SECOND OF 2 PARTS

Annette E. Bombrys, DO How to manage hyperthyroid Dr. Bombrys is a Fellow in Maternal– Fetal Medicine, Department of and Gynecology, at the disease in University of Cincinnati College of Medicine in Cincinnati, Ohio. Uncontrolled can be fairly Mounira A. Habli, MD Dr. Habli is a Fellow in Maternal– innocuous or life-threatening to mother and Fetal Medicine, Department of Obstetrics and Gynecology, at the University of Cincinnati College of CASE Life on the line consistent with the estimated gestational Medicine in Cincinnati, Ohio. age and shows adequate amniotic fl uid and Baha M. Sibai, MD no gross fetal anomalies. Dr. Sibai is Professor, Department A 32-year-old woman in the 24th week of her What is the likely diagnosis? of Obstetrics and Gynecology, at the University of Cincinnati College fourth pregnancy arrives at the emergency of Medicine in Cincinnati, Ohio. department complaining of cough and con-® Dowdenhis is aHealth classic example Media of un- The authors report no fi nancial gestion, shortness of breath, and swelling in diagnosed hyperthyroidism in relationships relevant to this article. her face, hands, and feet. The swelling has T pregnancy manifesting as thy- become worse over theCopyright past 2 weeks,For and personalroid storm. use only she had several episodes of bloody vomit- As the case illustrates, uncontrolled ing the day before her visit. The patient says hyperthyroidism in pregnancy poses a she has not experienced any leakage of signifi cant challenge for the obstetrician. fl uid, vaginal bleeding, or contractions. She The condition can cause , IN THIS ARTICLE reports good fetal movement. preterm delivery, intrauterine growth re- The patient’s medical history is unre- striction, preeclampsia, and—at its most ❙ Uncontrolled markable, but a review of systems reveals dangerous— storm.1 Thyroid hyperthyroidism: a 15-lb weight loss over the past 2 weeks, storm is a life-threatening emergency, Serious racing heart, worsening and short- and treatment must be initiated even consequences ness of breath, and diarrhea. before hyperthyroidism is confi rmed by Page 24 Physical fi ndings include exophthalmia thyroid function testing.2 The good news and an enlarged thyroid with a nodule on the is that these complications can be suc- ❙ Stepwise right side, as well as bilateral rales, tachy- cessfully avoided with adequate control cardia, tremor, and increased deep tendon of thyroid function. management of refl exes. There is no evidence of fetal car- Overt hyperthyroidism, seen in diac failure or goiter. 0.2% of , requires active in- Page 27 A computed tomography (CT) scan of tervention to avert adverse pregnancy the mother shows bilateral pleural effusions outcome and neurologic damage to the Did you miss the authors’ indicative of high-output cardiac failure. fetus. Subclinical disease, seen in 1.7% earlier article? Thyroid ultrasonography (US) reveals a of pregnancies, can also create serious diffusely enlarged thyroid gland with a right- obstetrical problems.1 Part 1 of this review, which appeared in the January sided mass. The effects of hyperthyroidism in preg- issue of OBG MANAGEMENT, The thyroid-stimulating hormone (TSH) nancy vary in severity, ranging from the covered the impact of hypo- level is undetectable. Fetal heart rate is in fairly innocuous, transient, and self-limited thyroidism on gestation. You the 160s, with normal variability and oc- state called gestational transient thyrotoxi- can fi nd it in our archive at www.obgmanagement.com casional variable deceleration. Fetal US is cosis to the life-threatening emergency of

www.obgmanagement.com February 2008 • OBG MANAGEMENT 21

For mass reproduction, content licensing and permissions contact Dowden Health Media. Hyperthyroid disease in pregnancy

TABLE 1

Is your pregnant patient hyperthyroid? Five-test lab panel offers a guide

TEST AND RESULT THYROID- THEN THE STIMULATING FREE TRI- FREE TOTAL TRI- TOTAL MOTHER’S HORMONE IODOTHYRONINE THYROXINE IODOTHYRONINE THYROXINE CONDITION IS …

