Thyroid Disease and Pregnancy

Etiology

Hypothyroidism

Overt hypothyroidism is defined as a low free T4 (FT4) with high thyroid stimulating hormone (TSH) levels. Worldwide, iodine deficiency is the main cause of overt hypothyroidism; in areas where iodine intake is sufficient, the most frequent cause is autoimmune thyroiditis (Hashimoto thyroiditis).[5][6] Subclinical hypothyroidism is defined as a normal free T4 with high TSH levels and is by far the most frequent thyroid dysfunction occurring in pregnancy. The prevalence depends on the definition of subclinical hypothyroidism, ethnicity, iodine intake, and study design. In most areas, prevalence is between 1.5% and 4.0%.[5]

The American Thyroid Association defines primary maternal hypothyroidism as an elevation of TSH, in the absence of the very rare causes of secondary hypothyroidism, such as pituitary tumors, central hypothyroidism, or thyroid resistance. Data suggests that pregnant women have a lower TSH upper limit than non-pregnant women (2.5-3.0 mU/L vs 4.0 mIU/L in non-pregnant women). Thus, overt hypothyroidism is defined as TSH exceeding 2.5 mU/L with low free T4 or TSH exceeding 10 mU/L regardless of T4 levels.[1] Some suggest using an upper limit of 2.5 mU/L in the first trimester and 3.0 mU/L in the second 2 trimesters.[7]

Overt maternal hypothyroidism has serious deleterious effects on the fetus and, as such, should be avoided. Additionally, there are greater risks of adverse events in women who are thyroid peroxidase antibody (TPOAb) positive compared to those who are TPOAb-negative. These adverse effects are independent of T3/T4 levels. Therefore, pregnant women with a TSH over 2.5 mU/L should be assessed for their TPOAb status.[7][8]

Hyperthyroidism

Thyrotoxicosis can manifest in pregnancy in 3 forms: gestational thyrotoxicosis, subclinical hyperthyroidism, and overt hyperthyroidism. Gestational hyperthyroidism is a time-limited form of thyrotoxicosis caused by human chorionic gonadotropin's excessive stimulation of the thyroid gland and is usually limited to the first trimester of pregnancy; this is more common in women with hyperemesis gravidarum and multiple gestations.[9] Subclinical hyperthyroidism is defined by TSH under the standard limit with average T4/T3 values, respecting the TSH and T4/T3 pregnancy reference values by trimester.[10]

As the body’s autoimmune response generally decreases as pregnancy progresses, the incidence of Graves hyperthyroidism decreases in the second and third trimesters after a slight increase in the first trimester.[7] Distinguishing between gestational transient thyrotoxicosis and Graves disease is important, as the disease course and treatment options differ. Gestational transient thyrotoxicosis (GTT) is mediated by high serum levels of hCG occurring in early pregnancy. As high levels of hCG are also associated with hyperemesis, GTT is usually associated with symptoms of nausea and vomiting. In both GTT and Graves disease, laboratory testing will demonstrate suppressed serum levels of TSH and elevated thyroid hormone levels. Patients with Graves disease often have an increased ratio of T3 to T4 (≥20:1), as preferential production of T3 occurs in Graves disease. By contrast, serum levels of T3 are often lower in women with GTT in the setting of hyperemesis.[7]

Of note, antibodies specific for the thyrotropin receptor (TRAb) are generally detectable in Graves disease but are absent in GTT. TRAb can be assessed as TSH receptor-binding immunoglobulin, which measures stimulating and blocking antibodies without distinction. Alternatively, thyroid-stimulating immunoglobulin can be measured, specifically by measuring the stimulation of TRAb.[11] Anti-thyroperoxidase antibodies, present in up to 80% of patients with this condition, are also common in Graves disease.[12]

