Because of the association of thyroid antibodies with particular obstetric outcomes and the effect of pregnancy on antibody titers, consideration of the autoimmune nature of most thyroid disease is important in the course of the illness during pregnancy and fetal consequences. There are two main types of thyroid antibodies: those that are directed towards cytoplasmic antigens (thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) antibodies) and those directed to the TSH receptor (TSHRAb). According to the NHANES III data, 10–15% of women of childbearing age, not known to have thyroid dysfunction, will be positive for TPOAB [17]. Another recent study of over 17,000 pregnant women screened in the first half of pregnancy indicates that approximately 5% will have TPO antibodies [18].

Thyroid autoimmunity, with normal thyroid function, has been associated with increased miscarriage rates in some, but not all, studies. This increase in miscarriage does not appear to be related to antibody titer or the presence of thyroid dysfunction. It is hypothesized that the increased risk of miscarriage may be due to:

• subtle maternal thyroid dysfunction
  
• an underlying autoimmune imbalance reflected by the presence of thyroid antibodies which results in rejection of the fetus
  
• thyroid antibodies which cross the placenta and directly affect the developing fetal thyroid gland, thus increasing early loss
  
• increased maternal age of women with thyroid autoimmunity [19].

Pregnancy is associated with a decrease in antibody titers due to trophoblast secretion of immunosuppressant factors [20]. For example, the TSH receptor antibodies associated with Graves’ disease have been shown to decrease substantially during gestation, resulting in clinical improvement and the ability to discontinue medication in many patients. Conversely, antibody titers will increase post partum and are responsible for flares of Graves’ disease in the postpartum period and the development of postpartum thyroiditis (see below) [21,22]. In women who continue to have high titers during pregnancy, passive placental transfer can lead to fetal thyroid disorders after mid-gestation (see below).

Hyperthyroidism complicates approximately 0.2% of pregnancies [23]. Hyperthyroidism is defined by excessive thyroid hormone production due to an overactive thyroid gland. A woman may be tested because of known thyroid disease, the presence of a goiter, symptoms suggestive of thyrotoxicosis or as part of a routine screening strategy. Based on biochemical tests, individuals might be identified with subclinical (suppressed TSH, normal T4 and T3) or overt (suppressed TSH and elevated T4 and/or T3) hyperthyroidism. In women with a depressed TSH yet a normal free T4, hypermetabolic symptoms may rarely be explained by T3 thyrotoxicosis. The most common cause of pre-existing hyperthyroidism is Graves’ disease, an autoimmune hyperthyroidism caused by stimulation of the thyroid gland by thyroid-stimulating hormone receptor antibody (TSHRAb). The differential diagnosis includes toxic solitary thyroid nodule, multiple nodular goiter, exogenous thyroid hormone, amiodarone ingestion, excess iodine intake, and subacute thyroiditis (Box 12.1) [24,25].

Clinical presentation depends on the severity of the thyrotoxicosis and its underlying cause (Box 12.2). Individuals with thyrotoxicosis may present with adrenergic symptoms of stare, lid lag, palpitations, anxiety, nervousness, weight loss, heat intolerance and menstrual irregularity. The thyroid exam may also be helpful when developing a differential diagnosis. For example, a diffuse, symmetric, soft goiter, which may have an audible bruit, is typical of Graves’ disease. A palpable nodule (usually >3 cm) is direct evidence of nodular thyroid disease and generalized thyroid tenderness is consistent with subacute thyroiditis [25]. Associated autoimmune manifestations of hyperthyroidism such as orbitopathy (proptosis, soft tissue periorbital swelling, extraocular muscle dysfunction), pretibial myxedema and clubbing are exclusive to Graves’ disease.

Thyroid storm is an acute, life-threatening exacerbation of thyrotoxicosis. The classic findings are fever, tachycardia, tremor, nausea, vomiting, diarrhea, dehydration, and delirium or coma. Thyroid storm is rare in pregnancy and its diagnosis is based entirely on clinical grounds in women with laboratory tests consistent with overt hyperthyroidism. Heart failure due to cardiomyopathy from excessive thyroxine in women with uncontrolled hyperthyroidism is probably more common in pregnant women [26].