No change No change ü ü ü Pregnancy

† ü ü ü ü Hyperthyroidism

† No change No change No change No change Subclinical hyperthyroidism

TABLE 2 Pregnant women who have a history Causes of hyperthyroidism of high-dose neck radiation, thyroid ther- in pregnancy apy, postpartum , or an infant born with should also be Graves’ disease tested at the fi rst prenatal visit.4 Adenoma Telltale signs and laboratory tests Toxic nodular goiter The of hyperthyroid- Thyroiditis ism can include nervousness, heat intol- erance, tachycardia, , goiter, Excessive thyroid hormone intake weight loss, thyromegaly, exophthalmia, Choriocarcinoma increased appetite, nausea and vomit- ing, sweating, and tremor.1 The diffi culty here? Many of these symptoms are also FAST TRACK seen in pregnant women who have nor- ACOG does not thyroid storm. This review will update you mal thyroid function, so that symptoms on how to manage this disorder for opti- alone are not a reliable guide. endorse routine mal pregnancy outcome. Instead, the diagnosis of overt hy- screening for thyroid perthyroidism is made on the basis of dysfunction in laboratory tests indicating suppressed pregnant women To screen or not to screen TSH and elevated levels of free thy- Routine screening for thyroid dysfunction roxine (FT4) and free triiodothyronine has been recommended for women who (FT3). Subclinical hyperthyroidism is have infertility, menstrual disorders, or type defi ned as a suppressed TSH level with 2 1 diabetes mellitus, and for pregnant wom- normal FT4 and FT3 levels. en who have signs and symptoms of the dis- The effects of hyperthyroidism on order. Some authors recommend screening laboratory values are shown in TABLE 1.

all pregnant women, but routine screening A form of hyperthyroidism called the T3– is not endorsed by the American College of toxicosis syndrome is diagnosed by sup- 2,3 Obstetricians and Gynecologists. pressed TSH, normal FT4, and elevated 4 Thyroid testing in pregnancy is rec- FT3 levels. ommended in women who: • have a family history of auto- immune thyroid disease What are the causes? • are on thyroid therapy The most common cause of hyperthy- • have a goiter or roidism in pregnancy—accounting for • have insulin-dependent diabetes mellitus. some 95% of cases—is Graves’ disease.2

22 OBG MANAGEMENT • February 2008 This autoimmune disorder is charac- TABLE 3 terized by autoantibodies that activate What causes severe the TSH receptor. These autoantibodies hyperthyroidism before cross the placenta and can cause fetal 20 weeks’ gestation? and neonatal thyroid dysfunction even when the mother herself is in a euthyroid Gestational transient thyrotoxicosis 4 condition. Choriocarcinoma Far less often, hyperthyroidism in pregnancy has a cause other than Gestational trophoblastic disease • Partial hydatidiform mole Graves’ disease; TABLE 2 summarizes the • Complete hydatidiform mole possibilities.1 Other causes of hyper- thyroidism in early pregnancy include choriocarcinoma and gestational tro- • had Graves’ disease with fetal or phoblastic disease (partial and complete neonatal hyperthyroidism in a pre- moles) (TABLE 3). vious pregnancy • have active Graves’ disease being Signs and symptoms treated with antithyroid drugs of Graves’ disease • are euthyroid or have undergone ab- Women who have Graves’ disease usu- lative therapy and have fetal tachycar- ally have thyroid nodules and may have dia or intrauterine growth restriction exophthalmia, pretibial , and • have chronic thyroiditis without goiter tachycardia. They also display other clas- • have fetal goiter on ultrasound. sic signs and symptoms of hyperthyroid- Newborns who have congenital hy- ism, such as muscle weakness, tremor, pothyroidism should also be screened for and warm and moist skin. thyroid .4 During pregnancy, Graves’ disease usually becomes worse during the fi rst trimester and ; symp- What are the consequences? toms resolve during the second and Hyperthyroidism can have multiple ef- FAST TRACK third trimesters.1 fects on the pregnant patient and her fe- The most tus, ranging in severity from the minimal Thyrotoxin receptor to the catastrophic. common cause of and antithyroid antibodies hyperthyroidism in Antithyroid antibodies are common in pa- Gestational transient thyrotoxicosis pregnancy is Graves’ tients with autoimmune thyroid disease, This condition is presumably related to disease, which as a response to thyroid antigens. The high levels of human chorionic gonado- accounts for about two most common antithyroid antibodies tropin, a substance known to stimulate are and TSH receptors. Unhappily for your pa- 95% of cases (anti-TPO). Anti-TPO antibodies are as- tient, the condition is usually heralded sociated with postpartum thyroiditis and by severe bouts of nausea and vomit- fetal and neonatal hyperthyroidism. TSH- ing starting at 4 to 8 weeks’ gestation. receptor antibodies include thyroid-stim- Laboratory tests show signifi cantly ulating immunoglobulin (TSI) and TSH- elevated levels of FT4 and FT3 and receptor . TSI is associated with suppressed TSH. Despite this signifi cant Graves’ disease. TSH-receptor antibody derangement, patients generally have no is associated with fetal goiter, congenital evidence of a hypermetabolic state. , and chronic thyroiditis This condition resolves by 14 to without goiter.4 20 weeks of gestation, is not associated Who do you test for antibodies? Test for with poor pregnancy outcomes, and maternal thyroid antibodies in patients does not require treatment with anti- who: thyroid medication.1 CONTINUED www.obgmanagement.com February 2008 • OBG MANAGEMENT 23 Hyperthyroid disease in pregnancy