Other Forms of Hyperthyroidism and Thyrotoxicosis

Graves disease and GTT are by far the most common causes of hyperthyroidism/thyrotoxicosis in pregnant women.[7][13] While hyperthyroidism (excess hormone production by the thyroid) is the most common form of thyrotoxicosis (excess thyroid hormone from any cause), other less common causes can cause thyrotoxicosis in pregnancy. These uncommon causes include thyroiditis, toxic multinodular goiter, toxic adenoma (ie, follicular adenoma), iodine-induced and drug-induced thyroid dysfunction, and factitious ingestion of excess thyroid hormones. These causes can often be differentiated based on the history, eg, a history of recent illness, iodine exposure, or psychiatric disorder.[2][7][14]

• Single toxic adenoma and toxic multinodular goiter involve autonomous nodules that produce thyroid hormones. These autonomous nodules are usually found in women aged 40 or older.[3] 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 as there are no competing stimulatory TRAbs to activate the fetal thyroid.[15] Ultrasound can aid in the differential diagnosis, but a definitive diagnosis is made by thyroid scintigraphy. However, scintigraphy procedures are contraindicated in pregnancy.[4][15]
• 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.
• Mutations in the thyroid hormone receptor can cause resistance to the thyroid hormone. This leads to increased TSH levels 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.[3][4][13]
• A few rare neoplastic causes result in hyperthyroidism in pregnancy. Struma ovarii is a type of ovarian teratoma that contains functional thyroid tissue.[2][13] A TSH-producing pituitary adenoma is another rare benign pituitary gland tumor capable of producing TSH. In a patient with thyroid cancer, metastatic lesions may have some functionality and produce TSH.[13] Please see the Medical Oncology section below.

Epidemiology

During pregnancy, spontaneous hypothyroidism has a prevalence of about 2% to 3%, with 0.3% to 0.5% of women presenting with overt hypothyroidism and 2% to 2.5% with subclinical hypothyroidism (elevated TSH but normal T3/T4).[16] On the other hand, overt hyperthyroidism can affect up to 0.1% to 0.4% of pregnancies.[17] Graves disease and GTT are the 2 most common causes of hyperthyroidism in pregnancy. The prevalence of new-onset Graves disease in pregnant women is estimated to be 0.05%, whereas that of GTT ranges from 2% to 11%.[7][18]

Pathophysiology

Normal Thyroid Physiology During Pregnancy

During pregnancy, the maternal body's metabolic needs are increased, resulting in changes in thyroid physiology. These changes in thyroid physiology are reflected in altered thyroid function tests. The different changes are as follows:

• Increased serum thyroxine-binding globulin (TBG) leads to an increase in the total T4 and T3 concentrations. Their levels peak by approximately week 16 of gestation and remain high until delivery.[19] 
• Stimulation of the TSH receptor by hCG increases thyroid hormone production and reduces serum TSH concentration.[14]

Therefore, women tend to have lower serum TSH concentrations during pregnancy than those in the nonpregnant state. Study results have shown that 15% of healthy women during the first trimester of pregnancy have TSH below the non-pregnant lower limit of 0.4 mU/L.[20] Studies have shown the overall prevalence of thyroid peroxidase antibody (TPOAb) in women of childbearing age is between 6% and 20%, and these women are at increased risk of developing hypothyroidism.[21] 

Trimester-Specific Ranges

The serum TSH concentration is the initial and most reliable measure of thyroid function during pregnancy.[22] As elaborated above, physiologic changes in TSH levels during pregnancy warrant close monitoring of TSH levels. Per the latest American Thyroid Association (ATA) guidelines, serum TSH levels during pregnancy should be defined using population and trimester-specific reference ranges. When population and trimester-specific normal ranges are unavailable, the ATA guidelines recommend reducing the lower limit of TSH by 0.4 mU/L and the upper limit by 0.5 mU/L. Free T4 levels measured by immunoassays are unreliable during pregnancy due to changes in binding proteins. Alternatively, measuring total T4 levels or free T4 index may be more reliable.[23]

Iodine Requirement During Pregnancy

There is an increase in iodine requirement during pregnancy due to increased maternal thyroid hormone production, as well as an increase in renal iodine clearance. Along with the above 2 factors, there is also a fetal iodine requirement; therefore, dietary iodine requirements are higher during pregnancy.[24] Women with sufficient iodine intake before and during pregnancy can easily adapt to the increased demand for thyroid hormone during pregnancy. However, in areas of iodine deficiency, where iodine requirements are not optimally replenished, maternal iodine deficiency frequently results. This has adverse effects on the fetus, including poor neurologic, cognitive, and musculoskeletal development.

