*5.5.1 Antithyroid drugs*

ATD are the first choice for treatment of Graves' Disease during pregnancy. Propylthiouracil (PTU) and methimazole (MMI) are equally effective in the management of hyperthyroidism during pregnancy. Propylthiouracil and methimazole inhibit thyroid hormone synthesis by interfering with intrathyroidal iodine utilization and the iodotyrosine coupling reaction, both of which are catalyzed by thyroid peroxidase. Antithyroid drugs do not directly affect iodine uptake or hormone release by the thyroid. Because of this, the clinical and hormonal improvement is delayed for 10-14 days after their implementation in the therapeutic regimen. PTU, but not methimazole, inhibits the conversion of T4 to T3 in peripheral tissues, thus theoretically it can ensure faster alleviation of the symptoms and reaching the desired levels of FT4. In clinical practice this is not considered relevant. Comparative study showed that methimazole generally normalizes serum T4 and T3 levels faster than PTU [71]. Both antithyroid agents are well absorbed from the gastrointestinal tract. They differ in their ability to bind to proteins in circulation, with PTU being strongly protein-bound, mainly to albumin, at physiologic pH, while methimazole binding to proteins is negligible [72]. Other studies have found that both drugs readily cross the placenta [73, 74]. The serum half-lives of PTU and methimazole are 1 and 4 to 6 hours, respectively. The intrathyroidal duration of action of both drugs is longer than that. Both drugs are metabolized in the liver and their metabolites are excreted by the kidney. However, so far there are no data, that the doses used to treat hyperthyroidism generally need to be altered in patients with liver or kidney disease. This characteristic, apart from their side effects, may determine the choice of the antithyroid drug in pregnancy and lactation, since PTU crosses the placenta and breast epithelium less readily than methimazole. So it is reasonable to begin therapy with PTU because there are no reported cases of PTU-associated aplasia cutis. However, if a woman cannot tolerate PTU for any reason, experience side effects does not want to take the prescribed number of pills (PTU usually requires multiple daily dosages, whereas MMI can often be given once daily), MMI may be substituted. The initial dose rarely exceeds more than 450 mg of PTU or 30 mg of MMI daily in order to achieve the predefined levels of FT4 and TSH. The median time, usually seven to eight weeks, to normalization of the maternal FT4 index for both PTU and MMI is equal [75], but improvement in these parameters may be seen earlier at three to four weeks. This fact, makes clinically relevant to reassess maternal FT4 or total T4 at an interval of three to four weeks and to adjust ATD dosage appropriately based upon the current levels of thyroid hormones. We should keep in mind, that maternal serum TSH levels may remain suppressed for several weeks after normalization of thyroid hormone levels. So measuring TSH level is not helpful early in treatment, and may mislead us to continue with the unnecessary high dose of ATD, causing drug induced hypothyroidism and thus depriving the developing fetus from crucially important maternal T4 delivery. As was discussed above, due to the changes of the activity of Graves' Disease throughout pregnancy, determined by fluctuations of TRAbs concentrations, in the late second and third trimesters the dose of ATD can be reduced or even stopped by 32 to 34 weeks of gestation in 30% of women [76]. Of course, the

same spectrum of adverse effects related to ATD therapy in the nonpregnant state applies to use during gestation.

Both drugs are showing similar fetal outcomes, in terms of thyroid function. The risk for congenital abnormalities had been considered to be higher in MMI than in PTU.

Aplasia cutis and also other malformations have been reported in the offspring of mothers who had taken methimazole during pregnancy [67, 77]. Aplasia cutis is a congenital localized absence of skin that occurs spontaneously in approximately 1 in 2000 births [78]. Many years, the fear from the possible development of this complication had restricted the use of methimazole during pregnancy, nevertheless, there is no definitive proof that MMI is actually responsible for the condition. Additional possible congenital malformation in children exposed to MMI during the first trimester of pregnancy are choanal and esophageal atresia, minor facial abnormalities and psychomotor delay, which either isolated or associated with aplasia cutis define the so called methimazole embryopathy [67, 77].

Because there are no reports of aplasia cutis in association with PTU, this drug is preferred by some physicians. Growing data from the literature for the causative roll of PTU for acute liver injury, had limited the use of the drug only during the first trimester of the pregnancy due to its lower risk for congenital malformations. Before pregnancy and during the second and third trimester methimazole is preferred, considered to be less hepatotoxic. Pregnancy itself does not appear to alter the maternal pharmacokinetics of MMI, although serum PTU levels may be lower in the latter part of gestation compared to the first and second trimesters [71].

