Hyperthyroidism is an uncommon condition that complicates approximately 0.1% to 0.4% of pregnancies. The condition is marked by increased levels of circulating thyroid hormones, T4 and T3, as well as a decreased level of thyroid-stimulating hormone (TSH), also known as thyrotropin. Though relatively rare, identification and treatment of overt hyperthyroidism are important to mitigate maternal and fetal complications. Ideally, hyperthyroidism is diagnosed before conception, and treatment is started to achieve euthyroid status. However, up to half of all pregnancies in the United States are unplanned, making an early diagnosis of thyroid dysfunction imperative. This review addresses the etiology, epidemiology, pathophysiology, and initial evaluation of hyperthyroidism in pregnancy, followed by a discussion of treatment, management, and complications.
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. This autoimmune condition is marked by the presence of thyrotropin (TSH)-receptor antibodies (TRAb), which can bind to thyroid receptors and cause their activation, leading to increased production of thyroid hormones.
The overall prevalence of Graves disease is 0.5%. The incidence of hyperthyroidism in pregnancy is 0.1% to 0.2%. Graves disease most often occurs in women between the ages of 20 and 40, with the incidence increasing with age. Clinically significant hyperthyroidism from other causes is much less common. For example, hyperthyroidism due to thyroid nodules is much less likely in women under the age of 40, with an incidence of less than 0.001% to 0.002%. In areas with known iodine deficiency, the prevalence of hyperthyroidism can be higher due to the development of functional thyroid nodules.
Throughout pregnancy, multiple physiologic changes contribute to fluctuating levels of thyroid hormones. Due to increased circulating estrogens, pregnancy brings a 50% increase in thyroxine-binding globulin (TBG), which binds circulating T4, causing a decrease in free T4 levels. To compensate, the thyroid grows in size and increases the production of T4 and T3 by 50%. Due to TSH's 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. The hCG levels peak between 8 to 12 weeks' gestation and gradually decrease thereafter.
Conversely, the developing placenta contains deiodinase type 3 (DIO3), which deactivates T4 and T3. Excessive function by this enzyme can lead to hypothyroidism. Typically, this effect is outweighed by increased hCG production in early pregnancy, leading to a net increase in free T4 with a decreased median TSH and reference range. This transient increase in free T4 usually resolves by mid-pregnancy as hCG levels plateau and decline.
There is also an increased dietary iodine requirement, from 150 micrograms to 250 micrograms daily, due to increased thyroid hormone synthesis during pregnancy. There is also an appreciable loss of iodine in urine due to the increased glomerular filtration rate in pregnancy.
Graves disease involves 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 usually requires medical management.
Pregnancy results in a period of immunosuppression to avoid rejection of the developing fetus. 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 pre-pregnancy state, and antibody titers increase. This increases the risk of relapse in Graves disease or another condition known as postpartum thyroiditis.
Many signs and symptoms of hyperthyroidism mirror normal physiologic processes of pregnancy, including tachycardia and dyspnea. Other symptoms of hyperthyroidism include diaphoresis, heat intolerance, palpitations, insomnia, frequent bowel movements, nervousness, increased appetite, pruritus, anxiety, and tremors. Physical exam findings may include goiter and hypertension. In those affected by Graves disease, exophthalmos or proptosis is present approximately 50% of the time, and pretibial myxedema less than 10% of the time.
When new-onset hyperthyroidism is suspected in pregnancy, laboratory evaluation is similar to the non-gravid patient. Evaluation starts with a TSH level, which is often decreased in pregnancy due to the stimulation of the thyroid by hCG, causing 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.
The interpretation of these laboratory studies is different in the pregnant patient, as the normal values vary between trimesters and the non-gravid state due to increasing levels of TBG. 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, respectively. If non-pregnant reference ranges are applied in error, misclassification of thyroid status can occur. Free T4 reference ranges need to be established by individual laboratories.
A definitive diagnosis of hyperthyroidism may be difficult due to normally fluctuating levels of thyroid hormone in pregnancy. If the diagnosis is uncertain, it is appropriate to observe the thyroid level trends with further laboratory testing rather than immediately start antithyroid drug therapy. Adverse outcomes have not been demonstrated with subclinical hyperthyroidism. TRAbs are usually measurable in Graves disease and can be used to confirm the diagnosis and differentiate from gestational transient thyrotoxicosis. It is important to note that the most frequently used assays do not differentiate between stimulatory and inhibitory TRAbs. If there is uncertainty about the diagnosis, more sensitive assays for stimulatory TRAbs can be used. TRAbs should also be measured in any woman with a history of Graves disease or 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 to 24 weeks’ gestation.