The World Health Organization (WHO) recommends daily 250 mcg of iodine intake during pregnancy and lactation.[25] The ATA guidelines recommend that all pregnant women consume approximately 250 mcg of iodine daily. In the United States, women planning a pregnancy or are currently pregnant should supplement their diet with a daily oral supplement containing 150 mcg of iodine in potassium iodide, starting 3 months before a planned pregnancy. Excessive iodine intake should be avoided during pregnancy, as it is also harmful and causes fetal hypothyroidism and goiter. As per WHO recommendations, the maximum permissible intake of iodine during pregnancy is 500 mcg daily.[26][27]

Hyperthyroidism 

Women with Graves disease typically report thyrotoxic symptoms, such as unintentional weight loss, palpitations, hand tremors, and heat intolerance, which may have been present before pregnancy. By contrast, patients with GTT rarely have severe thyrotoxic symptoms, and they lack typical signs of Graves disease, such as diffuse goiter and Graves ophthalmopathy. GTT spontaneously resolves as hCG levels decrease after about 10 to 12 weeks gestation, and the condition is not associated with adverse pregnancy outcomes.[11][28][29]

Histopathology

On pathologic examination of Hashimoto thyroiditis, a diffuse, symmetric thyroid enlargement is present. The capsule is often intact with a prominent pyramidal lobe. When cut, the surface is similar to that of lymph nodes, with a pale brown to yellow color. Interlobular fibrosis may or may not be present. Atrophy may also occur; in some patients, the gland may become nodular or asymmetric. However, necrosis or calcification does not occur and would suggest a different diagnosis.[30]

Graves disease is characterized by parenchymatous hypertrophy and hyperplasia. The central features are increased epithelium height and varying sizes and shapes of the follicles with reduced colloids. Lymphocytic and plasma cell infiltration is common between the follicles and may even contain lymphoid germinal centers. Other findings include papillary infoldings, cytologic evidence of increased activity, hypertrophy of the Golgi apparatus, increased number of mitochondria, and increased vacuolization of colloid. Significant overlap with the pathology appearance of Hashimoto disease is possible. All pathological changes tend to regress when euthyroidism is achieved.[12]

History and Physical

Hypothyroidism

The history and physical examination in pregnant women with hypothyroidism are similar to those with hypothyroidism in nonpregnant adults. Many women are asymptomatic, while others may have fatigue, constipation, weight gain, cold intolerance, muscle cramps, and problems with memory or concentration. Physical examination findings may include dry skin, puffiness of the face, periorbital edema, delayed relaxation of deep tendon reflexes, and bradycardia. Of note, some of these symptoms and signs of hypothyroidism can also be seen in normal pregnancy, so clinicians should not hesitate to order thyroid function tests when in doubt.[26]

Infants whose mothers experienced hypothyroidism during pregnancy are at risk of hypothyroidism themselves, which can impair cognitive development, possibly leading to mental retardation. In addition, they can develop a compressive goiter, requiring treatment.[7][8] Observations suggest an increased incidence of jaundice in neonates with hypothyroid mothers during pregnancy and a possible link to hypocalcemia, respiratory distress, urogenital malformations, and cardiovascular abnormalities.[26] 

Hyperthyroidism

Similarly, history and physical examination in pregnant women with thyrotoxicosis are indistinguishable from hyperthyroidism in non-pregnant adults. Some symptoms of hyperthyroidism may include palpitations, excessive sweating, heat intolerance, anxiety, insomnia, weight loss, and tremors. Physical examination findings may include tachycardia, lid lag, stare, diaphoresis, and hyperreflexia. Findings specific to Graves disease include diffuse goiter, ophthalmopathy (exophthalmos), and pretibial myxedema.