FIGURE 1 ease who have been treated surgically or Consequences of uncontrolled hyperthyroidism with ablative therapy prior to pregnan- cy. Even when these therapies achieve a 35 euthyroid state in the mother, TSI levels may remain elevated and lead to fetal 30 Treated and euthyroid hyperthyroidism. Uncontrolled Characteristics of hyperthyroidism in 25 hyperthyroidism

pregnancies the fetus include tachycardia, intrauterine 20 growth restriction, congestive heart fail- ure, , and goiter. Treating 15 affected the mother with antithyroid medications

of 4 10 will ameliorate symptoms in the fetus.

5 Thyroid storm This is the worst-case scenario—a rare

Percentage 0 Preeclampsia Heart PTD FGR but potentially lethal complication of failure uncontrolled hyperthyroidism. Thyroid Complications of pregnancy storm is a hypermetabolic state charac- terized by fever, nausea, vomiting, diar- Several studies have found a much higher risk of pregnancy complications in women who have uncontrolled hyperthyroidism, compared with their treated and euthyroid peers.5–7 rhea, tachycardia, altered mental sta- PTD = preterm delivery; FGR = fetal growth restrictions. tus, restlessness, nervousness, seizures, coma, and cardiac arrhythmias. It oc- curs in 1% to 2% of patients receiving Adverse pregnancy outcomes thioamide therapy.8 Pregnant women who have uncon- In most instances, thyroid storm is a trolled hyperthyroidism are at increased complication of uncontrolled hyperthy- risk of spontaneous miscarriage, con- roidism, but it can also be precipitated gestive heart failure, preterm delivery, by infection, surgery, thromboembolism, FAST TRACK intrauterine growth restriction, and preeclampsia, labor, and delivery. Thyroid storm can preeclampsia.1 Studies that evaluated pregnancy outcomes in 239 women Thyroid storm is a medical emergency be precipitated by with overt hyperthyroidism showed in- This manifestation of uncontrolled hy- infection, surgery, creased risk of adverse pregnancy out- perthyroidism is so urgent that treatment thromboembolism, comes, compared with treated, euthy- should be initiated before the results of 5–7 2,8 preeclampsia, labor, roid women (FIGURE 1). TSH, FT4, and FT3 tests are available. and delivery Delivery should be avoided, if possible, Fetal and neonatal hyperthyroidism until the mother’s condition can be stabi- Hyperthyroidism in the fetus or new- lized but, if the status of the fetus is com- born is caused by placental transfer of promised, delivery is indicated. maternal immunoglobulin antibodies Treatment of thyroid storm begins (TSI) to the fetus and is associated with with stabilization of the patient, followed maternal Graves’ disease. The incidence by initiation of a stepwise management of neonatal hyperthyroidism is less than approach (FIGURE 2, page 27). 1%. It can be predicted by rising levels of maternal TSI antibodies, to the point where levels in the third trimester are Treatment of hyper- three to fi ve times higher than they were thyroidism in pregnancy at the beginning of pregnancy.4 Two medications are available to treat Fetal hyperthyroidism develops hyperthyroidism in pregnancy: propyl- at about 22 to 24 weeks’ gestation in thiouracil (PTU) and methimazole. These mothers with a history of Graves’ dis- medications are known as thioamides.1,2 CONTINUED

