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1 TITLE: THYROID DISEASE IN PREGNANCY EFFECTIVE DATE: February 20th, 2015 POLICY STATEMENT: Pregnancy changes significantly the values influenced by the serum thyroid binding hormone level (i.e., total thyroxine, total triiodothyronine, and resin triiodothyronine uptake). BLOOD BORNE PATHOGEN EXPOSURE CATEGORY: I (Involves exposure to blood, body fluids, or tissues) FUNCTION: Care of Clients POINTS OF EMPHASIS: Thyroid Function and Tests in Pregnancy Several important physiologic changes occur in the thyroid gland during pregnancy. In women with normal thyroid function, thyroid gland volume, iodine clearance, estrogen-induced thyroxine-binding globulin, and thyroid hormone production increase by an average of 50%, whereas in the first trimester of pregnancy, rising levels of human chorionic gonadotropin (with stimulation of the thyrotropin/thyroid-stimulating hormone [TSH] receptor), cause TSH levels to fall. The fetal thyroid gland begins to form in the first trimester and produces thyroid hormones increasingly during the second and third trimesters. Type 3 placental deiodinase converts T4 to biologically inactive T3 in the periphery, thereby protecting the fetus from excessive thyroid hormone. Maternal hypothyroidism, especially presenting in the first trimester, can profoundly hinder fetal neurodevelopment. To assess thyroid (dys)function during pregnancy, the 2012 Endocrine Society guideline recommends using either the ff4 index or values 1.5 times the upper limits of the nonpregnant total T4 and T3 range in the second and third trimesters. The ft4 index is based on two estimates - total T4 and T3 resin uptake - with the latter estimating thyroxine-binding globulin concentrations. Ideally, ft4 is measured by equilibrium dialysis or ultrafiltration of serum. Changes in Thyroid Function Test Results in Normal Pregnancy and in Thyroid Disease Maternal status TSH FT4 FTI TT4 TT3 RT3U Pregnancy No change No change No change Increase Increase Decrease Hyperthyroidism Decrease Increase Increase Increase Increase or Decrease No change Hypothyroidism Increase Decrease Decrease Decrease Decrease or Increase No change TSH = thyroid-stimulating hormone; FT4 = free thyroxine; FTI = free thyroxine index; TT4 = total thyroxine; TT3 = total triiodothyronine; RT3U = resin triiodothyronine uptake Reprinted with permission from ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists. No. 32, November Thyroid disease in pregnancy. Obstet Gynecol 2001;98(5 pt 1): Plasma iodide levels decrease as a result of fetal iodide use and increased maternal renal clearance. In about 15 percent of pregnant women, these lower iodide levels are associated with a noticeable increase in thyroid gland size. Hypothyroidism

2 PRACTICE GUIDELINE Page 2 of 6 During pregnancy the prevalence of overt and subclinical hypothyroidism is 0.5% and 2% to 3%, respectively. Antithyroidal antibodies can be detected in <15% of women of childbearing age, making autoimmune thyroiditis the most common cause of hypothyroidism in this population. Although universal screening remains controversial, performing such screening would detect elevated TSH in approximately 2% to 4% of women. Hypothyroidism is usually caused by a primary thyroid abnormality, although a few cases are caused by hypothalamic dysfunction. In pregnant or postpartum women, the most common causes are chronic thyroiditis or chronic autoimmune thyroiditis (Hashimoto's disease), subacute thyroiditis, radioactive iodine therapy, thyroidectomy, and iodine deficiency. Hashimoto's disease is the most frequent cause in industrialized nations; worldwide, iodine deficiency is the most common cause. Signs and symptoms of hypothyroidism include fatigue, muscle cramps, constipation, cold intolerance, hair loss, and others. With progression of the disorder, voice changes, weight gain, intellectual slowness, and insomnia can occur. Untreated hypothyroidism progresses to myxedema and myxedema coma. Presentation of advanced hypothyroidism in pregnancy is unusual. Subclinical hypothyroidism is identified by an elevated TSH level in a pregnant woman without symptoms. Untreated maternal hypothyroidism increases the risk of preeclampsia. Whether subclinical hypothyroidism increases this risk is uncertain. Inadequate treatment of hypothyroidism is associated with low birth weight in neonates. Maternal hypothyroidism from iron deficiency increases the risk of congenital cretinism (growth failure, mental