Case 21. Thyroid Storm in Pregnancy

 An 18-year-old G2P1 at 35 weeks’ gestation has a history of Graves disease and is under treatment with oral methimazole (MMI). She states that over the last day, she has been feeling as though her “heart is pounding.” She also complains of nervousness, sweating, and diarrhea. On examination, her blood pressure (BP) is 150/110 mm Hg, heart rate (HR) is 140 beats per minute (bpm), respiratory rate is (RR) 25 breaths per minute, and temperature is 100.8°F (38.2°C). The patient appears anxious, disoriented, and somewhat confused. The thyroid gland is mildly tender and enlarged. The cardiac examination reveals tachycardia with III/VI systolic murmur. The fetal heart rate tracing shows a baseline in the 160 bpm range without decelerations. Deep tendon reflexes are 4+ with clonus. Her leukocyte count is 20 000/mm3.

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ANSWERS TO CASE 21:

Thyroid Storm in Pregnancy

Summary: An 18-year-old G2P1 at 35 weeks’ gestation is taking MMI for Graves disease. She has a 1-day history of palpitations, nervousness, sweating, and diarrhea. On examination, her BP is 150/ 110 mm H g, H R is 140 (bpm), RR is 25 breaths per minute, and temperature is 100.8°F (38.2°C). The patient appears anxious, disoriented, and somewhat confused. The thyroid is mildly tender and enlarged. Deep tendon reflexes are 4+ with clonus. She has a leukocytosis.

 Most likely diagnosis: Thyroid storm.

 Best management for this condition:A β-blocker (such as propranolol), corticosteroids, and propylthiouracil (PTU) or methimazole.

ANALYSIS

Objectives

1. Know that the most common cause of hyperthyroidism in the United States is Graves disease.

2. Recognize the clinical presentation and danger of thyroid storm.

3. Be aware of postpartum thyroiditis and its three-part presentation.

Considerations

This 18-year-old woman at 35 weeks’ gestation has a history of hyperthyroidism due to Graves disease. In the United States, the majority of hyperthyroidism is due to Graves disease; the clinical presentation is typically that of a painless, uniformly enlarged thyroid gland with occasional proptosis. She is being treated with MMI, which is the most commonly used medication for hyperthyroidism in pregnancy.

For whatever reason, which is not stated, the patient has symptoms of increased thyrotoxicosis of 1-day duration. Some possible reasons include noncompliance with the medication, or a stressor, such as surgery or an illness. This woman not only has the nervousness and palpitations of hyperthyroidism, but also autonomic instability, which is the hallmark of thyroid storm. H er blood pressure is 150/ 110 mm H g and her temperature is elevated. She is disoriented and markedly confused. Thyroid storm must be recognized because it carries a significant risk of mortality. The therapy consists of a β-blocking agent, such as propranolol, corticosteroids, and anti-thyroid medications. The preferred agent in this setting is PTU because of its faster onset of action and ability to inhibit peripheral conversion of T4 to T3. In a nonpregnant patient or a pregnant patient who is sufficiently ill, a saturated solution of potassium iodide oral drops may also be used; however, this agent may affect the fetal thyroid gland. Notably, the patient has a high white blood cell count. Methimazole has been rarely linked with possible fetal scalp defects and aplasia, so it is not used in the first trimester. Recently, the

Food and Drug Administration issued a blackbox warning regarding PTU because of the severe liver toxicity it can cause, as well as bone marrow aplasia, leading to leukopenia, and sepsis.

APPROACH TO:

Thyrotoxicosis in Pregnancy

DEFINITIONS

HYPERTHYROIDISM: A syndrome caused by excess thyroid hormone, leading to nervousness, tachycardia, palpitations, weight loss, diarrhea, and heat intolerance.

THYROID STORM: Extreme thyrotoxicosis leading to central nervous system dysfunction (coma or delirium) and autonomic instability (hyperthermia, hypertension, or hypotension).

GRAVES DISEASE: An autoimmune disease characterized by the production of abnormal antibodies which act on the thyroid-stimulating hormone receptor causing overstimulation of the thyroid. It is the most common cause of thyrotoxicosis in the United States, associated with a diffusely enlarged goiter.

FREE THYROXINE (T4): Unbound or biologically active thyroxine hormone.

THIONAMIDE ANTITHYROID MEDICATIONS: Propylthiouracil and MMI, medications that inhibit thyroid hormone synthesis, are the two thionamide medications approved for use in the United States.

CLINICAL APPROACH

Hyperthyroidism is rare in pregnancy, occurring in about 1 in 2000 pregnancies. Symptoms of thyrotoxicosis include tachycardia, heat intolerance, nausea, weight loss or failure to gain weight despite adequate food intake, thyromegaly, thyroid bruit, tremor, exophthalmos, and systolic hypertension. The most common cause of hyperthyroidism in pregnancy is Graves disease, an autoimmune disorder in which antibodies are produced which mimic the function of thyroid-stimulating hormone (TSH ). These antibodies stimulate the thyroid gland to produce more thyroid hormone, leading to the symptoms responsible for thyrotoxicosis. The diagnosis of hyperthyroidism is confirmed in the presence of elevated free thyroxine and low serum TSH levels. Treatment during pregnancy may be medical or surgical; however, generally, hyperthyroidism in pregnancy is managed medically. Propylthiouracil is generally accepted as the drug of choice in pregnancy. PTU inhibits the peripheral conversion of T 4 to T 3 but may cross the placenta somewhat.

