*4.3.1 Preparing for pregnancy in women with known Graves' Disease*

Graves' Disease is common in women of reproductive age. Pregnancy should be carefully planned because both the characteristic pathogenic antibodies and the treatment of GD may be deleterious to the fetus. Also, uncontrolled GD may lead to unfavorable outcomes of pregnancy such as miscarriage, gestational hypertension, preeclampsia, preterm birth, fetal growth restriction, fetal intrauterine death, fetal and neonatal goiter, neonatal abnormal thyroid function with potential life-long disability for the infant. Contraception is strongly advised in women with newly diagnosed GD or in those with uncontrolled GD until euthyroidism is reached by treatment. Many patients will first be prescribed ATDs, however options of ablative therapy with I131 or surgery (total thyroidectomy) are also considered. These options should be discussed with women with GD in relation to how they may interfere with a potential pregnancy. Benefits and risks of options used for management of GD in women of reproductive age desiring a pregnancy are given in **Table 2** [4].


#### **Table 1.**

*Causes of thyrotoxicosis in pregnancy and postpartum [27, 28, 32–36].*

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


#### **Table 2.**

*Benefits and risks of the options for management of GD in women desiring a pregnancy. Adapted and modified from [4]; TRAb – TSH receptor antibodies.*

Antithyroid drugs, thionamides propylthiouracil (PTU), carbimazol and methimazole (MMI) have been the traditional mode of treating GD. These drugs inhibit the enzyme thyroperoxidase which facilitates the addition of iodine to tyrosine in the production of thyroglobulin (**Figure 1**), an essential step in the formation of thyroid hormones. ATDs have their advantages, however, when it comes to preparing for pregnancy, counseling on the continuation of treatment and on what drugs should be preferred is of great use. ATDs can have adverse effects to the mother, but during pregnancy, they can cross the placenta and affect the fetus. Use of ATDs in the first trimester of pregnancy has been linked with congenital malformations. Later usage may lead to fetal/neonatal hypothyroidism and goiter. Carbimazol and methimazole administration during the first trimester and especially between 6 to 10 weeks has been associated in epidemiological and case-report studies with a pattern of anomalies (carbimazole/methimazole embryopathy) characterized by dysmorphic facies, choanal atresia, aplasia cutis congenita and other skin defects, heart and gastrointestinal abnormalities and abdominal wall defects [37]. Prudently, many authorities recommend for pregnant women with GD on ATDs, that PTU should be used in the first trimester and MMI thereafter. While PTU has a very small risk of maternal liver toxicity, it could be preferred in the first trimester, however, switching from one ATD to another at the beginning of pregnancy is not an easy process and it may lead to worsening in control of the thyroid function which in itself may increase the chance of congenital anomalies [37]. Recent reports show that PTU also is not devoid of the risk of congenital anomalies. In a Danish study, 2–3% of children exposed to PTU presented facial anomalies, necks cysts and urinary tract abnormalities, often requiring surgery in later life [38].

Women with GD treated with I131 before at least six months prior to conception who are in an euthyroid state had similar outcomes of their pregnancies as healthy controls in a retrospective study [39]. Obviously, I131 is contraindicated in pregnancy and women undertaking this treatment should prove a negative pregnancy test 48 hours prior to it [4].

Total thyroidectomy is the definitive treatment for GD but it can lead to surgical complications such as recurrent laryngeal nerve paralysis and hypoparathyroidism. Hypoparathyroidism is the most common complication after total thyroidectomy and is usually underrecognized. In a recent retrospective study of patients undergoing total thyroidectomy for benign thyroid conditions, the incidence of transient hypoparathyroidism was 43.3% and permanent was 13.4%. In patients with GD chronic hypoparathyroidism developed in 27.3% [40]. Entering pregnancy with hypoparathyroidism has its own potential risks for both mother and the fetus [41].

A preconceptional visit should ideally be planned for women with known GD of reproductive age that are considering pregnancy. This consultation should be given by a team of physicians that includes an endocrinologist and a maternalfetal medicine specialist/obstetrician with experience in dealing with GD during pregnancy. Women with GD seeking pregnancy should be euthyroid – exhibit normal levels of thyroid hormones for at least 1–2 months successively. It may be sensible that in patients who underwent thyroidectomy but especially in those previously treated with I131 ablative therapy, TRAb titers be assessed at the preconceptional visit, since the level of these antibodies could interfere with fetal thyroid development in the second half of pregnancy and they can remain increased many months even years. Pregnancy could be postponed if the levels are very high. For those with a total thyroidectomy, parathyroid function should be checked if not assessed before. For women with GD, other autoimmune conditions should be looked for and a thorough clinical exam complemented in specific cases with targeted tests should be prescribed. A recent systematic review and meta-analysis found overt polyautoimmunity in 14% of patients with autoimmune thyroid disease. Most common autoimmune conditions associated with GD were type 1 diabetes mellitus and autoimmune gastritis, but rheumatological, dermatological and neurological autoimmune disorders could also be found in GD affected patients [42]. Folic acid is usually recommended to these women in the preparation of pregnancy.