Hyperthyroidism in pregnancy is treated with medications that inhibit excessive thyroid hormone synthesis. The antithyroid drugs (ATD) most commonly used in the U.S. are the thioamides, propylthiouracil (PTU) and methimazole (MMI). Carbimazole is a prodrug of methimazole that is commonly used outside of North America, with similar efficacy and side effect profile. All ATDs can cross the placenta and affect the fetus.
Historically, PTU was commonly used for hyperthyroidism in all patients. However, it is associated with hepatoxicity 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. 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. PTU is associated with less severe birth defects 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 defects typically occur in isolation as opposed to methimazole embryopathy, which is linked to a constellation of defects. Due to the detrimental maternal health effects and the risk of fetal loss with untreated overt hyperthyroidism, treatment with antithyroid drugs is usually necessary, despite potential teratogenicity. If a patient does not tolerate PTU, treatment with methimazole is preferred to no treatment at all, even in the first trimester. 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. If the TSH becomes normal, it likely means that the fetus is receiving too much ATD.
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. PTU and methimazole are both effective antithyroid drugs but require different doses due to different pharmacokinetics. When switching, a 1 to 20 ratio of methimazole/PTU can be used as the initial conversion factor. PTU is given 100 to 300 mg daily between three doses due to a shorter half-life than methimazole, which is dosed 5 to 15 mg once daily. Thus, switching between the drugs may result in a period of hyperthyroidism until the dose can be appropriately adjusted.
Due to the natural immunosuppression during pregnancy, TRAb titers often decrease during the second half of pregnancy. Titers can be remeasured in the third trimester, and if levels are low or undetectable, the physician can consider tapering and discontinuing the antithyroid medication.
Side effects of thioamide therapy occur in up to 15% of women. The most common side effects are rash and pruritus. Other side effects include joint pain, fever, nausea, and taste alterations. More serious side effects like agranulocytosis, vasculitis, sepsis, and hepatotoxicity are rarer.
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, 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.
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 are poorly compliant with therapy, surgery can be considered. Surgery is also an option in 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.
If Graves disease has been previously treated outside of pregnancy with thyroidectomy or ablative therapy, there may be TRAbs that persist. These antibodies are IgG proteins and can cross the placenta and cause fetal hyperthyroidism. In this special scenario, treatment with a block-and-replace strategy may be warranted. This entails treating the fetal hyperthyroidism with antithyroid drug therapy while simultaneously maintaining maternal euthyroid status via levothyroxine, which does not cross the placenta as easily as ATDs.
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. 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. This ensures clearance of radioiodine and allows adequate timing to achieve a stable euthyroid state with levothyroxine.
Beta-blockers such as propranolol can be used in pregnancy for symptomatic control until a euthyroid state is maintained. 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.
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 to 22 weeks' 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.
TRAb should be remeasured between 18 to 22 weeks and 30 to 34 weeks to evaluate the risk of fetal and neonatal hyperthyroidism, respectively. While there is no consensus in professional societies, further monitoring may be used if TRAb levels are greater than 3 times the upper limit of normal or if there is a history of a newborn affected by a thyroid disorder. Further monitoring may include serial growth ultrasounds, amniotic fluid index, evaluation of the fetal heart rate, and fetal thyroid ultrasound to check for goiter.
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.
Gestational transient thyrotoxicosis (GTT), also known as transient gestational hyperthyroidism (TGH), is the most common cause of transient hyperthyroidism in pregnancy. It affects 1% to 3% of pregnancies and thus is encountered more frequently than Graves disease in pregnancy. 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 and subsequently causes rises in the 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 14-20 weeks’ gestation as hCG levels decline, and does not require treatment with antithyroid medication. 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. GTT can be differentiated from Graves induced hyperthyroidism by a lack of TRAbs. Those with GTT also lack goiter and ophthalmopathy on physical exam, and thyroid texture will appear normal on ultrasound. The incidence of GTT increases with increasing hCG levels. Higher hCG levels are more likely to occur in multifetal gestations and molar pregnancies. In GTT, hCG levels are usually higher than 200,000 IU/L.
