**2. Physiology of maternal and fetal thyroid in pregnancy**

Pregnancy induces several major changes to thyroid morphology and physiology. Diagnosis of thyroid dysfunction during pregnancy is complicated by the hormonal changes that take place, posing specific challenges for both detection and management. During pregnancy, thyroid gland physiologically undergoes moderate enlargement, typically increasing in size between 10 and 40% of volume, and increasing of vascularization. This enlargement can be more pronounced if there is underling iodine deficiency [13]. At the same time there are transient, reversible after delivery, changes in thyroid hormone physiology and iodine metabolism. In early gestation, the thyroid gland is stimulated not only by TSH, but also by the alpha subunit of human chorionic gonadotropin (hCG), produced by the syncytiotrophoblasts of the developing placenta, which binds to and stimulates the TSH receptor, increasing thyroid hormone production and resulting in a subsequent reduction in serum TSH concentration [14]. Normally, hCG starts to rise from the very beginning of pregnancy and peaks at around 9–11 weeks of gestational age. Due to this, there is a parallel decrease in serum

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

TSH in the first trimester. Generally, TSH concentrations in pregnant women are lower than in non-pregnant women. Physiologically TSH concentrations fluctuate during different periods of gestation. During the first trimester, approximately 15% of healthy women have TSH level below the lower limit of the reference range of 0.4 mU/L [15, 16]. The percentage of women with suppressed TSH falls to about 10% in the second trimester, and 5% in the third trimester [17]. The upper limit of TSH reference range during pregnancy is also decreased by about 0.5–1.0 mU/L, in comparison to the typical nonpregnant TSH reference range and this downward shift usually occurs in the latter first trimester of pregnancy but typically not before week 7 [18]. Levels of hCG then decline until approximately 20 weeks of gestation and remain stable for the remainder of the pregnancy [19], which is followed by a slight increase of TSH levels. The level of decrease of TSH depends on number of the developing fetuses, because hCG concentrations are higher in multiple pregnancies than in singleton pregnancies, and downward shift in the TSH reference interval is greater in twin pregnancies [20]. The degree of the lowering of TSH concentrations during pregnancy varies significantly between different racial and ethnic groups, that is why the recommended by American Thyroid Association (ATA) trimester-specific reference ranges for TSH levels shown on **Table 1** [21], require determination of population-based trimester-specific reference ranges for serum TSH through assessment of local population data.

The reduction of the lower TSH reference range, observed during pregnancy should be regarded in the light of the data that even if this represents an undergoing subclinical hyperthyroidism, it has not been associated with adverse pregnancy outcomes. In a small percentage of women, TSH can be undetectable (<0.01mU/L), but this is still represent a normal pregnancy. Therefore, a maternal TSH concentration that is low but detectable is likely not to be clinically significant [22].

Starting from the fourth week of gestation, the increase of estrogens causes the rise of circulating level of thyroid-binding globulin (TBG). Estrogens induce increase in the sialylation of the TBG, which is followed by a decrease of its hepatic clearance and by a prolongation of its serum half-life from 15 minutes to 3 days in comparison with the nonpregnancy time. TBG level reaches a plateau during midgestation and remain elevated until delivery. In the postpartum period TBG tend to normalize [23]. This rise of TGB level is followed by an increase of the total concentrations of thyroxine (TT4) and of triiodothyronine (TT3) in early pregnancy. There levels achieve a plateau early in the second trimester, at a concentrations value of 30–100% greater than prepregnancy [24]. To continue to maintain normal unbound thyroid hormone levels, thyroid gland needs to increase its thyroid hormone production. Some studies have reported a decrease, whereas others have stated even an increase of free T4 (FT4) and T3 (FT3) making the changes in free-hormone levels during pregnancy controversial. Despite this, pregnant women in general have lower free-hormone concentrations at term than nonpregnant women [17, 25, 26]. Because


#### **Table 1.**

*Generalized trimester-specific reference ranges for TSH levels [21].*

FT4 reference intervals in pregnancy vary widely between methods, interpretation of FT4 values requires method-specific as well as trimester-specific ranges.

The placenta is also an active player in thyroid hormone metabolism. It is a site for the inner ring deiodination of T4 and T3, generating the inactive iodothyronines, reverse T3 and 3,3′ -T2, respectively, and thus modulating the amount of active hormone that passes to the fetus [27]. Because of the increased thyroid hormone requirements and iodine glomerular filtration rate during pregnancy [28], adequate iodine availability is strongly necessary to meet these needs. In iodinereplete regions, women are able to meet the increased demands of pregnancy. If adequate iodine is not available, TSH rises and consequently goiter develops [29]. Thyroid hormones play a vital role in the early embryogenesis. They are essential for neurodevelopment, somatic growth, and tissue differentiation. Because, organogenesis of fetal thyroid gland occurs by around 12-th week of gestation and the gland becomes functionally active approximately eight weeks later by the 20-th week of gestation, till then, the fetus fully relay on maternal T4, which is the only thyroid hormone that can cross the placenta. Fetal deiodinase converts maternal T4 to the bioactive T3The [30].

After his thyroid gland becomes active and starts to produce hormones, fetal thyroidal turnover of iodine increases and becomes much higher than that in adults [30]. Fetal iodine store, which exclusively depends from maternal intake, must be continuously refilled. Iodine homeostasis, following fluctuating metabolic needs varies across the different trimesters. After parturition, maternal iodine continues to be the only source of iodine to the breast-fed neonate. Sodium Iodine symporter (NIS) is present in breast tissue and is responsible for concentrating iodine in colostrum and breast milk [31].

#### **3. Thyroid autoimmunity in pregnancy**

In around 10% of the women with childbearing potential thyroid antibodies could be found and they represents the most common autoimmune disease. Stagnaro-Green et al. in 1990 first demonstrated an association between pregnancy loss and thyroid antibodies. They showed, that there was a 2-fold increase in the risk of pregnancy loss (17% vs. 8.4%) in women with thyroid antibodies [32]. One meta-analysis discovered, that the presence of thyroid antibodies in pregnant women was connected with a 4-fold increased risk of miscarriage in cohort studies, and a 1.8-fold increased risk in case–control studies [33]. The association of thyroid autoimmunity and preterm birth is not unambiguously as the studies showed conflicting results. Some found significant association [33–36], while others [37] didn't show such correlation.

Following the changes of the activity of the immune system through pregnancy, the activity of Graves' Disease fluctuates. Concomitant changes of the TSH receptor antibody (TRAb) levels, generally reflecting the clinical course of the disease, are observed [38]. During the first trimester TRAb levels are usually elevated with a subsequently fall to even undetectable values during the second and third trimesters and may increase again postpartum [39, 40]. Due to this pattern of fluctuations of TRAb levels, exacerbation of the clinical symptoms of Graves' Disease may occur in the first trimester of gestation, followed by a remission in the second and third trimesters, because of the observed immune tolerance [41]. The decrease in TRAb levels, rather than increases in inhibitory anti-TSH receptor antibodies determines this clinical pattern [39]. From a clinician's point of view, the dosage of antithyroid drugs can be reduced or even discontinued late in gestation and restarted in the postpartum period [41].