#### *4.3.2 Pregnancy in women with Graves' Disease on anti-thyroid drugs*

For many women with Graves' Disease ATDs are a good choice of treatment gradually inducing remission of autoimmunity. Drugs can be stopped after 1–2 years of trail, and even though, hyperthyroidism will eventually develop in almost 50% of these patients, reactivation of TRAb positivity is not usually expected. In a prospective study on 218 patients with GD treated for 12 months with ATDs, only 5% of those that were TRAb-negative with treatment became hyperthyroid within 8 weeks after stopping the medication [43]. It has therefore been suggested that, under good clinical judgment, in women with GD on ATDs that become pregnant and that are considered in remission, drugs could be stopped at least during the first trimester of pregnancy, especially between weeks 6 to 10, the major teratogenic period [4]. This approach is very different from what is recommended for other autoimmune conditions in early pregnancy where discontinuation of the chronic medication is strongly discouraged. Clinical assessment and thyroid function tests are recommended frequently in these patients and if relapse is diagnosed and ATD therapy is required, PTU is the preferred drug during the first trimester. The risk of rapid relapse of hyperthyroidism after stopping ATDs during early pregnancy is higher in women that were treated less then 6 months, in those that required more then 5 mg MMI per day to remain euthyroid, in those with suppressed or low levels of TSH, in those with large goiters, with orbitopathy and those with high levels of TRAbs [44].

In women where ATDs can not be discontinued during pregnancy, MMI is usually changed with PTU for the first trimester and reintroduced thereafter. Some women will have a worsening of their symptoms with GD in the first trimester and

improvement later in pregnancy. Many pregnant women will not require ATDs by the third trimester as autoimmunity subsides characteristically in pregnancy. Normal THS levels and disappearance of maternal TRAb guide the decision to stop ATDs. If this is not done, there is a risk of overtreatment that can lead to hypothyroidism in the fetus (see below).

#### *4.3.3 When Graves' Disease is first diagnosed in pregnancy*

Uncontrolled maternal hyperthyroidism is associated with adverse maternal, fetal and neonatal outcomes [4]. When GD is first diagnosed during pregnancy, thionamides are the mainstay of treatment and they should be prescribed to achieve an euthyroid state. Beta-adrenergic blockers, which are generally considered safe in pregnancy, are also prescribed to control the hypermetabolic state until patients become euthyroid on ATDs. I131 is contraindicated in pregnancy and thyroidectomy, if required should ideally be performed in the second trimester. Thyroidectomy is considered for those women that have contraindications to ATDs, are not compliant with drug therapy, and in women where euthyroidism is not achieved despite large doses of ATDs. Preparation for surgery with beta-blockers and a short course of potassium iodide solution (50–100 mg/day) is permitted during pregnancy [4]. TRAb levels decrease slowly after surgery, therefore, continuation of monitoring should be in place for the remainder of pregnancy, since these antibodies can cross the placenta when in high titers (> 3 times the upper reference for the assay) and render the fetus hyperthyroid despite euthyroidism in the mother. Initial doses of ATDs for GD diagnosed in pregnancy depend on the severity of the symptoms and the degree of hyperthyroxinemia. During pregnancy MMI is prescribed at doses between 5–30 mg/d, typically in an average patient about 10–20 mg; CMZ at 10–40 mg/d and PTU at 100–600 mg/d (typically the average dose for PTU in an average patient is 200–400 mg/d). The beneficial effects of the drugs are seen gradually over weeks as the reservoir of hormones stored in the thyroid gland is consumed. The risk of maternal side effects from ATDs is not increased during pregnancy and is similar with one would expect in the non-pregnant state. Allergic skin reactions are the most common side effects while severe agranulocytosis and liver failure are rarely expected. Because of its potential risk of liver hepatotoxicity and liver transplant, some authorities recommend that the use of PTU should be limited to the first trimester of pregnancy and considered for use thereafter for those with MMI allergy and for those in thyroid storm [4]. The greatest concern however, with ATDs use in pregnancy remains their potential teratogenic effect and their risk of inducing fetal and neonatal hypothyroidism by crossing the placenta. Beta-blockers are considered safe in pregnancy even in the first trimester [45]. Usual doses for pregnancy are 10 to 40 mg of propranolol every 6 to 8 hours for several weeks. There is a concern related to fetal growth, fetal bradycardia and neonatal hypoglycemia with long term use of some beta-blockers [46], however propranolol and metoprolol have a more favorable safety profile then other beta-blockers during pregnancy [47].