Hydatidiform molar pregnancies are a type of gestational trophoblastic disease. Complete molar pregnancies are usually accompanied by incredibly high hCG levels and thus can have increased activation of TSH receptors. Complete removal of the molar pregnancy by dilation and suction curettage is required for treatment.
Single toxic adenoma and toxic multinodular goiter involve autonomous nodules that produce thyroid hormone. These autonomous nodules are usually found in women who are at least 40 years old. Thyroid hormone production by these nodules is usually less than in someone with Graves disease. Thus, antithyroid drugs may not be necessary. If antithyroid drugs 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. Ultrasound can aid in the differential diagnosis, but a definitive diagnosis is made by thyroid scintigraphy. This procedure is absolutely contraindicated in pregnancy.
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.
There can be mutations in the thyroid hormone receptor that cause resistance to thyroid hormone. This leads to increased TSH levels and a further increase in circulating thyroid hormone and increases fetal exposure to thyroid hormone. Pregnant women with thyroid hormone resistance have an increased risk of spontaneous abortion. There is also the possibility of TSH receptor mutations that cause hyperresponsiveness to hCG leading to hyperthyroidism, similar to gestational transient thyrotoxicosis.
There are a few rare neoplastic causes of hyperthyroidism in pregnancy. Struma ovarii is a type of ovarian teratoma that contains functional thyroid tissue. This can be a rare cause of hyperthyroidism in pregnancy. A TSH-producing pituitary adenoma is a rare benign tumor of the pituitary gland that is capable of producing TSH. In a patient with thyroid cancer, metastatic lesions may have some functionality and produce TSH.
Hyperthyroidism can also be caused by excessive intake of levothyroxine used to treat hypothyroidism.
With treatment and close laboratory observation, pregnancy outcomes are improved, and adverse outcomes are decreased. Women are at the highest risk of complications if their overall control of hyperthyroidism is poor. If untreated, 10% of women can experience congestive heart failure. Thyroid storm is life-threatening and complicates about 1% to 2% of pregnancies affected by hyperthyroidism.
Many pregnant women experience remission of Graves disease towards the end of pregnancy due to the immunosuppressive effects of pregnancy and associated decrease in TRAb titers. There is also the possibility that TRAbs may switch from stimulating to inhibitory activity.
There is an increased risk of exacerbation or relapse in the 3 to 18 months after delivery due to the rebounding immune system, with the highest risk 7 to 9 months postpartum. Most women who are in remission from Graves disease before pregnancy will relapse postpartum or experience thyroiditis.
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 thyroid storm, there is an increased risk of congestive heart failure, admission to intensive care, and maternal death. Appropriate levels of thyroid hormones are important for fetal development. Thyroid hormones are known to impact brain morphology by regulating migration, growth, and differentiation of fetal neuronal cells. Fetal complications of hyperthyroidism include prematurity, low birth weight, goiter, tachycardia, fetal hydrops, cardiac failure, early bone maturation, intrauterine growth restriction, and neurodevelopmental abnormalities. Fetal effects can be either due to transplacental passage of excess thyroid hormone or TRAbs that subsequently activate the fetal thyroid. The risk of fetal effects increases with increasing maternal TRAb concentrations.
Overtreatment with antithyroid drugs 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. Antithyroid drugs are metabolized by the newborn within 2 to 3 days of birth. TRAbs can then cause neonatal hyperthyroidism, affecting 15 to 2% of neonates in mothers with Graves disease. This may resolve within a few weeks or persist for 4 to 6 months. If neonatal hyperthyroidism persists, it is associated with 27% morbidity and 1.2% mortality. Possible sequelae include heart failure, hepatic dysfunction, microcephaly, craniostenosis, pulmonary hypertension, coagulopathy, and intellectual disability.
Thyroid storm is a life-threatening complication that can occur when hyperthyroidism is uncontrolled and is a manifestation of the most decompensated state of 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, or an infection. Patients may present with severe tachycardia, tachyarrhythmias, mental status changes, heat intolerance, fever, nausea and vomiting, diarrhea, congestive heart failure, and multi-organ failure. In addition to antithyroid drugs, thyroid storm requires intensive care admission, electrolyte replacement, fluid resuscitation, cooling, and oxygen. PTU or methimazole can be used to stop thyroid hormone synthesis. At least 1 hour after ATD therapy, potassium iodide or Lugol’s 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 be given to decrease the peripheral conversion of T4 to T3. If heart failure is present, digoxin can be used to increase cardiac output. It is also important to address the precipitating event of thyroid storm, such as antibiotics, for an underlying infection. If the patient is febrile, acetaminophen should be used rather than aspirin, since aspirin can increase circulating thyroid hormones.
