Graves' Disease and Pregnancy

*Nikolay Petrov Botushanov, Aleksandar Nikolaev Botushanov and Albena Dimitrova Botushanova*

### **Abstract**

Graves' Disease is an autoimmune organ specific disease characterized by excessive production of hormones from the thyroid gland and by its diffuse enlargement. The growth and function of the thyroid gland are stimulated by autoantibodies directed against the thyroid-stimulating hormone receptor. Pregnancies complicated by Graves' Disease are characterized with higher incidence of abortion, preterm delivery, low-birth- weight infants and neonatal mortality, as well as maternal complications such as heart failure, eclampsia and rarely thyroid storm. When fully controlled hyperthyroidism have excellent outcomes. Different therapeutic approaches are used in women with Graves' planning pregnancy and in those when the disease is diagnosed after they became pregnant. Thionamides are the first choice for treatment, with Propylthyouracil being preferred for the first trimester and Methimazole for the second and third trimester. Aplasia cutis and some other malformations were associated with methimazole use during pregnancy. Monitoring the effect of treatment should ensure keeping maternal FT4 in the high normal range. Block-and replace regimen is not recommended and rdioiodine therapy is absolutely contraindicated. Thyroidectomy may be considered before pregnancy or in rare cases in the second trimester. Iodine is avoided because of the risk of fetal hypothyroidism and goiter. The use of beta-blockers is controversial. Noenatal thyrotoxicosis may occur in association with maternal Graves' Disease due to maternal TSAbs cross through the placenta.

**Keywords:** Graves' Disease, pregnancy, thionamides, iodine, surgery

#### **1. Introduction**

Graves' Disease (GD) is an autoimmune organ specific disease characterized by excessive production of hormones from the thyroid gland (hyperthyroidism) and by its diffuse enlargement. The growth and function of the thyroid gland are stimulated by autoantibodies directed against the thyroid-stimulating hormone (TSH) receptor (TSHR). Nevertheless, other autoantibodies against thyroid peroxidase (TPO) and thyroglobulin (Tg) may also be present, TSHR is the major autoantigen of Graves' Disease, making antibodies against it (TRAb) the most characteristic for the disease. Graves' Disease (GD) is the most frequent cause of thyrotoxicosis in iodine sufficient countries [1], although the exact frequency of GD in general population is difficult to be established and differs from country to country. A meta-analysis of various studies has estimated the general prevalence of GD to be around 1% [2], which makes it one of the most frequent clinically relevant autoimmune disorders. Graves' Disease is a multifactorial disorder. Like

all autoimmune diseases, GD is characterized with the loss of immune tolerance to thyroid antigens and the initiation of a sustained autoimmune reaction caused by a complex interplay of genetic, hormonal and environmental factors. While detailed discussion of these factors is beyond the scope of this chapter, it is worth to mention that GD is typically a disease of women, with the female-to- male ratio ranges in different studies from 5 to 10 at any age [2, 3]. Autoimmune disorders are in general more prevalent in women and genetic and nongenetic factors may play role for that [4, 5]. Male hormones are considered to down-regulate immunity and thus play a protective role from autoimmunity, whereas the effect of estrogen is not always unequivocal [4, 5]. Despite this, little evidences in the literature are backing the role for sex hormones in the high prevalence of GD in women. Moreover thyroid autoimmunity often accompanies patients with Turner's syndrome, who have low estrogen levels [6]. Besides sex hormones, some genetic factors linked with the X chromosome could explain the epidemiologic evidence of a female preponderance in GD. In families with GD, a putative Graves' Disease susceptibility locus on the long arm of X chromosome was located by an linkage analysis [7]. Inactivation of the X chromosome, an epigenetic phenomenon, has been suggested to determine the female predisposition to thyroid autoimmunity. One study showed that this phenomenon is more frequently observed in patients with GD or autoimmune thyroiditis than in healthy controls [8]. Never mind, what the predisposing factors for GD could be, pregnancy, itself, is a well-known risk factor for thyroid autoimmunity. Pregnancy can influence and change the course of a pregestational Graves' Disease or can become a reason for the development of GD during the pregnancy or after delivery. The risk of development of GD in postpartum year increases fourfold to eightfold [9]. The reasons for this could be explained by the observed abrupt fall in the level of pregnancy-associated immunosuppressive factors immediately after delivery (rebound immunity) [9]. The factors involved in the immune alterations of the postpartum period may include, but are not limited to estrogen and progestin [9, 10]. Approximately 2–3% of all pregnancies are complicated by thyroid disease [11], making thyroid disorders the second most common significant pathology affecting women during pregnancy after diabetes mellitus [12]. Detailed understanding of the physiology, pathophysiology, diagnosis and treatment is required to limit the effects on both maternal and fetal health.
