Hyperthyroidism in Pregnancy

Etiology

Thyroid disorders are the second most prevalent endocrine conditions observed during pregnancy.[4] Hyperthyroidism in pregnancy requiring treatment is most often caused by Graves' disease, which is estimated to account for 85% to 95% of clinically significant cases of hyperthyroidism.[2][3][5][6] This autoimmune condition is characterized by the presence of thyrotropin-receptor antibodies, which can bind to thyroid receptors and activate them, leading to an increase in the production of thyroid hormones.[6]

Epidemiology

The overall prevalence of Graves' disease is 0.5%.[7] The incidence of hyperthyroidism in pregnancy is 0.1% to 0.2%.[8] Graves' disease most often occurs in women between the ages of 20 and 40, with the incidence increasing with age.[1] Clinically significant hyperthyroidism from other causes is much less common. For example, hyperthyroidism due to thyroid nodules is much less likely in people younger than 40, with an incidence of less than 0.001% to 0.002%.[9] In areas with known iodine deficiency, the prevalence of hyperthyroidism can be higher due to the development of functional thyroid nodules.[5]

Pathophysiology

Throughout pregnancy, multiple physiologic changes contribute to fluctuating levels of thyroid hormones. Due to the increased circulating estrogens, pregnancy results in a 50% increase in thyroxine-binding globulin (TBG), which binds circulating T4, decreasing free T4 levels. To compensate, the thyroid gland increases in size and doubles the production of T4 and T3.[2][8][9][10] Due to thyroid-stimulating hormone (TSH) homology with human chorionic gonadotropin (hCG), rising hCG levels in the first trimester lead to stimulation of the thyroid, in turn causing a further elevation in free T4.[5][7][9][11] 

Graves' disease involves thyrotropin receptor antibodies(TRAbs) that bind the TSH receptor and impact the production of thyroid hormones. These antibodies can be stimulatory or inhibitory. In Graves' disease, the net effect of TRAbs is stimulatory, causing a pathologic increase in free T4 that may require medical management.[2][3][5][9] Pregnancy results in a period of immunosuppression to avoid rejection of the developing fetus.[2] Antibody titers, including TRAbs, decrease as the pregnancy progresses, especially in the second and third trimesters. In the postpartum period, the immune system returns to the prepregnancy state, and antibody titers increase. This change increases the risk of relapse in Graves' disease or another condition known as postpartum thyroiditis.[2][10]

The developing placenta in pregnancy contains deiodinase type 3, which deactivates T4 and T3. Overactivity of this enzyme can result in hypothyroidism. Typically, this effect is offset by increased hCG production in early pregnancy, resulting in a net increase in free T4 and a decrease in median TSH.[9][12] This transient increase in free T4 usually resolves by midpregnancy as hCG levels plateau and decline.

History and Physical

Many signs and symptoms of hyperthyroidism mirror normal physiologic processes of pregnancy, including tachycardia and dyspnea.[5][9] Other symptoms of hyperthyroidism include diaphoresis, heat intolerance, palpitations, insomnia, frequent bowel movements, nervousness, increased appetite, pruritus, anxiety, and tremors. Physical examination findings may include goiter and hypertension. In individuals affected by Graves' disease, exophthalmos or proptosis is present in approximately 50% of cases, and pretibial myxedema is present in less than 10% of cases.[1][3][9] Identifying a history of Graves' disease is important even if surgery or radioiodine ablation was performed, since TRAbs may persist and cause fetal hyperthyroidism.[5][11]

Evaluation

When new-onset hyperthyroidism is suspected in pregnancy, laboratory evaluation is similar to that of the nongravid patient.[9] Evaluation begins with a TSH level, which is often decreased during pregnancy due to the stimulation of the thyroid by hCG, resulting in negative feedback on TSH production. If the TSH level is lower than the reference range, thyroid hormone levels should be checked to help differentiate overt hyperthyroidism from normal physiologic changes in pregnancy. Most commonly, free T4 levels are evaluated. Total levels of T4 and T3, free T4 index, or TBG may be clinically useful if available.[5][11][12][13]

The interpretation of these laboratory studies is different in the pregnant individual, as the normal values vary between trimesters and the nongravid state due to increasing levels of TBG.[9][11][13] Reference ranges for TSH are trimester-specific. TSH ranges from 0.1 to 2.5 mIU/L, 0.2 to 3.0 mIU/L, and 0.3 to 3.5 mIU/L in the first, second, and third trimesters.[7] If nonpregnant reference ranges are applied in error, misclassification of thyroid status can occur.[7] Individual laboratories must establish reference ranges for free T4.[13]