retardation, other neuropsychologic defects). Iodine therapy in the first and second trimesters significantly reduces neurologic abnormalities associated with this disorder. Cretinism also occurs with untreated congenital hypothyroidism. Newborn screening for congenital hypothyroidism is offered throughout the United States. Treatment in the first several weeks of life can result in nearly normal intelligence and growth. Hyperthyroidism Thyrotoxicosis is a clinical and biochemical state resulting from excess production of and exposure to thyroid hormone because of any etiology. Hyperthyroidism, which occurs in 0.2 percent of pregnancies, is thyrotoxicosis resulting from hyperfunction of the thyroid gland. The many signs and symptoms of hyperthyroidism include tremors, nervousness, insomnia, excessive sweating, heat intolerance, tachycardia, hypertension, and goiter. Graves' disease is responsible for 95 percent of hyperthyroidism cases in pregnancy. Distinctive ophthalmic signs include eyelid lag or retraction; dermal signs include localized and pretibial myxedema. The diagnosis of this disease is generally based on an elevated free thyroxine (FT4) level or free thyroxine index (FTI), with suppression of thyroid-stimulating hormone (TSH) in the absence of thyroid mass or nodular goiter. Thyroid storm, a rare condition affecting 1 percent of pregnant women with hyperthyroidism, is characterized by severe, acute exacerbation of the signs and symptoms of hyperthyroidism. Thyroid storm is a medical emergency. Unless hyperthyroidism is treated adequately, pregnant women are at increased risk for severe preeclampsia, preterm delivery, heart failure, and, possibly, miscarriage. Low birth weight in neonates also can occur. Graves' disease and its treatment (thioamides) increase fetal and neonatal risks. Fetal thyrotoxicosis needs to be considered in women who have a history of Graves' disease; if this condition is diagnosed, appropriate consultation should be sought. Because of antibodies that cross the placenta, the possibility of neonatal immune-mediated hypothyroidism or hyperthyroidism is an additional concern. Hyperthyroidism incidence ranges around 9.2% during the year after childbirth. This may include Grave s disease, Hashimoto s thyroiditis, and postpartum thyroiditis. Outside of the peurperium, Graves disease has a general population incidence of 1% and is the most common etiology of hyperthyroidsim. It accounts for 80 to 90% of hyperthyroidism during pregnancy. However, postpartum thyroiditis is about 20 times more likely to occur after birth than Grave s disease. The incidence of postpartum thyroiditis is approximately 4.1% to 7% compared with a 0.2% incidence of Graves disease in the postpartum period.

3 Clinical presentation during the postpartum period is challenging as it can be difficult to differentiate from the normal puerperium experience. Women with hyperthyroidism most frequently report feeling sleepless and manic, although they may also report excessive fatigue. The presenting symptom may also be mood disturbance, which can confuse the clinical picture for postpartum depression. Other symptoms include irritability and palpitations. Some women experience heat intolerance, mood swings, and sweats, all of which overlap with normal postpartum symptoms. Lack of milk production has been associated, in some literature, with hypothyroidism rather than over production of thyroid hormone, but there have been minimal studies on this relationship. Postpartum Thyroidistis Similarly, postpartum thyroiditis is characterized by autoimmune dysfunction often occurring during the first 6 months after childbirth. It encompasses a disease range from postpartum hyperthyroidism, hyperthyroidism followed by hypothyroidism, and hypothyroidism, in isolation. In this condition, lymphocytes cause destruction of the thyroid, with an initial release of thyroid hormone as the thyroid follicles are attacked. Occasionally, this autoimmune process can result in eventual destruction of the thyroid, as in Hashimoto s thyroiditis. Thyroid peroxidase antibodies are usually present, and the T4 to T3 ratio is elevated in contrast to Graves disease, in which free T3 is often at least 3 times the level of free T4. Thyroid peroxidase antibodies are thought to be a marker of disease in this case in contrast to TSH receptor antibodies, which are the cause of hyperthyroidism in Grave s disease. Thyroid hormone levels may also be lower in early pregnancy and rise during the