**5. Graves' Disease and pregnancy**

As it has been already discussed, generally there are three scenarios in which Graves' Disease may affect a pregnancy. *First*, women with preexisting active Graves' Disease. *Second,* women in remission, who may experience a relapse during pregnancy. *Third*, Graves' Disease may occur for the first time during gestation

[46]. The women with prepregnancy active disease (either treated or untreated) may undergo exacerbation during the first trimester. Those, with previously diagnosed GD, who stayed in clinical remission and remained euthyroid throughout the whole pregnancy, hyperthyroidism may recur in the postpartum period. We must be very careful in this situation, because this may represent either the thyrotoxic phase of postpartum thyroiditis (PPT) or in up to 25% or relapse of Graves' Disease. Even in those with PPT, Graves' Disease may recur after resolution of PPT, triggered by the destruction of the thyrocytes [47].

#### **5.1 Diagnosis**

Diagnosis should begin with taking complete case history, medical history and family history. The clinical diagnosis of hyperthyroidism may be *difficult* because pregnancy is itself a hypermetabolic state with symptoms of palpitations and heat intolerance. In addition, patients will usually have increased irritability, decreased exercise tolerance, heat intolerance, fatigue and increasing shortness of breath during physical activity. The examination usually reveals the presence of a diffuse goiter, sometimes with a bruit or thrill and eye changes. The clinician must recognize this constellation of symptoms so that the patient can be appropriately screened for hyperthyroidism. Once, hormonally hyperthyroidism has been established, it is very important to go deeper into the specific reason which causes it, because all types of thyrotoxicosis are characterized with similar changes of thyroid hormones. Different reasons for hyperthyroidism during pregnancy require different therapeutic approaches. Some are self-limiting and do no require treatment with ATD but only follow up.

#### **5.2 Differential diagnosis**

The most common cause of nonautoimmune hyperthyroidism is gestational transient thyrotoxicosis (GTT), defined as transient hyperthyroidism, limited to the first trimester of pregnancy. It is associated with hyperemesis gravidarum (HG) and is characterized by elevated serum FT4 and suppressed or undetectable serum TSH. It is differentiated from Graves' Disease by the absence of anti-TSH-receptor antibody (TRAb) [48]. Hyperemesis gravidarum often presents in the first trimester of pregnancy with severe nausea and vomiting [49]. It may result in dehydration and ketonuria. Thyroid hormones return to their normal trimester specific reference ranges within 15 weeks, due to resolution of vomiting. Initially FT4 normalized spontaneously; however, serum TSH may remain suppressed for several other weeks and does not require ATD therapy, because this condition is self-limiting [50]. Rarely, for example in the case of dual or triple pregnancy, connected with very high level hCG, the use of ATD is required due to the severity of symptoms. For the clinical practice, it is very important to differentiate between GTT and Graves' Disease. The presence of goitre, thyroid eye disease (Graves' orbitopathy) and TRAbs in Graves' Disease and their absence in GTT can help for proper diagnosis. Because in both conditions there are similar changes of TSH (low) and FT4(high) levels, using a free T3/free T4 ratio could be discriminatory. Often the patients with gestational thyrotoxicosis have significantly lower or even normal T3 values [51].

Subclinical hyperthyroidism, defined as a serum TSH concentration below the lower limit of reference range, with FT4 and FT3 concentrations within normal reference range, affects up to 1.7% of pregnant women. This condition has not been found to be associated with adverse outcomes and doesn't require ATD therapy [31].