A definitive diagnosis of hyperthyroidism may be difficult due to normally fluctuating levels of thyroid hormone in pregnancy. If the diagnosis is uncertain, observing the thyroid level trends with further laboratory testing is appropriate rather than immediately starting antithyroid medication therapy.[12] Adverse outcomes have not been demonstrated with subclinical hyperthyroidism.[7][8][10] TRAbs are usually measurable in Graves' disease and can be used to confirm the diagnosis and differentiate it from gestational transient thyrotoxicosis.[2][5][11][13] 

Notably, the most frequently used assays do not distinguish between stimulatory and inhibitory TRAbs. If there is uncertainty about the diagnosis, more sensitive assays for stimulatory TRAbs can be used.[9] TRAbs should also be measured in any woman with a history of Graves' disease or a history of positive TRAbs, who has had a neonate affected by Graves' disease or has had recent radioiodine ablation or thyroidectomy. This screening is recommended by the American Thyroid Association and the Endocrine Society between 20 and 24 weeks of gestation.[2][3][5][13]

Treatment / Management

Hyperthyroidism in pregnancy is treated with medications that inhibit excessive thyroid hormone synthesis. The antithyroid drugs (ATDs) most commonly used in the United States are thioamides, propylthiouracil (PTU), and methimazole (MMI). Carbimazole is a prodrug of methimazole that is commonly used outside of North America, with a similar efficacy and adverse effect profile.[3][9][13] All ATDs can cross the placenta and affect the fetus.[2][5][6][8](A1)

Historically, PTU was commonly used for hyperthyroidism in all patients. However, it is associated with hepatotoxicity that can lead to liver failure and subsequent need for transplantation. Therefore, methimazole is more commonly used now if tolerated. An exception to this is during early pregnancy due to methimazole and carbimazole's association with a rare embryopathy, which includes aplasia cutis, abdominal wall defects, esophageal atresia, choanal atresia, eye abnormalities, urinary tract abnormalities, and circulatory defects.[2][5][8][14] After the first trimester, when the majority of organogenesis is complete, patients are then transitioned to methimazole. This transition is necessary to decrease the likelihood of hepatotoxicity.[2][5][11][15] PTU is associated with less severe congenital abnormalities that may not be discovered until years after birth. Some congenital defects noted at birth include unilateral kidney dysgenesis or agenesis, situs inversus, and cardiac outflow tract defects. These abnormalities typically occur in isolation as opposed to methimazole embryopathy, which is linked to a constellation of defects.[7][11][12] 

Due to the detrimental maternal health effects and the risk of fetal loss with untreated overt hyperthyroidism, treatment with ATDs is usually necessary, despite potential teratogenicity.[7][12] Untreated overt hyperthyroidism is also linked to congenital anomalies.[15] If a patient does not tolerate PTU, treatment with methimazole is preferred to no treatment at all, even in the first trimester.[16] ATDs cross the placenta and can correct fetal hyperthyroidism caused by maternal TRAbs. However, ATDs can overcorrect fetal hyperthyroidism even if the mother is euthyroid, causing fetal hypothyroidism. Thus, the goal of treatment is to use the lowest dose of antithyroid medication possible, with a TSH target slightly lower than the reference range and a maternal free T4 at the high end of normal.[2][3][5][11] If the TSH becomes normal, it likely means that the fetus is receiving too much ATD.[9](B2)

When treatment is initiated, dose-adjusted, or transitioned between drugs, thyroid function tests should be obtained to confirm a euthyroid state; testing can be performed every 2 to 4 weeks as indicated to ensure the maintenance of euthyroid status.[3][11][13] PTU and methimazole are both effective ATDs, but require different doses due to different pharmacokinetics. When switching, a 1:20 ratio of methimazole/PTU can be used as the initial conversion factor.[5] PTU is given 100 to 300 mg daily, divided into 3 doses due to a shorter half-life than methimazole, which is dosed 5 to 15 mg once daily.[9] Thus, switching between the drugs may result in a period of hyperthyroidism until the dose can be appropriately adjusted.[7](A1)