Evaluation

Hypothyroidism

Hypothyroidism during pregnancy is defined as elevated TSH levels above the population and trimester-specific reference range. This can present as overt hypothyroidism, defined as increased trimester-specific TSH and low free T4 levels, or subclinical hypothyroidism, defined as increased trimester-specific TSH and normal free T4 levels. Hypothyroidism is diagnosed based on a low free T4 or total T4 and high TSH (except for rare cases of central hypothyroidism where TSH will also be low). In pregnancy, there are changes in the ranges of both these hormones requiring the use of gestational trimester-specific reference ranges.

Thyroid antibody testing (thyroid peroxidase antibody) confirms the autoimmune nature of hypothyroidism and may also identify antibody-positive women who are at risk of postpartum thyroiditis. Subclinical hypothyroidism is diagnosed when TSH is above the reference range while the T4 level is normal. The TSH level is difficult to interpret during the first trimester due to the weak thyromimetic action of hCG. Isolated hypothyroxinemia occurs most frequently in the third trimester. The clinical significance is not clear as it may arise due to hemodilution. 

Hypothyroidism diagnosed during pregnancy can be treated according to TSH levels and should be titrated to achieve a target TSH in the lower half of the trimester-specific reference range. If these are unavailable locally, maternal TSH concentrations should be maintained at less than 2.5 mU/L in the first trimester and less than 3.0 mU/L in the second and third trimesters.[13] Typical dosing in those who are levothyroxine-naïve is demonstrated in Table. Dosing in levothyroxine-naïve hypothyroidism individuals diagnosed during pregnancy below. Dosage typically increases by approximately 30% to 50% compared to the pre-pregnancy dose.[7] Thyroid function tests should be performed every 4 to 6 weeks to ensure adequate dosing in response to the TSH levels. However, it should be noted that there are substantial population differences in the 'normal’ TSH upper reference limit, and significant changes from a prior baseline should also be noted.[7][26]

Table. Dosing in levothyroxine-naïve hypothyroidism individuals diagnosed during pregnancy 

Thyroid Antibodies in Euthyroid Pregnant Women

Studies have shown the overall prevalence of TPOAb in women of childbearing age is 6% to 20%.[21] These women are at higher risk of developing hypothyroidism during pregnancy, and therefore, thyroid function should be monitored in these women. Additionally, study results have shown that TPOAb positivity has been associated with spontaneous pregnancy loss as well as an increased risk of preterm delivery.[31] At present, there is not sufficient evidence to warrant supplementation of levothyroxine in euthyroid pregnant women with TPOAb positivity. A small dose of levothyroxine 25 to 50 mcg daily can be considered in TPOAb-positive euthyroid pregnant women with a prior history of miscarriage.[26]

Hyperthyroidism

Overt hyperthyroidism during pregnancy is characterized by decreased TSH and increased free T4 levels. Subclinical hyperthyroidism is characterized by decreased TSH and normal free T4 levels. Remember, transient subclinical hyperthyroidism can be seen during the first trimester of pregnancy due to adaption in thyroid physiology, as discussed above. In gestational thyrotoxicosis, there is a physiological decrease in TSH levels during the first trimester due to hCG-mediated stimulation of the TSH receptor, peaking between 7 and 11 weeks of gestation.[32] Gestational thyrotoxicosis can be differentiated from Graves disease by careful history and examination. Additionally, in Graves disease, TSH receptor antibodies are elevated on blood testing.

Most instances of a low TSH in early pregnancy are not pathological and are due to TSH suppressive effects of β-human chorionic gonadotrophin (β-hCG). Detection of thyroid stimulating hormone receptor antibodies (TRAbs) in serum is diagnostically helpful in distinguishing Graves disease from other pathological and non-pathological causes of a low TSH.[28][29] Due to the natural immunosuppression during pregnancy, thyroid receptor antibody 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 provider can consider tapering and discontinuing the antithyroid medication.[4][13][33]

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 the usual anti-thyroid drugs.[3][13][33]

