**5.3 Laboratory**

The usual findings from the laboratory studies show low, below the trimesterspecific 95% lower confidence limit, TSH level together with elevated serum thyroid hormone (FT4 and FT3) concentrations. We should always consider the fact that up to 50% of women with hyperemesis gravidarum may have similar changes of theh hormonal levels (suppressed serum TSH level and/or elevated FT4) [52]. An elevated free T3 index or free T3 level may be the most clinically useful test to distinguish hyperthyroid patients from those with hyperemesis gravidarum as less than 15% of hyperemetic women have elevations in these measures. TSH receptor antibodies are usually detectable and may also be of diagnostic utility. High levels of TRAb cross placental barrier [53]. and the risk of fetal and neonatal thyrotoxicosis increases with TSRAb values 3–5 times above normal [54, 55].

#### **5.4 Pregnancy outcomes**

Maternal hyperthyroidism is associated with increased morbidity for both mother and fetus. Prior to the development of ATD, only about 50% of hyperthyroid women were be able to conceive. About in half of those who conceived, spontaneous miscarriage and premature delivery occurred [56]. The degree and duration of hyperthyroidism strongly correlate with pregnancy outcomes for both mother and fetus. The highest risk was reported in those with uncontrolled or poorly controlled disease and a decreased risk in those appropriately treated with ATD. Established thyrotoxicosis during gestation or before a planned pregnancy, requires appropriate treatment, because in cases with uncontrolled maternal hyperthyroidism in the first trimester, the period of embryogenesis, there is an increased risk for congenital malformations (imperforate anus, polydactyly, harelip) [57]. The use of ATD during this period itself is not associated with a higher incidence of structural anomalies. For optimal pregnancy outcomes it is very important to keep maternal hyperthyroidism under control, avoiding the development of drug induced hypothyroidism, understanding the crucial significance of thyroid hormones for the normal embryogenesis. Significantly, subclinical hyperthyroidism, has not been found to be associated with adverse pregnancy outcomes and doesn't require antithyroid therapy [22]. Pregnancy complications reported in hyperthyroid women vary in frequency in different studies and include: miscarriage from 8 to 10–21% [58, 59], preterm delivery [58, 60, 61] from 3 to 14% to 21–88%, preeclampsia [60] from 2–11%, heart failure [61] from 3–63%, stillbirth [58, 61] from 0% -7 to 50%, small for gestational age [59, 62] and thyroid storm during delivery.

### **5.5 Treatment**

Unfortunately, because the cause of the immune dysregulation in Graves' Disease remains unclear, the available treatments are directed at the thyroid gland rather than the underlying autoimmunity. In general, the available therapies include: Antithyroid drugs, surgery and radioiodine, with predominant use of ATD in pregnancy hyperthyroidism, surgery in exception, during the second trimester and iodine ablation being absolutely contraindicated. Because the degree of hyperthyroidism can vary from patient to patient, those who are relatively asymptomatic may remain undiagnosed and untreated till the delivery, when usually aggravation of thyrotoxicosis is observed. Even when they had been properly diagnosed, they may do not want to accept the diagnosis and ask whether specific treatment is really necessary, fearing of possible side effects of the drugs both for them and for their developing fetuses. Usually they consider their complaints to be related with

the pregnancy itself. Those with overt hyperthyroidism require restoration of a euthyroid state because of potentially negative outcomes, both for the mother and the fetus. Fully controlled hyperthyroidism substantially decrease the potential risk for these negative outcomes and at the same time is not a reason for recommending abortion.

Therapeutic approaches differ from case to case. In the *first* scenario, when GD is preceding pregnancy, the woman will be advised to conceive after restoration of euthyroidism. Taking into account patent's plan for the time of the future pregnancy, treatment with thionamide drugs is started, and the treatment continues throughout the whole pregnancy. In this case, the patient should be fully aware of the possible side effects of ATD, both for the mother and fetus and of the need for frequent monitoring of thyroid hormones levels. To avoid this an if the woman with GD is willing to postpone her future pregnancy, than alternatively radioiodine ablation can be offered. Pregnancy should be delayed for at least 4 months after radioiodine therapy, but a longer period, 6 months or even a year, is usually required for restoring euthyroid state and establishing the necessary stable dose of the inevitable postablational replacement therapy with thyroid hormones. Surgery may also be considered as an alternative because of more rapid restoration of euthyroidism.

In the *second* scenario, if GD is diagnosed during pregnancy, ATD are almost the only therapeutic option. Radioiodine is absolutely contraindicated, because it may result in congenital hypothyroidism and may cause malformations. Thyroidectomy is restricted to exceptional cases.

In the *third* scenario, if GD is established after delivery and when the possibility of transient, self-limiting destructive thyrotoxicosis has been excluded, it is prudent to start thionamide treatment. In this case breast feeding should be stopped, because of the risk for development of neonatal hypothyroidism (see below). Radioiodine ablation with its delayed effect of achieving euthyroidism, the need for concomitant use of ATD to control symptoms in some cases and the need for isolation for several days, usually is not well accepted by the mothers. Surgery is an option in patients who experienced side effects of ATD use, or found it difficult to adhere to the prescribed drugs, either due to the number of pills or to the frequency of their intake.

Decision to initiate ATD treatment depends on the severity of the clinical symptoms and the pretreatment levels of FT4, FT3 and TSH. In mild cases with Graves' Disease, when FT4 values are at or slightly above the reference range, treatment may be withheld with a subsequent monitoring of the thyroid status as long as there is a satisfactory clinical progression of pregnancy. In other words, the pregnant woman with Graves' Disease should be kept in slight *subclinical hyperthyroidism*, because there are no reported gestational adverse effects of maternal subclinical hyperthyroidism [63]. The goal of treatment is to keep the patient euthyroid, using the lowest possible dose of antithyroid drugs necessary to maintain FT4 levels in the upper one-third of the normal non pregnant range or up to 10% above the normal range [64]. This level will ensure fetal euthyroidism, because FT4 in the mother's serum correlates with fetal FT4 levels in cord blood [65]. Maternal serum T3 levels may not be as helpful because there is no correlation with fetal thyroid function [66] The dose should be adjusted every 2–4 weeks to maintain a serum FT4 of 1.7 to 2.0 ng/L and TSH at or just below at the 95% confidence interval trimester-specific lower limit [67]. The presence of detectable TSH is an indication to decrease ATD dose [60]. A low TSH level is not a reliable index to judge the adequacy of treatment, because it doesn't promptly reflect the changes in thyroid function like FT4. It is important to monitor TSH level, because a high level always indicates over dosage of ATD and the need for proper dosage correction of the drugs. Because of

#### *Graves' Disease and Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.97640*

the expected immunosuppression during the second and third trimester, a partial and transient remission of Graves' Disease may occur and appropriate reduction of the dose or even discontinuation of ATD could be done. Otherwise excessive doses of ATDs, indeed, may affect fetal thyroid function, with the development of hypothyroidism and/or goiter [68, 69]. Relapse of the hyperthyroidism is frequent in postpartum period [70].