postpartum period. Grave s Disease Grave s disease is characterized by the presence of TSH receptor antibodies. These antibodies bind to TSH receptors on the thyroid, stimulating thyroid production and secretion. This autoimmune reaction is often suppressed during pregnancy because of general immune response suppression, and improvement may even be seen for many women during the second part of gestation. However, during the postpartum period this relative autoimmune suppression ends, and TSH receptor antibodies will increase in number. This stimulates the thyroid to secrete increased thyroid hormone. In Graves disease, overabundant free T4 is converted to free T3 in peripheral tissues, further adding to the elevated levels of free T3. EQUIPMENT: 1. Lab supplies 2. Gloves BELIEVE MIDWIFERY SERVICES PRACTICE GUIDELINE Page 3 of 6 PROCEDURE: Hypothyroidism Screening 1. TSH and FT4 or FTI testing should be performed in pregnant women with suspected hyperthyroidism or hypothyroidism. The 2012 Endocrine Society guidelines recommends ordering a ft4 index. 2. The Endocrine Society recommendations regarding identifying factors that suggest a need for screening are as follows: a. Infertility b. History of miscarriage or preterm labor c. Currently treated with levothyroxine d. Older than 30 years e. Goiter f. Symptoms and signs suggestive of an underactive thyroid g. Type 1 diabetes mellitus or other autoimmune disease h. Residing in a region with presumed iodine deficiency i. History of thyroid surgery and/or head and neck irradiation j. Positive anti-thyroidal antibodies, primary thyroid peroxidase antibodies 3. The American Thyroid Association has added: a. massive obesity (body mass index >40), b. history of ingestion of amiodarone or lithium, and c. recent contrast dye exposure 4. Although there was no well-defined normal TSH range for the pregnant population in the past, recent studies have demonstrated value for trimester-specific ranges. The accepted upper limit for trimester-

4 PRACTICE GUIDELINE Page 4 of 6 specific ranges. The accepted upper limit of normal for TSH in the first trimester is 2.5 miu/l and 3.0 miu/ L during later pregnancy. 5. ft4 levels should be interpreted with caution during pregnancy. With TSH levels of 2.5 to 10 miu/l, a starting levothyroxine dose of 50 mn/day is recommended. 6. The nonpregnant total T4 should be multiplied by 1.5 to achieve second and third trimester-specific target levels. Treatment of Hypothyroidism 7. The replacement dose of T4 must be increased by 30% to 50% during gestational weeks 4 to 6 to avoid maternal hypothyroidism; this is usually accomplished by adding two tablets weekly to the baseline seventablet regimen. 8. Clients with hypothyroidism are encouraged to contact their provided immediately when pregnancy is confirmed. Untreated overt hypothyroidism is associated with adverse maternal and fetal outcomes. Maternal complications include spontaneous abortion, anemia, gestational hypertension, placental abruption, and postpartum hemorrhage. Adverse fetal outcomes include preterm birth, low birth weight, and fetal distress. Continued Management of Hypothyroidism 9. Thyroid function tests should be reassessed within 40 days and subsequently every 4 to 6 weeks, including in euthryoid women with thyroid autoimmunity in early pregnancy. 10. Once stable, thyroid levels should be evaluated each trimester. 11. After delivery, the levothyroxine dose in most hypothyroid women requires reduction to the prepregnancy dose. 12. A recent cross-sectional study of 384 pregnant women found that excessive iodine intake during late pregnancy (urinary iodine excretion >250 mg/l) can lead to subclinical hypothyroidism, and such women with subclinical hypothyroidism identified during pregnancy have increased risk for severe preeclampsia. 13. Although clear indication exist for the treatment of overt hypothyroidism, there has been conflicting evidence regarding subclinical hypothyroidism. The 2012 Endocrine Society guideline recommends levothyroxine replacement in such patients; however, the American Thyroid Association guideline does not. Hyperthyroidism 14. Women with hyperthyroidism may appear anxious or agitated with a rapid speech pattern. When examining a woman with Graves disease, findings may include tachycardia, loss of weight, a diffusely enlarged thyroid goiter, and the characteristic bulge of Graves opthalmology or exophthalmos. 