Due to natural immunosuppression during pregnancy, TRAb titers often decrease during the second half of pregnancy.[2][5][7][9] Titers can be remeasured in the third trimester, and if levels are low or undetectable, the clinician can consider tapering and discontinuing the antithyroid medication.[2][3][9][11] Adverse effects of thioamide therapy occur in up to 15% of women, with rash and pruritus being the most common.[1][3] Other reported effects include joint pain, fever, nausea, and changes in taste. More severe complications—such as agranulocytosis, vasculitis, sepsis, and hepatotoxicity—are rare.[1][9](A1)

Potassium iodide (KI) is another medication that can be used to treat mild hyperthyroidism. However, there have been limited studies in pregnancy. Most use in pregnancy has been in Japan, which has shown effectiveness in treating mild hyperthyroidism with minimal adverse effects. Of note is that Japan has a higher iodine intake than most of the world, so the effectiveness of KI cannot be extrapolated to other countries. Nevertheless, KI can be considered in women with mild hyperthyroidism who do not tolerate ATDs.[2][9][12]

Surgery is optimally performed outside of pregnancy. In women who do not attain adequate control of hyperthyroidism with high doses of ATDs, who have an allergy to ATDs, or who are poorly compliant with therapy, surgery can be considered. Surgery is also an option for patients who have a large goiter causing compression issues. Total or subtotal thyroidectomy can be performed in pregnancy, preferably in the second trimester, when the risk of fetal loss and complications is lowest.[2][3][5][11](B2)

If Graves' disease has been previously treated outside of pregnancy with thyroidectomy or ablative therapy, there may be TRAbs that persist. These antibodies are immunoglobulin G proteins and can cross the placenta, potentially causing fetal hyperthyroidism.[1][9][12] In this special scenario, treatment with a block-and-replace strategy may be warranted. This approach entails treating the fetal hyperthyroidism with ATD therapy while simultaneously maintaining maternal euthyroid status via levothyroxine, which does not cross the placenta as easily as ATDs.[5][9][12](A1)

Radioiodine ablation (RAI) is a procedure that can be used to destroy active thyroid tissue. However, RAI is absolutely contraindicated in pregnancy due to the ability of radioiodine to cross the placenta and subsequently ablate the fetal thyroid, leading to congenital hypothyroidism.[3][5][8][13] Before fetal thyroid development, RAI carries a risk for spontaneous abortion or fetal malformations. Women who elect to undergo RAI outside of pregnancy are advised to avoid conception for at least 6 months.[3][5][8][13] This recommendation ensures clearance of radioiodine and allows adequate timing to achieve a stable euthyroid state with levothyroxine.[13] Further, beta-blockers such as propranolol can be used in pregnancy for symptomatic control until a euthyroid state is maintained.[1][2][5] Once the euthyroid status is stable, beta-blockers should be discontinued due to the risk of intrauterine growth restriction, fetal bradycardia, and neonatal hypoglycemia with continued use.[2][3][9][16](A1)

Fetal Surveillance

The fetal thyroid has some function at 12 weeks, but fetal thyroxine levels are not sufficient until 18 to 20 weeks of gestation.[17] In women with Graves' disease, the fetal anatomy ultrasound provides an opportunity to screen for evidence of fetal thyroid anatomy and function. This survey should be completed between 18 and 22 weeks of gestation. Findings that may indicate thyroid dysfunction are an enlarged thyroid, intrauterine growth restriction, hydrops, advanced bone maturity, fetal tachycardia, goiter, oligohydramnios, or cardiac failure.[3][9][11][13](A1)

TRAb should be remeasured between 18 and 22 weeks and 30 and 34 weeks to evaluate the risk of fetal and neonatal hyperthyroidism, respectively.[2][5] While there is no consensus among professional societies, further monitoring may be indicated if TRAb levels exceed 3 times the upper limit of normal or if there is a history of a newborn affected by a thyroid disorder.[3] Further monitoring may include serial growth ultrasounds, amniotic fluid measurements, evaluation of the fetal heart rate, and fetal thyroid ultrasound to check for goiter.[3][5][11](B2)

Differential Diagnosis

While Graves' disease is the most common cause of clinically significant hyperthyroidism in pregnancy, other causes must be considered to determine if treatment is necessary.[9]

