Therapy insight: Management of Graves› disease during pregnancy

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Nature Clinical Practice Endocrinology &#38 Metabolism (Impact Factor: 7.55). 07/2007; 3(6):470-8. DOI: 10.1038/ncpendmet0508
Source: PubMed

ABSTRACT The diagnosis of Graves' disease in pregnancy can be complex because of normal gravid physiologic changes in thyroid hormone metabolism. Mothers with active Graves' disease should be treated with antithyroid drugs, which impact both maternal and fetal thyroid function. Optimally, the lowest possible dose should be used to maintain maternal free thyroxine levels at or just above the upper limit of the normal nonpregnant reference range. Fetal thyroid function depends on the balance between the transplacental passage of thyroid-stimulating maternal antibodies and thyroid-inhibiting antithyroid drugs. Elevated levels of serum maternal anti-TSH-receptor antibodies early in the third trimester are a risk factor for fetal hyperthyroidism and should prompt evaluation of the fetal thyroid by ultrasound, even in women with previously ablated Graves' disease. Maternal antithyroid medication can be modulated to treat fetal hyperthyroidism. Serum TSH and either total or free thyroxine levels should be measured in fetal cord blood at delivery in women with active Graves' disease, and those with a history of (131)I-mediated thyroid ablation or thyroidectomy who have anti-TSH-receptor antibodies. Neonatal thyrotoxicosis can occur in the first few days of life after clearance of maternal antithyroid drug, and can last for several months, until maternal antibodies are also cleared.

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    • "Antithyroid drugs (ATDs), radioactive iodine ( 131 I), or surgical excision of the thyroid gland are the major treatment options for controlling hyperthyroidism. During pregnancy, radioactive iodine treatment is contraindicated and surgery is recommended only when the hyperthyroid condition is refractory to ATDs (Abalovich et al., 2007; Chan and Mandel, 2007). Thus, ATDs are the treatment of choice for active Graves' disease during gestation. "
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    ABSTRACT: Propylthiouracil (PTU) and methimazole (MMI) are antithyroid drugs used to treat hyperthyroidism. Despite the widespread use of PTU and MMI during pregnancy, modest clinical data and less animal data are available on the teratogenic potential of these drugs. We evaluated the teratogenicity of in utero exposure to PTU or MMI in mice and rats. First, pregnant C57Bl/6 mice were treated daily with PTU (10 or 100 mg/kg), MMI (2 or 20 mg/kg), or vehicle from gestation day (GD) 6 to 16. GD 18 fetuses were evaluated for gross and histopathological abnormalities. Next, pregnant Sprague-Dawley rats were treated daily with PTU (50 or 100 mg/kg), MMI (10 or 20 mg/kg), or vehicle from GD 6 to 19, followed by evaluation for gross and histopathological abnormalities at GD 20. In mice treated with PTU or MMI, no significant histopathological abnormalities or external gross malformations, and no adverse effects on placental weight, litter size, resorption rates, or fetal weight were observed at GD 18. In rats, no adverse effects on litter size, placental weights, or maternal body weights were observed with either PTU or MMI treatment. PTU treatment (50 and 100 mg/kg) and MMI (10 mg/kg) treatment resulted in a decrease in crown-rump length in rat fetuses but no external gross malformations or histopathological abnormalities were observed. We did not observe either gross external malformations or histopathological malformations in mice or rats treated long-term with high doses of PTU or MMI during pregnancy
    Birth Defects Research Part B Developmental and Reproductive Toxicology 08/2014; 101(4). DOI:10.1002/bdrb.21113 · 1.17 Impact Factor
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    • "It has been assumed that placental transport of PTU is less than MMI, it has been assumed that fetal and neonatal thyroid effects of PTU is less than with MMI (based on lower placental transport), it has been assumed that MMI exposure during pregnancy leads to greater impairment of neurocognitive development than with PTU exposure, and it has been assumed that MMI produces structural defects and that PTU does not. A thoughtful review and analysis of literature by Mandel has demonstrated that these assumptions are not correct [2] [6]. Given the uncommon nature of Graves' disease in pregnancy and the weak link between the antithyroid medications and malformations, we have taken a different approach to assess the potential developmental toxicity of the drugs which are being used to treat the disease in pregnancy. "
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    ABSTRACT: The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR) model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action.
    International Journal of Pediatric Endocrinology 01/2009; 2009:936154. DOI:10.1155/2009/936154
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    • "Typically, the disease resolves with loss of maternal antibodies in the first four months of life, but if untreated may lead to death.(Chan and Mandel 2007; Zimmerman 1999) In addition to stimulatory antibodies, women with Graves' may produce antibodies antagonistic to the TSH receptor and the ratio of stimulatory to antagonistic TSH receptor antibodies may change during pregnancy. In a study of pregnant women, the stimulatory activity of anti-TSH-receptor antibody specificity was lost over time, with antibody specificity becoming predominantly that of TSH receptor blockade.(Kung "
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    ABSTRACT: Pregnancy has both short-term effects and long-term consequences on the maternal immune system. For women who have an autoimmune disease and subsequently become pregnant, pregnancy can induce amelioration of the mother's disease, such as in rheumatoid arthritis, while exacerbating or having no effect on other autoimmune diseases like systemic lupus erythematosus. That pregnancy also leaves a long-term legacy has recently become apparent by the discovery that bi-directional cell trafficking results in persistence of fetal cells in the mother and of maternal cells in her offspring for decades after birth. The long-term persistence of a small number of cells (or DNA) from a genetically disparate individual is referred to as microchimerism. While microchimerism is common in healthy individuals and is likely to have health benefits, microchimerism has been implicated in some autoimmune diseases such as systemic sclerosis. In this paper, we will first discuss short-term effects of pregnancy on women with autoimmune disease. Pregnancy-associated changes will be reviewed for selected autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroid disease. The pregnancy-induced amelioration of rheumatoid arthritis presents a window of opportunity for insights into both immunological mechanisms of fetal-maternal tolerance and pathogenic mechanisms in autoimmunity. A mechanistic hypothesis for the pregnancy-induced amelioration of rheumatoid arthritis will be described. We will then discuss the legacy of maternal-fetal cell transfer from the perspective of autoimmune diseases. Fetal and maternal microchimerism will be reviewed with a focus on systemic sclerosis (scleroderma), autoimmune thyroid disease, neonatal lupus and type I diabetes mellitus.
    Immunological Investigations 02/2008; 37(5):631-44. DOI:10.1080/08820130802205886 · 1.90 Impact Factor
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