Increase in thyroglobulin antibody and thyroid peroxidase antibody levels, but not preterm birth-rate, in pregnant Danish women upon iodine fortification

OBJECTIVE The presence of thyroid antibodies in pregnancy has been associated with preterm birth. In the non-pregnant population, the implementation of the Danish iodine fortification program has increased the prevalence of thyroid antibodies. This study investigated the prevalence of thyroid peroxidase antibodies (TPOAbs) and thyroglobulin antibodies (TgAbs) in pregnant Danish women before, during and after implementation of the iodine fortification program and association with preterm birth. DESIGN Comparative cohort study of 1368 pregnancies from three cohorts gathered before (1996-1998), during (2000-2003) and after (2008-2009) the iodine fortification program. METHODS In cohort 1 (n = 297), TPOAbs were measured (DYNOtest (BRAHMS)). In cohorts 2 (n = 148) and 3 (n = 923), both TPOAbs and TgAbs were measured (Kryptor immunofluorescent assay (BRAHMS)). The prevalence and effect of antibody positivity were explored using three cut-offs: TPOAbs and/or TgAbs >100 kU/L, TPOAbs and/or TgAbs >60 kU/L and TPOAbs >30 and/or TgAbs >20 kU/L. National preterm birth data were extracted from the National Birth Registry. RESULTS In the three cohorts, TPOAb levels >60 kU/L were found in 5.4, 8.1 and 12.0% (χ2(2, n = 1367) = 11.7, P = 0.003) respectively, and TPOAbs and/or TgAbs >60 kU/L in 8.1 and 16.2% in cohorts 2 and 3 respectively (χ2(2, n = 1070) = 6.5, P = 0.01). TgAb levels (>20 kU/L) had increased plenty-fold from cohort 2 to 3 (χ2(1, n = 1071) = 136.5, P < 0.001). Preterm birth occurred in 4.1% of all pregnancies with no effect from antibody positivity (TPOAbs and/or TgAbs >60 kU/L, χ2(1, n = 1039) = 0.0, P = 0.98, aOR = 1.1, 95% CI (0.4-2.7)). The national preterm birth-rate showed no increase over the same period. CONCLUSIONS Thyroid antibody positivity in Danish pregnant women has more than doubled upon the implementation of the iodine fortification program without an increase in preterm birth-rate.

Careful Assessment of Maternal Thyroid Function Can Prevent Cases of Fetal Goitrous Hypothyroidism

We feel that clarification is needed with regard to the maternal MMI therapy and thyroid status. First, MMI therapy was initiated upon discovery of a low fT4 level, no detectable thyroid antibodies, but suppressed TSH levels. We wonder what the reasons were for this treatment. The low fT4 level was not consistent with a diagnosis of hyperthyroidism (more likely hypothyroidism). The suppressed TSH found only 6 months after pregnancy could be a sign of postpartum thyroiditis defined by guidelines as ‘thyroid dysfunction within the first year postpartum’ (although this is almost always associated with antibody positivity) [2–4] . According to guidelines, such patients should not be treated with antithyroid drugs (ATD), but followed in order to detect a possible subsequent hypothyroid period. Even in cases of subclinical hyperthyroidism (low TSH, normal fT4), thyroid function tests should be repeated after 3–6 months to make sure that the TSH is persistently suppressed before considering treatment with ATD [5] . Unless the stated fT4 value is an error, the reported beneficial effect of MMI treatment is questionable, and we believe that the woman should not have been started on MMI therapy without further investigation. However, there are no details in the article of the woman’s symptoms or clinical findings beDear Editor, We read with interest the article ‘A rare case of recurrent fetal goiter’ by Kornacki et al. [1] . The authors report 2 cases of fetal goiter found in 2 consecutive pregnancies in the same woman. The first was discovered when the mother was 29 weeks pregnant and it led to an acute cesarean section and soon thereafter the death of the child because intubation was hindered by a large neck mass. Six months thereafter, the mother was started on methimazole (MMI) therapy (dose not communicated) after thyroid function tests had shown a TSH of <0.005 μIU/ml (normal range: 0.27–4.2 μIU/ml), free T4 (fT4) of 0.135 ng/dl (normal range: 0.932–1.71 ng/dl) and no detectable thyroid antibodies. One year after treatment start, she became pregnant again, and at 19 weeks of gestation a fetal goiter was discovered by ultrasound examination. Amniocentesis revealed hypothyroidism of the fetus, which was treated by a total of 8 intra-amniotic levothyroxine injections throughout the remaining pregnancy. With this treatment, the fetus became euthyroid with normal growth measurements and did not have any airway obstruction at delivery. The child was found to be hypothyroid 7 days later and was started on daily levothyroxine treatment. Received: January 31, 2013 Accepted after revision: February 21, 2013 Published online: June 10, 2013

Corrigendum to “Challenges in Interpretation of Thyroid Function Tests in Pregnant Women with Autoimmune Thyroid Disease”

[This corrects the article DOI: 10.4061/2011/598712.].

Comment on “intrauterine diagnosis and management of fetal goiter: A case report”

No absract.