Fetal Surveillance

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 fetalis, advanced bone maturity, fetal tachycardia, goiter, oligohydramnios, or cardiac failure.[34][35] Further monitoring may include serial growth ultrasounds, amniotic fluid index, evaluation of the fetal heart rate, and fetal thyroid ultrasound to check for goiter.[3][4]

Treatment / Management

Hypothyroidism 

Overt hypothyroidism warrants treatment with thyroid hormone replacement to keep TSH level in the trimester-specific range. There is ample research demonstrating the detrimental effects of untreated overt hypothyroidism on maternal and fetal health. On the other hand, there is insufficient evidence about the treatment of subclinical hypothyroidism during pregnancy to give definitive recommendations.[18] Assays by various manufacturers may also result in different reference ranges, so this should be considered.[8]

The thyroid function tests should be checked every 4 to 6 weeks until week 20 and at least once around the 30th week of gestation. Most women (50% to 85%) with preexisting hypothyroidism before pregnancy have an increased demand for thyroid hormone requirements during pregnancy, which increases with the progression of pregnancy by approximately 30%.[36] Of note, T4, but not T3, crosses the placental barrier, so treatment with T3 alone or combined with T4 can lead to ineffective treatment of the fetus. Please see levothyroxine dosing for levothyroxine-naïve hypothyroidism patients diagnosed during pregnancy above.[26](B2)

Treatment for subclinical hypothyroidism is generally recognized to be beneficial in preventing adverse events, particularly pregnancy loss. Most study results show greater improvement when thyroid replacement is initiated earlier in pregnancy. The ATA recommends initiation of thyroid replacement therapy in subclinical hyperthyroidism when TSH is greater than 10 mU/L and consideration of treatment when TSH is between 2.5 and 10 mU/L.[8] However, in the setting of positive thyroid peroxidase antibodies, the ATA recommends thyroid replacement when TSH exceeds 2.5 mU/L.[18] Guidelines differ among the European endocrine societies.

Hyperthyroidism 

The treatment goals for hyperthyroidism during pregnancy are maintaining mild maternal hyperthyroidism while avoiding fetal hypothyroidism.[37] To maintain mild maternal hyperthyroidism, maternal free T4/total T4 should be maintained at the upper limit of normal of the reference range using the lowest effective dose of antithyroid drugs. If the TSH and total T4 levels are within normal limits, the fetus is likely exposed to excessive anti-thyroid drugs. The treatment for hyperthyroidism during pregnancy is indicated based on etiology as well as the severity of hyperthyroidism.

Graves disease is the most common cause of thyrotoxicosis during pregnancy. Although the autoantibodies do not attack the fetal thyroid, excess maternal thyroid can cause fetal/neonate central hypothyroidism by suppressing the pituitary release of TSH.[26] The management of Graves disease complicating pregnancy is as follows:(B3)

Antithyroid Drugs

• Thioamides. Methimazole (MMI) and propylthiouracil (PTU) are most commonly used for the treatment of hyperthyroidism during pregnancy.[38] Please see StatPearls' companion references, "Methimazole" and "Propylthiouracil" for further information.
• MMI is contraindicated in the first trimester of pregnancy due to potential teratogenic effects. Methimazole is associated with rare embryopathy, including aplasia cutis, abdominal wall defects, esophageal atresia, choanal atresia, eye, urinary tract, and circulatory defects. Therefore, PTU is recommended as the first-line drug in the first trimester.[3][33][39] 
• After the first trimester, when most organogenesis is complete, patients are then transitioned to methimazole. This transition is necessary to decrease the likelihood of hepatotoxicity, which is a rare but severe adverse event associated with PTU.[40] 
• Thionamides can cross the placental barrier but should not cause fetal hypothyroidism when appropriately dosed.[26] The lowest dose of antithyroid medication should be used to achieve this, with a TSH target slightly lower than the reference range and a maternal-free T4 at the high end of normal. As noted above, if the TSH becomes normal, it likely means that the fetus is receiving too much anti-thyroid drug.[2][3][13]
• Up to 15% of women experience adverse events related to thioamides. The most common are rash and pruritus, but more serious effects such as agranulocytosis, vasculitis, sepsis, and hepatotoxicity can occur. 
• Beta-blockers. Short-term treatment with beta-blockers such as propranolol and metoprolol can be used for symptomatic control. However, long-term treatment with beta-blockers should be avoided due to the risk of intrauterine fetal growth retardation.[41]
(A1)

Surgery

Thyroidectomy is rarely needed and only reserved for patients who cannot tolerate thioamides due to severe side effects or when euthyroidism cannot be achieved despite using large doses of thioamides. Surgery is also an option in patients who have a large goiter causing compression issues. When indicated, it should be performed during the second trimester.