Thyroid function tests could be carried out every 2 to 4 weeks in these patients at the beginng of the ATDs course and every 5 to 6 weeks after reaching and euthyroid state. When specific population lab values for pregnancy by trimester are not available, it is recommended to use the reference ranges for nonpregnant patients [4]. [See Thyroid function tests in pregnancy above]. The aim of GD treatment is to maintain maternal TT4/FT4 values at or just above the pregnancy specific upper limit of normal on the lowest effective dose of ATDs, to avoid potential harm to the fetus. Worthy of mentioning, ATDs are considered more potent in the fetus then in the mother, hence, in a well controlled mother, we could expect hypothyroidism in the fetus.

#### **4.4 Fetal and neonatal consequences**

Fetal and neonatal outcomes of GD are related to the control of the maternal hyperthyroid state, the presence or absence of TRAbs and the effect of ATDs. Uncontrolled maternal thyrotoxicosis can negatively influence how pregnancy progresses. TRAbs, when in high levels can cross the placenta and lead to fetal hyperthyroidism and goiter and ATDs, by also crossing the placenta, can lead to fetal hypothyroidism and goiter. When assessing a fetus in a mother with GD, a maternal-fetal specialist checks with the use of ultrasound the fetal neck in both grayscale and color doppler, looking for signs of fetal goiter. Assessment of fetal growth, Doppler studies for assessment of fetal oxygenation, bones, heart rate, amniotic fluid volume are also performed. The exact incidence of fetal goiter is not known but it may be up to 1 in 5,000 births, usually, but not exclusively, in association with maternal Graves' Disease [48]. It has been estimated form different studies that the incidence of fetal goiter with either hypo- or hyperthyroidism in mothers with treated or untreated Graves' Disease is about 10% [49–53]. Fetal hypothyroidism is found more frequently than fetal hyperthyroidism in mothers with GD because of the inadequate use of ATDs [50, 51]. Fetal goiter can be diagnosed prenatally by ultrasound with the demonstration of an anterior cervical echogenic mass of variable size. (**Figure 2**) Large fetal goiters may lead to obstruction of fetal swallowing with consequent polyhydramnios and an increased risk of preterm birth; the neck may be hyperextended. As with other causes of obstructive polyhydramnios (duodenal stenosis, esophageal atresia) this becomes evident usually after 24 weeks' gestation. With fetal goiter there may also be a higher risk of birth dystocia because of the inadequate head flexion during labor and increased incidence of neonatal breathing problems and difficulties in intubation. Fetal goiter harbors thyroid dysfunction. Ultrasound is not a reliable tool to distinguish between fetal hyperand hypothyroidism. In some cases of fetal hyperthyroidism there can be associated intrauterine growth restriction with accelerated bone maturation, tachycardia, intrauterine death by cardiac failure or thyrotoxicosis and craniosynostosis [54, 55]. In severe fetal hypothyroidism there can be a delay in bone maturation [56] and there may be impaired growth and bradycardia. There are usually no other associated structural anomalies and the incidence of chromosomal or genetic anomalies is not increased in fetal goiters in maternal Graves' Disease. In terms of management, in most cases of fetal goiter, assessment of the maternal condition can help decide whether the cause is fetal hypothyroidism or hyperthyroidism. In uncertain cases,

#### **Figure 2.**

*Ultrasound imaging of a fetal thyroid goiter (A in gray scale, B with color doppler). Courtesy of the Fetal Medicine Foundation, reproduced with permission.*

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

cordocentesis and measurement of fetal blood thyroid hormones and TSH can help distinguish between hypothyroidism, with low thyroid hormones and high TSH, due to ATDs and hyperthyroidism, with high thyroid hormones and low TSH, due to TRAbs [49, 57]. Normal ranges for the thyroid hormones level in the fetal blood have been previously reported [58, 59].