15. If significant tachycardia is present accompanied by fever and central nervous system effects, then thyroid storm should be considered. This condition is life threatening and needs to be addressed immediately. 16. In contrast, women in the hyperthyroid phase of postpartum thyroiditis and Hashimoto s thyroiditis will present with milder symptoms than Graves disease. They will not have severe agitation, exophthalmos, or significant vital sing changes, but may have palpitations, fatigue, and mood changes. Postpartum thyroiditis and Hashimoto s thyroiditis typically present initially as a hyperthyroid episode followed by hypothyroidism. 17. The thyrotoxic state (hyperthyroidism) usually occurs 2 to 6 months postpartum, most frequently at 3 months. Symptoms are mild because of milk elevation of thyroid hormone and are usually 1 to 2 months in duration. Postpartum thyroiditis is usually temporary, whereas Hashimoto s thyroiditis frequently results in permanent destruction of the thyroid tissue. Diagnosis of Hyperthyroidism 18. Initial evaluation should include a TSH level. If low or absent, both free T3 and free T4 need to be evaluated. 19. In Graves disease, the free T3 to free T4 ratio is often greater than 3:1, whereas in postpartum thyroiditis, the inverse is true. 20. Additional assessment includes TSH receptor antibodies and thyroid peroxidase antibodies. TSH receptor antibodies are present in up to 95% of women with Graves disease but rarely occur in women with postpartum thyroiditis or Hashimoto s thyroiditis. If TSH receptor antibodies are positive, a radioiodine uptake test is indicated to differentiate among thyroiditis causes and thus to guide treatment. However, some endocrinologists will delay radioiodine evaluation if a woman is breastfeeding and proceed with

5 PRACTICE GUIDELINE Page 5 of 6 treatment because breastfeeding must be withheld for several days after the scan. The radioiodine uptake test is normal or elevated during Graves disease and low in postpartum thyroiditis. Treatment of Hyperthyroidism 21. Hyperthyroidism in pregnant women is treated with a thioamide (propylthiouracil or methimazole). Recent studies have found no significant differences between propylthiouracil and methimazole in mean FT4 or TSH levels in newborn cord-blood samples, as well as no cases of aplasia cutis and similar rates of fetal anomalies for both agents. Women treated with propylthiouracil or methimazole can breastfeed safely. a. Until thioamide therapy reduces thyroid hormone levels, a beta blocker (e.g., propranolol) can be used to reduce symptoms. b. Agranulocytosis, a side effect of thioamides, usually presents with sore throat and fever. If these symptoms develop, a complete blood cell count should be obtained, and the thioamide should be discontinued. Other side effects include hepatitis, vasculitis, and thrombocytopenia. c. Although suppression of fetal and neonatal thyroid function can occur with thioamide therapy for Graves' disease, it is usually transient, and treatment is rarely required. Fetuses of women with Graves' disease should be monitored for normal heart rate and appropriate growth; unless problems are detected, ultrasound screening for fetal goiter is not necessary. The newborn's physician needs to be aware that the mother has Graves' disease because of the associated risk of neonatal thyroid dysfunction. d. The goal is to maintain FT4 or FTI in the high-normal range using the lowest possible thioamide dosage. e. Measuring the FT4 or FTI every two to four weeks can be helpful. 22. Treatment is required for Graves disease with either methimazole or propylthiouracil (PTU). Both limit thyroid peroxidase, whereas PTU will also stop free T4 from changing to T3. Neither medication is contraindicated during breastfeeding and neither have shown to have any long-term effects on the breastfeeding infants thyroid function and intellectual and physical development. However, if the woman is no longer breastfeeding, methimazole may be the preferred medication, as it has a longer half-life with fewer side effects and once-daily dosing contributing to better adherence. a. Some experts recommend methimazole (20-30mg/day) as first line, with PTU (up to 300 mg/day) as second line with breastfeeding mothers because of the risk of hepatotoxicity with PTU. b. Liver function tests and a CBC should be considered prior to initiating PTU, and repeating these tests was well as a thyroid panel 4 to 6 weeks after starting on this medication would be appropriate. 