If Graves disease has been previously treated outside of pregnancy with thyroidectomy or ablative therapy, there may be persistent thyroid receptor antibodies. These antibodies are immunoglobulin G proteins that can cross the placenta and cause fetal hyperthyroidism.[2][13][33] In this special scenario, treatment with a block-and-replace strategy may be warranted. This entails treating fetal hyperthyroidism with antithyroid drug therapy while simultaneously maintaining maternal euthyroid status via levothyroxine, which does not cross the placenta as easily as thioamides.[33] Further, radioactive iodine ablation is contraindicated during pregnancy. Subclinical hyperthyroidism, as well as gestational thyrotoxicosis, do not require treatment during pregnancy, and rather, observation is recommended with periodic monitoring of thyroid function tests every 4 to 6 weeks.(A1)

Differential Diagnosis

The differential diagnosis for pregnant individuals with hypothyroidism is similar to that of non-pregnant patients, with the exception that symptoms like weight gain, fatigue, or constipation can also be related to normal pregnancies. Some conditions that can mimic hypothyroidism include hypothalamic disorders, Addison disease, anemia, depression, chronic fatigue syndrome, and estrogen-secreting tumors. Similarly, the differential for hyperthyroidism in pregnant individuals is similar to those who are not pregnant. Some conditions that mimic hyperthyroidism include pheochromocytoma, Cushing syndrome, malignancy, tachyarrhythmia, and hydatidiform mole.

Medical Oncology

Thyroid Nodules and Thyroid Cancer During Pregnancy 

The prevalence of thyroid nodules during pregnancy varies between 3% and 21%.[42] The evaluation and management of thyroid nodules during pregnancy are similar to those with non-pregnant patients. A thyroid ultrasound should be performed, and indications for fine needle aspiration (FNA) are similar to those in non-pregnant patients. FNA is safe to be performed during pregnancy. All women with thyroid nodules should have a TSH level measured to rule out follicular adenoma, ie, toxic adenoma. Results from multiple studies confirm that carcinoma of the thyroid gland is the second most frequent pregnancy-associated cancer, behind carcinoma of the breast. Registry studies suggest that thyroid cancer is present in between 14 and 27 per 100,000 mothers giving birth.[25][43] 

The prevalence of thyroid cancer varies widely due to differences in study design and patient population. The prognosis of differentiated thyroid cancer is not largely influenced by pregnancy.[44] Given the slow growth of differentiated thyroid cancer, definitive management (thyroidectomy) can usually be delayed up until after delivery. The biopsy-proven thyroid cancer nodules should be monitored with a thyroid ultrasound every trimester. In rare circumstances, such as rapidly growing thyroid nodules or in the presence of metastases, surgery is indicated during pregnancy. In such cases, the second trimester is the safest period for performing the surgery.[18][45] 

Complications

Hypothyroidism

Untreated hypothyroidism during pregnancy may result in adverse maternal and fetal events, including preeclampsia, preterm delivery, gestational hypertension, postpartum hemorrhage, low birth weight, neuropsychological and cognitive impairment in the fetus, and increased perinatal morbidity and mortality.[46][47][48]

Hyperthyroidism

Hyperthyroidism can also have multiple effects on the pregnant woman and fetus, varying in severity from the minimal to the catastrophic. If left untreated, it can lead to hypertension, congestive heart failure, thyroid storm, increased miscarriage rate, premature labor, stillbirth or neonatal death, low birth weight baby, and fetal abnormalities.[49]