• Gestational transient thyrotoxicosis (GTT), also known as transient gestational hyperthyroidism (TGH), is the most common cause of transient hyperthyroidism in pregnancy, affecting 1% to 3% of pregnancies and thus is encountered more frequently than Graves' disease in pregnancy.[2][5][7][11] The transient hyperthyroidism is due to homology between the beta subunit of hCG and TSH. Increasing hCG levels in the first trimester cause weak stimulation of the thyroid, resulting in rises in free T4, total T4, and total T3 levels, as well as a decrease in the TSH level. This transient rise in thyroid hormone levels typically resolves by 14 to 20 weeks' gestation as hCG levels decline, and does not require treatment with antithyroid medication.[2][3][5][17] GTT is often associated with nausea and vomiting that can be as severe as hyperemesis gravidarum. Up to 50% to 70% of women with hyperemesis gravidarum present with hyperthyroidism.[1][3][7] GTT can be differentiated from Graves' hyperthyroidism by a lack of TRAbs. Those with GTT also lack goiter and ophthalmopathy on physical examination, and thyroid texture will appear normal on ultrasound.[2][7] The incidence of GTT increases with increasing hCG levels. Higher hCG levels are more likely to occur in multifetal gestations and molar pregnancies.[2][5] In GTT, hCG levels are usually higher than 200,000 IU/L.[7]
• Hydatidiform molar pregnancies are a type of gestational trophoblastic disease. Complete molar pregnancies are typically associated with extremely high hCG levels and may result in increased activation of TSH receptors.[9] Complete removal of the molar pregnancy by dilation and suction curettage is required for treatment.[8]
• Single toxic adenoma and toxic multinodular goiter involve autonomous nodules that produce thyroid hormones. These autonomous nodules are typically found in women aged 40 years or older.[2][7] Thyroid hormone production by these nodules is usually less than that of someone with Graves' disease. Thus, ATDs may not be necessary. If ATDs are used, there is a greater risk of fetal hypothyroidism than in Graves' disease, since there are no competing stimulatory TRAbs to activate the fetal thyroid.[5] Ultrasound can aid in the differential diagnosis, but a definitive diagnosis is made by thyroid scintigraphy. This procedure is absolutely contraindicated in pregnancy.[5]
• Subacute thyroiditis, also known as DeQuervain subacute thyroiditis, is a rare cause of thyroid inflammation precipitated by a viral infection, which can cause the release of thyroid hormones.[9]
• Mutations in the thyroid hormone receptor can cause resistance to thyroid hormone. These mutations lead to increased TSH levels and a further increase in circulating thyroid hormone, resulting in increased fetal exposure to thyroid hormone. Pregnant women with thyroid hormone resistance have an increased risk of spontaneous abortion.[9] There is also the possibility of TSH receptor mutations that cause hyperresponsiveness to hCG, leading to hyperthyroidism, similar to gestational transient thyrotoxicosis.[2][3][9]
• There are a few rare neoplastic causes of hyperthyroidism in pregnancy. Struma ovarii is a type of ovarian teratoma that contains functional thyroid tissue and can be a rare cause of hyperthyroidism in pregnancy.[1][9] A TSH-producing pituitary adenoma is a rare benign tumor of the pituitary gland that is capable of producing TSH.[9] In a patient with thyroid cancer, metastatic lesions may have some functionality and produce TSH.[9]
• Hyperthyroidism can also be caused by excessive intake of levothyroxine, used to treat hypothyroidism.[11]

Prognosis

With treatment and close laboratory observation, pregnancy outcomes are improved, and adverse outcomes are decreased.[3][9][10][11] Pregnant individuals are at the highest risk of complications if their overall control of hyperthyroidism is poor. If untreated, 10% of patients can experience congestive heart failure.[1] A thyroid storm is life-threatening and complicates about 1% to 2% of pregnancies affected by hyperthyroidism.[3] Many pregnant individuals experience remission of Graves' disease towards the end of pregnancy due to the immunosuppressive effects of pregnancy and associated decrease in TRAb titers.[12] There is also the possibility that TRAbs may switch from stimulating to inhibitory activity.[16]

There is an increased risk of exacerbation or relapse 3 to 18 months after delivery due to the rebounding immune system, with the highest risk 7 to 9 months postpartum.[5][11][12] Most people who are in remission from Graves' disease before pregnancy will relapse postpartum or experience thyroiditis.[1] Thyroid hormones play a crucial role in the neurocognitive development of the fetus, as well as in fetal growth. Other complications seen with hyperthyroidism in pregnancy include preeclampsia, preterm birth, and fetal hyperthyroidism.[4]