The treatment of Graves' Disease during pregnancy should aim to achieve normalization of FT4 and FT3 levels with strict monitoring of maternal thyroid function at an appropriate intervals. Careful surveillance of fetal development to optimize fetal outcomes is also important, and this makes the team approach with a close collaboration between endocrinologist and obstetrician crucial. Apart from monitoring the laboratory parameters, there are clinical signs of improvement, that include maternal weight gain, decrease in pulse rate and appropriate fetal growth, that should be followed up. Clinical signs and laboratory values must always be considered together when a therapeutic decision is necessary, and if for example, there is a detected lack of maternal weight gain in conjunction with mild elevations in thyroid hormone levels, the initiation of a low dose of ATD should be considered.

#### *5.5.1.1 Antithyroid drugs: effect on the Fetus*

In pregnancies complicated with concomitant Graves' Disease, fetal thyroid status is influenced by two maternal factors, both of which cross the placenta: maternal ATD dosage and maternal TRAb activity. There are two potentially opposing influences on fetal thyroid function by maternal TRAb, because they can be with either stimulating or blocking effect on the developing fetal thyroid gland. Different assays for maternal TRAb exist. Some, like one of the most commonly used radioreceptor assay does not distinguish between blocking and stimulating antibodies, so their peripheral effect can be estimated only by assessing the thyroid function [79]. The currently available bioassay is the thyroid stimulating immunoglobulin (TSI), which measures the generation of cyclic adenosine monophosphate by cells that express TSH receptor when incubated with the patient's serum [66].

Because both PTU and MMI can cross the placenta and they may decrease fetal thyroid hormone production The dose–response relationship between maternal ATD dose and neonatal thyroid function is controversial, as some studies have

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

reported a direct correlation [66, 69, 80] and others have not demonstrated this [64, 69, 73]. There are data showing that ATD drugs even at low daily dosages (PTU ≤ 100 mg, MMI ≤ 10 mg) at term may affect the fetal thyroid function. An elevated cord TSH level was found in 23% of babies born to such PTU-treated mothers and in 14% of those treated MMI [81]. There is an individual variability in serum PTU and MMI levels after a standard oral dose and that could partly explain the observed lack of correlation between maternal dosage and fetal thyroid function [81, 82]. Transplacental passage of maternal TRAb resulting in excessive fetal thyroid stimulation is the second factor that can influence fetal thyroid function. Usually, this becomes clinically relevant at 24 to 26 weeks, of gestation. Maternal levels reflect the degree of fetal exposure [83]. At term there is a strong correlation between maternal and cord TRAb levels with development of neonatal hyperthyroidism. Clinically relevant is to measure the maternal TRAb levels at term, because the combination of continued use of maternal ATD therapy with low maternal TRAb levels may lead to elevated serum TSH levels in approximately 50–60% of infants [80]. This shows how important is to adjust appropriately the maternal ATD dosage during pregnancy especially when maternal immune thyroid stimulation is low. In nonimmune types of thyrotoxicosis, like toxic adenoma for example, dose relationship between ATD and the risk of suppression of the fetal thyroid function is more profound, since there is no contribution of fetal thyroid stimulation by the maternal immune system. Therefore, it is not surprising that fetal thyroid status is not strictly correlated with maternal ATD dosage. Inappropriately high doses of ATD may result in development of fetal or neonatal goiter, which in the most severe cases if markedly enlarged at birth may cause respiratory distress. In the past, due to the concomitant iodide therapy and ATD, goiter occurred more frequently. The combined inhibitory effect on the fatal thyroid gland of iodide and ATD resulted in the development of goiter. One clinical approach is to perform a fetal utrasound in all women who are still taking relatively high ATD doses at 26 to 28 weeks (PTU ≥450 mg/day, MMI ≥30 mg/day) [84]. If a fetal goiter is detected this could be due to either fetal hyperthyroidism, transplacental passage of stimulating TRAbs, or to fetal hypothyroidism caused by transplacental passage of maternal ATD therapy. In both situations intrauterine growth retardation may occur. The presence of fetal tachycardia (160–180 beats per minute) and advanced fetal bone age is highly suggestive of hyperthyroidism [85, 86]. When caused by maternal ATD use, a quick resolution within two weeks after birth of the neonatal goiter is observed, reflecting the discontinuation of drug exposure [69]. Therefore, stopping maternal ATD therapy and monitoring the fetal goiter by ultrasound is advisable. Other therapeutic approach for treatment of the fetal goiter due to maternal ATD exposure includes intra-amniotic levothyroxine injections [87, 88], but because it was done concomitantly with lowering of the maternal PTU dose, it is difficult to estimate the relative importance of each factor on the resolution of the fetal goiter. The cessation of maternal ATD therapy alone may result in decrease in the fetal goiter assessed ultrasonographically [89]. Discontinuation or decreasing the dose of ATD therapy is crucial in cases where hypothyroidism is suspected because of transplacental ATD passage. Fetal goiter must be followed with sequential ultrasounds and if no reduction in size, within two to three weeks, occurs, fetal thyroid function should be determined by performing periumbilical blood sampling, and intra-amniotic levothyroxine therapy should considered if necessary. Several studies have reported no cognitive and somatic defects in development of children exposed to maternal ATD in utero [90–93] and this was so even after accounting for higher dosage or first trimester exposure. These were cross sectional studies that measured cognitive development by intelligence quotient. Therefore, it is unknown if transient, or more subtle developmental changes might have been present.