24 OBG MANAGEMENT • February 2008 Hyperthyroid disease in pregnancy

PTU blocks the oxidation of iodine in FIGURE 2 the thyroid gland, thereby preventing Management of thyroid storm the synthesis of T4 and T3. The initial dosage for hyperthyroid women who are not pregnant is usually 300 to 450 Stabilize patient mg/day in three divided doses every Airway, breathing, circulation (ABCs) 8 hours, and this dosing strategy can also be applied to the pregnant patient. Maintenance therapy is usually achieved Give propylthiouracil (PTU), 600 with 100 to 150 mg/day in divided doses to 800 mg orally followed by 150 mg every 8 to 12 hours.9 every 4 to 6 hours (methimazole is an alternative if oral administration of Methimazole works by blocking the or- PTU is impossible) ganifi cation of iodide, which decreases thyroid hormone production. The usu- al dosing, given in three divided doses 1–2 hours after administering PTU, give: every 8 hours, is 15 mg/day for mild • Potassium iodide, 2–5 drops orally hyperthyroidism, 30 to 40 mg/day for every 8 hours, or moderately severe hyperthyroidism, and • Lugol’s solution, 8 drops every 60 mg/day for severe hyperthyroidism. 6 hours, or Maintenance therapy with methimazole • Sodium iodide, 0.5–1.0 g intravenously is usually given at a dosage of 5 to 15 (IV) every 8 hours mg/day.9 In the past, PTU was considered the drug of choice for treatment of hyper- Immediately initiate dexamethasone, 2 mg IV or intramuscularly every thyroidism in pregnancy because clini- 6 hours, for 24 hours (4 doses) cians believed it crossed the placenta to a lesser degree than did methima- zole, and because methimazole was associated with fetal esophageal and Immediately initiate propranolol, FAST TRACK 20–80 mg orally every 4–6 hours, or choanal atresia and fetal cutis aplasia 1–2 mg IV every 5 minutes, until a total of Whatever regimen (congenital skin defect of the scalp).1,2 6 mg, then 1–10 mg IV every 4 hours Available evidence does not, however, you select to treat support these conclusions.8,10 What- hyperthyroidism of ever medication regimen you choose, pregnancy, adopt Give phenobarbital, 30–60 mg orally thyroid function should be monitored every 6–8 hours, as needed for agitation a program of close 1) every 4 weeks until TSH and FT4 and restlessness monitoring of thyroid levels are within normal limits and 2) function every trimester thereafter. FIGURE 3 (page 31) presents an algorithm for man- Aggressive management of thyroid storm is indicated, aging hyperthyroidism in pregnancy. following a stepwise approach. Each medication used to treat thyroid storm plays a specifi c role in suppress- ing thyroid function. Propylthiouracil (PTU) blocks ad- CASE Resolved ditional synthesis of thyroid hormone and inhibits the conversion of thyroxine (T4) to triiodothyronine (T3). Me- thimazole blocks additional synthesis of thyroid hor- The patient in thyroid storm described at the mones. Saturated solution of potassium iodide (SSKI), beginning of this article requires aggressive Lugol’s solution, and sodium iodide block the release of thyroid hormone from the gland. Dexamethasone is used management, as outlined in the algorithm in to decrease thyroid hormone release and peripheral con-