Complications

Treatment of overt hyperthyroidism in pregnancy is essential to decrease the risk of maternal and fetal complications. Maternal complications include an increased risk of pregnancy loss, gestational hypertension, preeclampsia, placental abruption, and preterm labor. When thyrotoxicosis progresses to a thyroid storm, there is an increased risk of congestive heart failure, admission to the intensive care unit, and maternal death.[2][3][5][14] Management of thyroid dysfunction may decrease the maternal risk of preeclampsia.[18]

Appropriate levels of thyroid hormones are also important for fetal development. Thyroid hormones impact brain morphology by regulating fetal neuronal cell migration, growth, and differentiation.[3] Fetal complications of hyperthyroidism include prematurity, low birth weight, goiter, tachycardia, fetal hydrops, cardiac failure, early bone maturation, intrauterine growth restriction, neurodevelopmental abnormalities, and other congenital anomalies. Fetal effects can be attributed to the transplacental passage of excess thyroid hormone or TRAbs, which subsequently activate the fetal thyroid.[2][5][13][15] The risk of fetal effects increases with increasing maternal TRAb concentrations.[2]

Overtreatment with ATDs in pregnancy can cause fetal hypothyroidism. Conversely, women who receive adequate antithyroid treatment during pregnancy usually give birth to a euthyroid neonate. However, TRAbs that previously crossed the placenta will still be present. ATDs are metabolized by the newborn within 2 to 3 days of birth. TRAbs can then cause neonatal hyperthyroidism, affecting 1.5% to 2% of neonates in mothers with Graves' disease. This may resolve within a few weeks or persist for 4 to 6 months.[2][5][9][11] If neonatal hyperthyroidism persists, it is associated with 27% morbidity and 1.2% mortality.[11] Possible sequelae include heart failure, hepatic dysfunction, microcephaly, craniostenosis, pulmonary hypertension, coagulopathy, and intellectual disability.[11]

Thyroid Storm

A thyroid storm is a life-threatening complication that can occur when hyperthyroidism is uncontrolled. The complication is a manifestation of the most decompensated state of the disease. In addition to uncontrolled hyperthyroidism, there is usually a precipitating event before a thyroid storm. These events can include labor, cesarean section, preeclampsia, trauma, hypoglycemia, diabetic ketoacidosis, or an infection.[2][3][9][19] Patients may present with severe tachycardia, tachyarrhythmias, mental status changes, heat intolerance, fever, nausea and vomiting, diarrhea, congestive heart failure, and multiorgan failure.

In addition to ATDs, thyroid storm requires intensive care admission, electrolyte replacement, fluid resuscitation, cooling, and oxygen. Propylthiouracil or methimazole can be used to stop thyroid hormone synthesis. At least 1 hour after ATD therapy, potassium iodide or Lugol solution can be given to block further hormone release from the thyroid. If given before or too soon after ATDs, KI can worsen the thyroid storm. Beta-blockers can be used to improve tachycardia and tachyarrhythmias. High-dose glucocorticoids can also decrease the peripheral conversion of T4 to T3. If heart failure is present, digoxin can increase cardiac output.

Addressing the precipitating event of thyroid storm, such as antibiotics, in cases of an underlying infection, is also extremely important. If the patient is febrile, acetaminophen should be used instead of aspirin, as aspirin can increase circulating thyroid hormones.[3][9][19] On initial presentation, fetal distress may be noted. As the mother receives treatment, the fetal status may improve. Delivery should be avoided if possible, since both labor and cesarean section can worsen thyroid storm.[3]

Postpartum Thyroiditis

Postpartum thyroiditis (PPT) is a condition that typically occurs within 6 weeks of delivery but may happen up to 1 year postpartum due to immune rebound after normal immunosuppression of pregnancy.[8][9] Antithyroid peroxidase antibodies are present, and TRAbs are typically absent.[8] Often, there is a period of transient hyperthyroidism caused by autoimmune destruction of thyroid tissue and subsequent release of thyroid hormone stores.[8][9] This is then followed by a period marked by hypothyroidism, which may persist.[8][9] Differentiating PPT from new-onset Graves' disease is important. PPT does not require treatment with ATDs, as hyperthyroidism is transient. However, beta-blockers can be used for symptomatic control during this period.[8][9] The overall incidence of PPT is 5.4%. Women with type 1 diabetes mellitus are at a 3 to 4 times higher risk.[8]