**2. Physiological changes of the thyroid gland and the thyroid hormone metabolism during pregnancy**

The maternal thyroid gland and thyroid hormone metabolism undergo significant changes in pregnancy. The volume of the gland and its blood supply increase in pregnancy [3]. Plasma volume expands thus increasing total T4 and T3 pool size (T4 - thyroxine and T3 - tri-iodothyronine). The placenta produces estrogen that induces hepatic synthesis of thyroid-binding globulin (TBG), the main protein involved in serum transport of TH, thus increasing levels of total T4 (TT4) and T3 (TT3) in the maternal plasma. Thyroid hormone production is dependent of iodine supply so iodine metabolism needs to keep up with these changes, hence, there is an increase in iodine requirements during pregnancy to both meet the maternal and fetal demands and to overcome the increased clearance by the kidneys. The placenta also produces HCG (human chorionic gonadotropin), a glycoprotein hormone with molecular similarity of its α-subunit with TSH (thyroid stimulating hormone) which acts as an agonist of TSH raising transiently free T4 levels and decreasing serum TSH levels. These changes are more relevant to the first trimester, and, beyond it, maternal thyroid hormone levels gradually return to those seen in the nonpregnant state [4].

Thyroid hormones are essential for normal development of the fetus and particularly of the fetal brain. The fetal thyroid gland only starts to produce adequate amounts of thyroid hormones in the second trimester; the first trimester fetus relies on maternal delivery of thyroid hormones to develop [2]. In the first part of pregnancy, before the fetal thyroid starts to work, T4 can be detected in fetal blood and brain, indicating that there is relevant transfer of maternal thyroid hormones to the fetus. The way maternal thyroid hormones are transferred across the placenta and in the fetal brain is not completely understood. Even though thyroid hormones are lipophilic, they can not passively cross the placenta nor the fetal blood–brain barrier because they are charged and thus can not cross a phospholipid bilayer [5]. Passage across the placenta and into the fetal brain is thought to be dependent on the function of several mechanisms [6] including: the existence of a specific transportation system, the function and expression of iodothyronine deiodinases (D) (enzymes that TH) in the placenta and fetal brain, and proteins within trophoblast and fetal brain which specifically bind TH. At the level of the placenta specific transporters capable of transporting maternal TH like monocarboxylate transporters MCT8 and MCT10 have been identified [6, 7]. Deiodinases found in the placenta in high concentration are D3, the main inactivating enzyme that catalyze monodiodination of T4 to reverse T3 and of T3 to T2, but also, D2, which the primary activating enzyme in tissues and locally catalyzes the monodeiodination of T4 to T3 [8]. The iodine released by this process might be used as a substrate by the fetus for the synthesis of its own thyroid hormones. D2 has been identified in the fetal brain [9] converting T4 to active T3, thus making it readily available. In the serum, TH are bound to liver-synthetized transportation proteins mainly TBG but also albumin and transthyretin. Transthyretin has been identified in the placenta and fetal choroid plexuses and is thought to play a role in transporting TH into the cells [10]. TSH does not cross the placenta and TSH in the fetal blood remains relatively constant throughout pregnancy between 4–8 mU/L [11]. The coordination and interplay between these systems ensures adequate availability of maternal TH to the fetus in a critical period of development (**Figure 1**).

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

**Figure 1.**

*The interaction between the fetal-placental unit and the maternal endocrine system during pregnancy. TRH – Thyrotropin releasing hormone; TSH – Thyroid stimulating hormone; T3 - tri-iodothyronine; T4 – Thyroxine; HCG - human chorionic gonadotrophin; TBG - thyroid hormone binding globulin; D3 - type 3 iodothyronine deiodinase; D2 - type 2 iodothyronine deiodinase; rT3 – Reverse T3.*

#### **3. Thyroid function tests in pregnancy**

The physiological changes occurring in the thyroid gland from the beginning of pregnancy reflect in changes of the thyroid function tests. International guidelines recommend that ideally, for each population, there should be available trimester specific normal ranges for TSH and maternal TH [4]. These data should be derived from studies in healthy pregnant women with no known thyroid disease, with no evidence of thyroid autoimmunity and with an adequate amount of iodine intake for each trimester of pregnancy. In the absence of such data, which in many clinical settings can be difficult to obtain, in order to determine normal first-trimester reference ranges for TSH it has been suggested that the lower limit of its reference interval used in the non-pregnant state can be reduced by 0.4 mU/L and the upper limit by 0.5 mU/L [4]. For a healthy young pregnant woman the upper limit of TSH would therefore correspond to a value of 4.0 mU/L in the first trimester. This downshifting of the normal TSH reference interval only applies to the first trimester values, between 7 and 12 weeks of pregnancy since in the second and third trimesters, TSH levels recover and intervals valid outside pregnancy could be used.

The second most common test used to investigate thyroid function outside as well as in pregnancy is free T4 (FT4). FT4 represents the thyroxin that is not bound to plasmatic proteins; it constitutes less then 0.1% of total T4 (TT4) but is the active form that is up taken by cells. Precise measurement of FT4 is difficult in pregnancy in part because of the limitation of the widely used commercial immunoassays to account for thyroid hormone concentration changes that occur under the influence of increased levels of TBG, nonesteryfied fatty acids and decreased albumin.

Therefore, it has been suggested that TT4 and the index of T4 are more accurate in determining shifts in thyroid hormone levels in pregnancy. With TT4 it is important to acknowledge that its level increases by 50% during weeks 7 to 16 and remain high thereafter throughout pregnancy. When the level of TT4 is determined before 16 weeks, an adjustment to the upper limit of the non-pregnancy interval by 5% per week between weeks 7 to 16 could be made. A TT4 measurement with reference value 1.5 times the non-pregnancy range may be used in second and third trimesters as discussed above. When trimester-specific FT4 values are not available, use of the reference range for non-pregnant patients is recommended [4, 12–14].