Diagnosis during pregnancy

The clinical features of hyperthyroidism can be easily confused with findings or symptoms typical of pregnancy. Suggestive complaints include nervousness, heat intolerance, palpitations, thyromegaly or goiter, failure to gain weight or weight loss, and exophthalmos. Although nausea is common in early pregnancy, the occurrence of hyperemesis gravidarum together with weight loss may also signify overt hyperthyroidism. Thyroid testing may be beneficial in this circumstance but routine testing in women with hyperemesis gravidarum is not recommended. Importantly, one must consider the impact of gestational age on measurement of TSH. It is important to not overdiagnose hyperthyroidism in the first trimester as 10–20% of women will have a suppressed TSH. Subclinical hyperthyroidism (suppressed TSH with normal free T4) has not been shown to adversely affect pregnancy [27]. At present, there is no convincing evidence that subclinical hyperthyroidism should be treated in nonpregnant individuals and treatment during pregnancy is also unwarranted [28]. Indeed, it should be considered contraindicated because maternal antithyroid drugs cross the placenta and may cause fetal thyroid suppression [29].

Once a diagnosis of biochemical hyperthyroidism is confirmed in pregnancy by a suppressed TSH and an elevated free T4 and/or freeT3, it is important to determine the cause. A woman may have previously undiagnosed Graves’ disease, nodular thyroid disease or a condition unique to pregnancy. Gestational thyrotoxicosis, also referred to as first-trimester thyrotoxicosis or HCG- related thyrotoxicosis, is typically associated with hyperemesis gravidarum. It can also be due to high levels of HCG resulting from molar pregnancy. Both conditions are associated with high HCG levels that lead to TSH receptor stimulation and transient hyperthyroidism. Women with gestational thyrotoxicosis are rarely symptomatic, have minimal thyroid enlargement, and are TSHRAb negative [30]. With expectant management of hyperemesis gravidarum, serum free T4 levels usually normalize in parallel with the decline in HCG concentrations as pregnancy progresses beyond the first trimester. Similar results would be expected with definitive treatment of a molar gestation.

It may be challenging to decide between gestational hyperthyroidism and primary thyroid disease in the first trimester (see Box 12.1). Since radio-active iodine thyroid scanning is prohibited during pregnancy, the clinician must rely more on clinical presentation. If clinical findings are inconclusive, it may be helpful to measure TSHRAb. TSH receptor antibodies are positive in 80% of patients with Graves’ disease [31].

Management

The goal of management of thyrotoxicosis is primarily to normalize, but not suppress thyroid hormone levels and to secondarily treat bothersome adrenergic symptoms of hyperthyroidism. Antithyroid drugs cross the placenta and may cause fetal thyroid suppression, so the minimal dose to achieve adequate metabolic control is preferred. Treatment options for nonpregnant women include treatment for 12–24 months with antithyroid medication, radio-active iodine to partially ablate the thyroid gland, and near-total thyroidectomy. The selection of one of these three depends on patient and clinician preferences, plans for pregnancy as well as clinical characteristics such as severity of thyrotoxicosis, size of the thyroid gland, and presence of ophthalmopathy. For example, in cases of toxic thyroid nodules, radio-active iodine is the preferred choice outside pregnancy. The risk of permanent hypothyroidism is less than when treating Graves’ disease with radio-active iodine, and antithyroid drugs generally do not result in remission of the hyperthyroidism related to thyroid nodules. Moreover, if symptoms related to compression are present with multinodular goiters or there is a question of malignancy in a nodule, a near-total thyroidectomy may be recommended.

Preconceptional counseling

Pregnancy outcomes

Severe thyrotoxicosis is associated with poor obstetric outcomes, but controlled hyperthyroidism is tolerated well during pregnancy [32,33]. Pregnant women with hyperthyroidism are at increased risk for spontaneous pregnancy loss, congestive heart failure, thyroid storm, preterm birth, pre-eclampsia, fetal growth restriction, and associated increased perinatal morbidity and mortality [32,34]. Fetal risks depend on degree of thyrotoxicosis, underlying cause of the thyrotoxicosis and treatment modality used. In most cases, the perinate of a hyperthyroid mother is euthyroid. Placental transfer of TSHRAb, however, can cause fetal Graves’ disease. This manifests as fetal tachycardia, high output cardiac failure, hydrops, craniosynostosis, intrauterine growth restriction (IUGR) and fetal goiter [35,36]. This occurs in approximately 2–10% of offspring of affected women [37]. The risk to offspring is directly related to maternal antibody titer in the third trimester [38]. Fetuses of low-risk mothers, those without detectable serum antibody levels, are rarely identified with goiter and are typically euthyroid at delivery.

Fetal goiter may also result from excessive thio-amide exposure. In this case the fetus is hypothyroid, not hyperthyroid. Current data indicate that thio-amides carry an extremely small risk for causing hypothyroidism in the neonate [39,40] and at least four long-term studies have found no abnormal intellectual and physical development in these children [41].

Chronic exposure to hyperthyroidism from inadequately treated maternal hyperthyroidism may impair maturation of the fetal hypothalamic-pituitary-thyroid axis. This can lead to central congenital hypothyroidism in the infant [42].

Thio-amide drugs