23. In addition to the antithyroid medication, these women often require treatment for tachycardia, palpitations, and anxiety. This can be achieved with a nonspecific beta-blocker. Propranolol can be used safely during pregnancy, whereas atenolol should be avoided during this time. Either propanolol or atenolol is appropriate during the postpartum period. 24. In contrast, no antithyroid treatment is required or recommended for postpartum thyroiditis or hashimoto s thyroiditis. However, if women have symptoms such as palpitations or irritability and are not yet hypothyroid, it is appropriate to treat with propranolol for the duration of the thyrotoxic period. Once TSH begins to rise to near normal levels, thyroxine supplementation should be offered but is not required for a TSH below 10 miu/l unless the woman is planning a subsequent pregnancy. After initiating thyroxine, TSH should be checked every 6 to 8 weeks. If women choose not to be treated, they should also have their TSH rechecked in 4 to 8 weeks and if still elevated at that time be treated with thyroid replacement. Approximately 30% to 50% of women will remain in a hypothyroid condition and require ongoing levothyroxine treatment. Although Hashimoto s thyroiditis usually will require ongoing thyroid replacement throughout life, many women recover from postpartum thyroiditis by one year postpartum. However, they will remain at risk in the 5 to 10 years following birth for developing hypothyroidism and should be evaluated annually for changes in thyroid function. 25. This extreme hypermetabolic state is associated with a high risk of maternal heart failure. Diagnosis is based on a combination of signs and symptoms: fever, tachycardia out of proportion to the fever, altered mental status (nervousness, restlessness, confusion, seizures), vomiting, diarrhea, and cardiac arrhythmia. An inciting event (e.g., surgery, infection, labor, delivery) may be identified. Untreated thyroid storm can result in shock, stupor, and coma. Serum-free triiodothyronine (FT3), FT4, and TSH levels help confirm the diagnosis, but treatment should not be delayed for test results.

6 PRACTICE GUIDELINE Page 6 of If hyperthyroidism is diagnosed during pregnancy, the infant should have both TSH and T4 levels drawn at 3 to 4 weeks of life. Also, any breastfeeding newborns whose mothers are being treated for hyperthyroidism should also have this thyroid testing at about one month of life, although the amounts of antithyroid medication passing through breast milk are minimal > During breastfeeding, methimazole should be limited to 20mg per day and PTU from 350 to 300 mg per day. Thyroid Nodules and Cancer 27. A thyroid nodule first discovered during pregnancy should prompt a detailed history regarding risk factors for malignancy. Historical points suggesting cancer include: a. rapidity of onset, b. presence of hoarseness, c. local compression symptoms, d. a family history of thyroid cancers of multiple endocrine neoplasia type 2 syndromes, or e. history of childhood head and neck irradiation 28. Any pregnant woman with a thyroid nodule should undergo a TSH, ft4, and ultrasound examination. Thyroid function tests are typically normal in most patients with thyroid cancer. 29. In women with thyroid cancer or suspicious nodules, levothyroxine should be used to suppress TSH. 30. Fine needle aspiration should be performed for predominantly solid nodules >1cm in diameter. For nodules 5 to 10 mm in diameter, the decision to biopsy is driven by the presence of risk factors and by suspicious characteristics of the nodule itself (eg., microcalcifications, intranodular blood flow, irregular shape). The needle aspiration can be performed during any part of the pregnancy. 31. If the cytology confirms or is suspicious for cancer, ten thyroidectomy is recommended. Surgery can be performed during the second trimester or after delivery. 32. Considering most well-differentiated thyroid cancers are slow growing, delaying treatment until after delivery is an acceptable strategy. References: Ahmad, S., Geraci, S. A., & Koch, C. A. (2013). Thyroid disease in pregnancy. The Southern Medical Association. 106(9), Goldstein, A.L. (2013). New-onset Graves Disease in the Postpartum Period. Journal of Midwifery & Women s Health, 58(2), Schroeder, B.M. (2002). ACOG practice bulletin on thyroid disease in pregnancy. American Family Physicians. Retrieved July, 2008 from: Originated: July, 2008 Penny Lane DNP, CNM, IBCLC DATE: 7/1/2008 up-dated 7/5/2013 up-dated 2/20/2015 Holly Hopkins MSN, CNM DATE: 8/20/2011 Michelle Burton DATE: 6/4/2012