In fetal hypothyroid goiter the first-line of treatment is to reduce or even discontinue maternal ATD medication aiming to maintain maternal blood thyroxine in the upper level of the gestational age-specific normal range. As noted before, GD, similar to other autoimmune conditions, improves during pregnancy and consequently requires less medication. The second-line of treatment is intra-amniotic injection of levothyroxine (100 μg/kg) every 1–2 weeks until delivery at term [49, 60]. The goiter usually decreases in size within a few days to weeks after the first course of treatment. Subsequent injections are given depending on sonographic evidence of re-enlargement of the gland or serial measurements of levels of thyroid hormones in amniotic fluid or fetal blood [49, 61, 62].

In fetal hyperthyroid goiter the treatment is administration of ATDs to the mother [63]. Occasionally, the mother should also be given levothyroxine, as the dose of ATDs can be appropriate for the fetus but could lead to hypothyroidism in the mother (one of the few occasions block and replace therapy is used) [4]. The fetal goiter usually decreases in size after initiation of the treatment, but if this does not occur measurement of levels of thyroid hormones in fetal blood [24] may be needed and the dose of ATDs adjusted. Follow-up should be arranged depending on the clinical context, but generally at every 2–4 weeks to monitor fetal growth, size of the tumor, fetal heart rate, amniotic fluid volume and cervical length (for the prediction of risk of preterm birth). Delivery in the case of fetal goiter should take place in a hospital with neonatal intensive care capacities and pediatric surgery facilities, ideally around 38 weeks. With large goiters, where there is hyperextension of the neck, cesarean section is preferred for delivery. An EXIT (ex utero intrapartum treatment) procedure may be required to access and stabilize neonatal breathing while maintaining placental flow through the umbilical cord from the mother [24]. Adequately treated fetal thyroid goiters generally have good prognosis. However, fetal hyperthyroidism may lead to neonatal thyrotoxicosis [64] and, to long term intellectual impairment [65] while fetal hypothyroidism may result in long term abnormal psychomotor development [66].

Neonatal thyroid function abnormalities are frequent in newborns of mothers with GD. In a recent study in 32 newborns from mothers with GD, 3 cases had hypothyroidism and 2 had hyperthyroidism despite not showing a goiter. These affected babies all had higher levels of TRAbs in their cord blood at delivery and in the follow-up tests [67]. Newborns of mothers with GD can present with hyperthyroidism but also with central or primary hypothyroidism. There are no clear guidelines as to how these neonates should be followed, but most authorities do recommend testing for TRAbs in the cord blood/blood with subsequent discharge of negative testing newborns. FT4 and TSH can be performed at 3 to 5 days of life and repeated at 10 to 14 days. For hyperthyroid newborns MMI and beta-blockers can be used [68]. Maternal TRAbs passed to the newborn will be cleared from the neonates' serum within weeks to months as in the case of other maternal autoimmune conditions [48].

#### **4.5 The postpartum in women with GD**

Worsening of GD, relapse or need for increased medication do occur after delivery even in mothers that were previously under remission [69, 70] and women should be counseled and informed about this. Pregnant women with

positive TRAbs in early pregnancy are at high-risk of developing postpartum GD. Postpartum GD usually occurs after 3 months from delivery and this helps in differentiating it from other forms of thyrotoxicosis specific to this period that tend to develop earlier. Women with known GD before or during pregnancy should be regularly checked with thyroid function tests in the postpartum. Treatment options for postpartum GD are the same as for any GD patient. ATDs are an initial good choice since in many instances GD postpartum can be transient and mothers can continue breastfeeding on them. Both MMI (up to maximal recommended dose of 20 mg/d) and PTU (up to maximal dose of 450 mg/d) can be safely administered in breastfeeding mothers [4]. Monitoring the infants for appropriate growth and development routinely is advised [4]. It may be necessary to check the infants' thyroid function when antithyroid drugs are administered at higher doses. Medication should be taken just after breastfeeding, which should provide a 3 to 4 hours lactating free interval [71]. Considering the possibility of side effects of severe hepatic injury of PTU in mothers and infants [72], and high incidence of general side effects with PTU [73], MMI is the preferred drug in the treatment of breastfeeding women. The use of I131 is strictly contraindicated during lactation. If circumstances require it I123, when available can be used in lactating women. The half-life of 123I is 13 hours so breast milk should be pumped and discarded for 3–4 days until the radioactive iodine has cleared from the body [74]. Similarly, Tc-99 m pertechnetate administration requires breast milk to be pumped and discarded during the day of testing [4].