FIGURE 2. As her symptoms diminish, fe- version of T4 to T3. Propranolol is used to treat maternal tachycardia by inhibiting the adrenergic effects of exces- tal tachycardia resolves. The patient’s FT4 sive thyroid hormones. Finally, phenobarbital is used to level begins to decline, consistent with ap- treat maternal agitation and restlessness caused by the propriate treatment, and she is discharged increased catabolism of thyroid hormones. home and instructed to continue PTU and SOURCE: Adapted from ACOG.2

CONTINUED www.obgmanagement.com February 2008 • OBG MANAGEMENT 27 Hyperthyroid disease in pregnancy

labetalol and to follow up at the endocri- FIGURE 3 nology and high-risk obstetrics clinics as Management of hyperthyroidism soon as possible. in pregnancy The patient does not follow this ad- vice. Consequently, she presents at 33 5/7 Patient has a history of hyperthyroidism weeks in a hypertensive crisis, with symp- toms similar to those she fi rst exhibited plus acute pulmonary edema. Fetal heart rate is Measure thyroid-stimulating hormone (TSH) initially in the 130s, with good variability and free thyroxine (FT4) and occasional decelerations (FIGURE 4A), but decelerations then become worse (FIGURE 4B) and emergency cesarean sec- tion is performed. Abnormal Normal A male infant is delivered, weighing 2,390 g. Apgar scores are 0 at 1 minute and Adjust Monitor TSH and FT4 9 at 5 minutes. A 25% propylthiouracil every trimester is noted at the time of delivery. or methimazole Mother and fetus are stabilized and incrementally Abnormal discharged. ■ Normal

Monitor TSH and FT4 References every 4 weeks 1. Casey BM, Leveno KJ. Thyroid disease in preg- nancy. Obstet Gynecol. 2006;108:1283–1292. 2. American College of Obstetrics and Gynecology. FIGURE 4 ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number Weakening fetal status in a mother 37, August 2002. (Replaces Practice Bulletin Num- ber 32, November 2001). Thyroid disease in preg- who is in thyroid storm nancy. Obstet Gynecol. 2002;100:387–396. A 3. Mitchell ML, Klein RZ. The sequelae of untreat- ed maternal hypothyroidism. Eur J Endocrinol. 2004;151 Suppl 3:U45–48. 4. Mestman JH. Endocrine diseases in pregnancy. In: Gabbe S, Niebyl JR, eds. Obstetrics: Normal and Problem Pregnancies. 4th ed. Philadelphia: Churchill Livingstone; 2002:1117–1168. 5. Davis LE, Leveno KJ, Cunningham FG. Hypothy- roidism complicating pregnancy. Obstet Gynecol. 1988;72:108–112. 6. Davis LE, Lucas MJ, Hankins GD, Roark ML, Cun- ningham FG. Thyrotoxicosis complicating pregnan- cy. Am J Obstet Gynecol. 1989;160:63–70. 7. Kriplani A, Buckshee K, Bhargava VL, Takkar D, B Ammini AC. Maternal and perinatal outcome in thy- rotoxicosis complicating pregnancy. Eur J Obstet Gynecol Reprod Biol. 1994;54:159–163. 8. Belford MA. Navigating a thyroid storm. Contem- porary OB/GYN. 2006; October:38–46. 9. Lazarus JH, Othman S. Thyroid disease in relation to pregnancy. Clin Endocrinol (Oxf). 1991;34:91–98. 10. Kent GN, Stuckey BG, Allen JR, Lambert T, Gee V. Postpartum thyroid dysfunction: clinical assess- ment and relationship to psychiatric affective mor- bidity. Clin Endocrinol (Oxf). 1999;51:429–438.

Fetal heart rate is initially in the 130s with good variability and occasional decelerations (A), but then deteriorates, with increasing decelerations (B), an indication for immediate delivery.

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