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 or cesarean section can worsen thyroid storm.
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. Antithyroid peroxidase antibodies are present, and TRAbs are typically absent. Often, there is a period of transient hyperthyroidism caused by autoimmune destruction of thyroid tissue and subsequent release of thyroid hormone stores. This is then followed by a period marked by hypothyroidism, which may persist. It is important to differentiate PPT from new-onset Graves disease. PPT does not require treatment with ATDs, as the hyperthyroidism is transient. However, beta-blockers can be used for symptomatic control during this period. The overall incidence of PPT is 5.4%. Women with type 1 diabetes mellitus are at 3 to 4 times higher risk.
Women who are planning to get pregnant often seek pre-conceptual counseling. In women with Graves disease, this is an opportune time to discuss treatment options before pregnancy. Some women may opt to undergo surgery or radioiodine ablation (RAI) to cure their Graves hyperthyroidism, especially in women with high TRAb titer or history of fetal thyroid issues in a previous pregnancy. Surgery may be preferred to RAI in women with especially high titers, as RAI can initially increase TRAb titers. This route potentially mitigates the need for antithyroid drugs and avoids the adverse maternal side effects and potential teratogenicity from PTU and methimazole, but requires thyroid hormone replacement for life. Thyroid hormone levels need to be optimized with levothyroxine before pregnancy. In some cases, TRAbs persist and can cross the placenta and cause fetal hyperthyroidism, necessitating a block-and-replace strategy as detailed above.
Most non-pregnant women with Graves disease use methimazole due to a lower risk of hepatotoxicity than PTU. Some women may prefer to switch to PTU before becoming pregnant. If a patient chooses to remain on methimazole until after becoming pregnant, it is important to counsel the patient on the risk of methimazole embryopathy if she is not changed to PTU before organogenesis. When compared to the risk of methimazole embryopathy, the risk of PTU-induced hepatotoxicity is lower.
Subclinical hyperthyroidism is typically not associated with adverse effects and does not require treatment. Treatment could lead to fetal hypothyroidism and adverse outcomes. Using the correct trimester-specific reference ranges and interpreting them appropriately aids in avoiding unnecessary treatment while also avoiding adverse outcomes of undertreatment.
Breastfeeding is not contraindicated while on ATDs as long as the dose is low. Women should take their ATD right after breastfeeding to allow some metabolism before their next lactation. If ATD doses are high, monitoring of neonatal free T4 is warranted. PTU passes into breast milk to a lesser degree than methimazole, but methimazole is preferred since PTU can cause maternal hepatotoxicity. Radioiodine ablation of the maternal thyroid is absolutely contraindicated when breastfeeding due to I-131 passage into breastmilk and its concentration in maternal breast tissue.
The concept of universal screening for thyroid disease in pregnancy has been a point of controversy. While professional obstetric societies recommend targeted screening for thyroid disease in those who are at high risk for thyroid dysfunction, there are some arguments for universal screening. Thyroid function tests are relatively low cost. If all pregnant women are screened for thyroid disease at the initial prenatal visit, many cases of both overt hyperthyroidism and hypothyroidism can be diagnosed earlier. This allows for earlier intervention to optimize thyroid hormone levels to decrease maternal and fetal risks.
Without universal screening, all members of the health care team should be aware of the symptoms of hyperthyroidism in pregnancy to know when to screen for thyroid disease. Physicians, physician assistants, nurse practitioners, nurses, and medical assistants should all know how to take a history that includes previously diagnosed thyroid disease, including any thyroid procedures.
Primary care providers and endocrinologists should inquire whether a patient with Graves disease is planning future pregnancies. This allows the patient to optimize their thyroid hormone levels with appropriate medication and to get adequate counseling during the preconception period, as it is recommended to postpone conceptions until the patient is euthyroid and stable. Any changes to an antithyroid medication regimen should be made by five weeks gestation to minimize the exposure to inappropriate medication and to optimize thyroid hormone levels early in the pregnancy.
Neonatology should be made aware of following neonates born to women with Graves disease for signs and symptoms of transient hyperthyroidism or neonatal Graves disease due to TRAbs that crossed the placenta before birth.
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