**4. Graves' Disease in pregnancy**

### **4.1 Incidence and pathophysiology**

Graves' Disease is one of the most common causes of thyrotoxicosis in women of reproductive age. It has been reported in as much as 1 in 500 pregnancies [15] but is more frequent in the years prior and after conception. GD presents clinically in pregnancy as outside pregnancy with hyperthyroidism, goiter, ophthalmopathy. The condition is autoimmune and is characterized by the presence of abnormal autoantibodies (TRAbs) directed against the TSH receptor in the thyroid gland. These antibodies, unlike anti-thyroperoxidase and anti-tyroglobulin antibodies, do have a pathogenic role in the thyroid-related and extra-thyroidal manifestation of GD and in pregnancy can cross the placenta and act on the fetal thyroid gland [16]. TRAbs are the pathogenic hallmark of GD and are measurable in around 95% of patients with active Graves' hyperthyroidism but can also be found, sometimes in high levels, in patients with a history of treated GD [17]. TRAbs are usually of the stimulating type, but blocking or neutral autoantibodies have been described [18]. TRAbs can cross the placenta by hijacking normal physiological mechanisms of antibody transfer that become functional after 16 weeks of pregnancy and can get into the fetal blood and act on the fetal TSH receptor, therefore they also have a pathogenic role in the fetal consequences of maternal GD, especially when in high titers (> 2 to 3 times the upper limit of normal [4].

The types of assays used in clinical settings for TRAb determination are relevant to pregnancy. There are two major methods to assess TRAbs in maternal blood: by using "receptor assays" and the newer "bioassays". Receptor or TSH Binding Inhibitory Immunoglobulin (TBII) assays detect serum autoantibodies that can block the binding of THS to an in vitro prepared receptor. They are of three generations, with the third-generation TRAbs assays reaching very high sensitivity and specificity [19]. They do not measure antibodies' activity and can not distinguish between stimulating or blocking TRAbs types, hence they do not predict the phenotype of maternal or fetal GD and do not correlate well with the clinical and biochemical severity of the disease in neither mother nor the fetus [20]. The new bioassays are functional tests that characterize the biological properties of TRAbs – stimulating (TSAbs) or blocking (TBAbs). New bioassays are commercially available to measure either TSAbs or TBAbs [21–23]. The functional activity of TRAbs relevant in pregnancy since, depending on their type, they can cause either hyperthyroidism or hypothyroidism in the fetus, for whom we do not readily have access to blood to assess fetal thyroid function as for the mother. Moreover, many women with a history of GD enter pregnancy in a euthyroid state either by taking medication (ATDs) or after undergoing surgery/radioiodine therapy, however, TSAbs and TBAbs can stay elevated for years after these procedures. As stated by international guideline [4]. TRAbs should be determined during pregnancy for the following categories:

*Pregnancy in Women with Graves' Disease: Focus on Fetal Surveillance DOI: http://dx.doi.org/10.5772/intechopen.96245*


Fetal and neonatal hyperthyroidism has been reported in 1–5% of infants of mothers with GD [24]. In a follow-up study of 47 newborns of mothers with TRAbs during pregnancy, 9 infants developed hyperthyroidism and 5 required ATD medication [25]. A maternal TRAb serum concentration approximately 3 times the upper limit of normal for the assay in the second and third trimesters predicted neonatal hyperthyroidism with 100% sensitivity and 43% specificity [25]. A similar risk cutoff for TRAb level was also found in other studies [26]. It is therefore recommended to take into consideration determining TRAb levels at the initial thyroid function assessment during early pregnancy for those with a history of GD and maybe even in those that present for the preconceptional visit. TRAbs should definitely be measured at the first visit in pregnant women with previous GD that underwent radioiodine or surgery, in those requiring ATDs and in those that are first diagnosed with GD in pregnancy. If maternal TRAb is undetectable or low in early pregnancy, no further testing could be proposed. However, for those with elevated levels, repeated testing should occur at 18–22 weeks to guide fetal follow-up. If levels are persistently high at 18–22 weeks, repeat testing at 30–34 weeks guides neonatal monitoring [4].

#### **4.2 Differential diagnosis**

Graves' Disease can rarely first manifest in the first trimester of pregnancy when it is important to be distinguished from gestational transient thyrotoxicosis (GTT) or in the postpartum when it should not be confused with the thyrotoxicosis phase of the postpartum thyroiditis (PPT). Gestational transient thyrotoxicosis is defined as hyperthyroidism of new-onset in the first trimester of pregnancy; it is usually associated with hyperemesis gravidarum and is mediated by the interaction of high level of HCG with the TSH receptor, hence it is expected to be more common with multiple gestation, hydatidiform mole and choriocarcinoma, where HCG levels are higher, but it can occur in any pregnant woman. In GTT there are no previous signs or symptoms of GD and importantly, TRAbs are not detectable. The condition is self-limiting and improves in the second trimester of pregnancy, therefore ATDs, which are known teratogenic, should be avoided. Supportive treatment with hydration, antiemetics, electrolyte replacement and occasionally a shortcourse of beta-blockers is sufficient [27]. Postpartum thyroiditis is characterized by inflammation secondary to autoimmunity (antithyroid peroxidase antibodies [TPO], anti-thyroglobulin antibodies) against the thyroid gland that manifests as new-onset thyroid dysfunction specifically developing in the first 12 months after a pregnancy in a previously euthyroid woman [28]. The condition typically ensues with a hyperthyroid state where the reservoir of thyroid hormones stored in the gland is released consequent to inflammation, followed by a hypothyroid state. The thyrotoxicosis state is more common in the first 6 months after delivery and again is different from GD because it lacks the presence of TRAbs and is generally

characterized by milder symptoms: palpitations, heat intolerance, fatigue and irritability. PPT is encountered in women with known TPO antibodies in the first trimester or in those with a personal or familial history of thyroid disease or other autoimmune conditions. It tends to recur after each pregnancy and in most cases the affected women recover their euthyroid function within 12 months, however, some of them may be persistently hypothyroid. PPT has a prevalence of about 5% [29]. Complete and partial hydatidiform moles as in gestational trophoblastic disease can sometimes present with thyrotoxicosis in pregnancy. This is more rare than previously believed. In a recent cohort-study, completed by a systematic review and meta-analysis of cases of hydatidiform moles in missed-miscarriages, in 295 women with a confirmed histological diagnosis of hydatidiform mole in the first trimester there were no cases of thyrotoxicosis [30]. However, in a review of 196 patients treated for gestational trophoblastic disease over a 5-years period at a major specialized center, 7% (14/196) patients had biochemical hyperthyroidism and 4 had clinical signs and symptoms of hyperthyroidism [31]. Causes of thyrotoxicosis in pregnancy are described in **Table 1** [27, 28, 32–36].