#### *5.5.2 Beta-adrenergic blockers*

Considering the relation between thyroid hormones and sympathetic nervous system, beta-adrenergic blocking agents may be used transiently to control adrenergic symptoms, while waiting for ATD therapy to decrease thyroid hormone levels. The fact, that combined use of ATD and propranolol in comparison with ATD alone was related with a higher rate of spontaneous first trimester miscarriages, although the similar levels of thyroid hormone [94], beta-blockers should be used for short period and with caution.

#### *5.5.3 Iodides*

As was previously discussed, chronic use of iodides during pregnancy has been associated with hypothyroidism and goiter in neonates, sometimes in severe cases resulting in asphyxiation because of tracheal obstruction [95]. Iodides should not be used as a first line therapy in women with Grave's because of the well-known dual effect of iodine upon the thyroid function and the risk for provocation of a latent autoimmune disorder and also for aggravation of the thyrotoxicosis increasing the iodine store in an already hyperfunctioning thyroid gland. Iodides could be used transiently if needed in preparation for thyroidectomy.

#### *5.5.4 Surgery*

Subtotal thyroidectomy for Graves' Disease is rarely considered during pregnancy. The reasons for such treatment could be the need to use high levels of ATD (PTU 450 mg/day, MMI 40 mg/day) to control the clinical symptoms and thyroid hormonal levels, if compressive symptoms due to goiter size develop or if a patient is allergic to ATD therapy or noncompliant to the therapeutic regiment. The surgery is usually performed in latter half of the second trimester. The surgery in the first trimester is relatively contraindicated, because that this is the time of the highest spontaneous abortion rate and surgery and anesthesia could possibly further increase the risk, but if clinically indicated subtotal thyroidectomy may be done in some specific cases [96].

#### *5.5.5 131I therapy*

The use of 131I therapy is completely contraindicated in pregnancy. The most vulnerable for the fetus period to 131I therapy is that after 12 weeks gestation, because at this period the fetal thyroid begins to concentrate radioiodine at higher rate than the maternal thyroid and other fetal tissues are generally more radiosensitive [97]. It is essentially important to exclude pregnancy in all women prior to radioiodine therapy. The therapeutic administration of 131I to a nursing mother is contraindicated and lactation should be stopped immediately if this occurs.

#### **5.6 Lactation**

Because the ATD present in breast milk in sufficient concentrations that can influence infant's thyroid, their use in breast-feeding women was considered contraindicated. Due to the ability of PTU to bind more tightly with protein than MMI, less amount of PTU is available in the milk. The ratio of milk to serum levels is found to be lower for PTU (0.67) [98] than for MMI (1.0) [99], moreover the amount of ingested drug secreted in breast milk is approximately six

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

times higher for MMI than for PTU (0.14 vs. 0.025% of the ingested dose) [99]. Despite this, the fetal thyroid function assessed in newborns breast-fed by mothers treated with ATD with daily doses of PTU (50–300 mg), MMI (5–20 mg), or carbimazole (5–15 mg) for periods ranging from three weeks to eight months, remained normal, even in overtreated women with elevated serum TSH levels [100]. Data from the literature show that ATD therapy (PTU 300 mg/day, MMI 20 mg/day) may be considered relatively safe during lactation [100]. Generally, PTU would be preferred than MMI, because of its less availability in breast milk. It is wise the drug to be taken by the mother after a feeding. So far, there are no reports of the development of ATD side-effects in an infant breast fed by a mother treated with ATD [101].