Methimazole is another option. Both PTU and MMI cross the placenta and can lead to some transient neonatal hypothyroidism. Because MMI has been possibly associated with aplasia cutis (congenital skin or scalp defects), PTU is usually the drug of choice in the first trimester of pregnancy, due to the possible fetal effects of MMI; after the first trimester, the pregnant woman is usually switched to MMI due to the reported hepatic toxicity of PTU. Radioactive iodine is contraindicated in pregnancy due to fetal effects. Thyroidectomy is reserved for those patients who are noncompliant with or cannot tolerate medical therapy. Risks from surgery include vocal cord paralysis and hypoparathyroidism.

Thyroid storm is a rare but life-threatening complication of hyperthyroidism. Symptoms suggestive of storm include altered mental status, hyperthermia, cardiac arrhythmia, hypertension, vomiting, and diarrhea. Infection, surgery, labor or delivery, or other stressors may trigger thyroid storm in patients with hyperthyroidism.

Congestive heart failure can result from the effects of thyroxine on the myocardium. Because the mortality rate associated with thyroid storm is high, accurate early identification is crucial. These patients are best monitored in an intensive care unit. H igh-dose propylthiouracil is administered by mouth or nasogastric tube. β-Blockers are used to control the symptoms of tachycardia; however, they should be used with caution in those patients with congestive heart failure. Acetaminophen or cooling blankets are used for hyperthermia. Corticosteroids may also be used to prevent the peripheral conversion of T 4 to T 3.

Maternal hyperthyroidism may result in either fetal hyper- or hypothyroidism. When identified antenatally, the fetus should be treated either with maternal administration of PTU or injection of intra-amniotic thyroxine (fetal hypothyroidism). Failure to identify fetal thyrotoxicosis can result in nonimmune hydrops and fetal demise.

Postpartum Thyroiditis

About 5% of postpartum women will have postpartum thyroiditis with the peak onset at 6 months post delivery. There are three phases: hyperthyroid, hypothyroid, and euthyroid (although some will remain hypothyroid). The pathophysiology is similar to H ashimoto’s thyroiditis (lymphocytic infiltration) and is associated with antimicrosomal antibodies and antiperoxidase antibodies. Risk factors include type I diabetes (25% risk) and previous postpartum thyroiditis (20% risk). Treatment is antithyroid medications during the hyperthyroid phase, and monitoring carefully to switch to thyroid replacement during the hypothyroid phase.

Hypothyrodism

Recently, subclinical maternal hypothyroidism has gained interest, since this condition may be associated with adverse effects on neurological development and childhood intelligence. There is some evidence that levothyroxine replacement in the first trimester may lead to better outcomes. Currently, there is no consensus on universal screening for maternal hypothyroidism; however, those patients at increased risk or with symptoms should certainly undergo screening.

Hyperparathyroidism

Rarely, hyperparathyroidism can affect pregnant women. The patient may have kidney stones, or lethargy or pain. The diagnosis is made by an elevated serum calcium level, low serum phosphate, and elevated parathyroid hormone level (primary hyperparathyroidism). In the first and second trimesters, surgery (parathyroidectomy) is  the treatment of choice. In the third trimester, oral phosphate, a low calcium diet, and expectant management are generally preferred unless symptoms are significant. Surgery is usually performed after delivery.

COMPREHENSION QUESTIONS

21.1 A 25-year-old third-year G1P0 medical student had been diagnosed with borderline hypothyroidism 4 years ago and has thyroid studies done annually. Last year, her thyroid panel was within normal limits. She is currently at 15 weeks’ gestation, and has had a thyroid panel drawn today. Which of the following changes is likely to have occurred today as compared to last year’s result?

A. Elevation of serum TSH levels

B. Elevation of serum total thyroxine levels

C. Decrease in serum thyroid-binding globulin levels

D. Decrease in serum-free T 4 levels

E. No effect on TSH or total thyroxine levels

21.2 A 25-year-old G1P0 woman at 16 weeks’ gestation complains of some intermittent palpitations, and feeling very warm despite the air conditioning. Which of the following is the best screening test for hyperthyroidism?

A. Serum TSH levels

B. Serum thyroid-binding globulin levels

C. Serum antithyroid antibody levels

D. Serum total thyroxine levels

E. Serum transferrin levels

21.3 A 24-year-old woman delivered vaginally at term about 2 months previously. She was in good health until 1 week ago, when she began to complain of nervousness, tremulousness, and feeling palpitations. The TSH is 0.01 mIU/ L (normal: 0.5– 5). Which of the following is the most likely abnormality?

A. Immunoglobulin G (IgG) antibodies stimulating the TSH receptor

B. Antimicrosomal antibodies

C. Dominant nodule of the thyroid gland

D. Positive urine drug screen

E. Urine catecholamines

21.4 A 23-year-old G1P0 woman at 16 weeks’ gestation is suspected of hypothyroidism. Which of the following is most consistent with hypothyroidism in pregnancy?

TSH Free Thyroxine

Thyroid-Binding

Globulin Total Thyroxine

A. Unchanged Elevated Decreased Unchanged

B. Decreased Elevated Unchanged Decreased

C. Increased Decreased Elevated Unchanged

D. Unchanged Decreased Decreased Elevated

E. Unchanged Unchanged Unchanged Decreased

ANSWERS

21.1 B. The high estrogen levels during pregnancy lead to increased levels of thyroid-binding globulin and total T4, but the active or free T4 and TSH levels remain unchanged. In general, pregnancy is a euthyroid state.

21.2 A. A TSH level is considered the best screening test for hyperthyroidism. A low level suggests hyperthyroidism; an elevated level suggests hypothyroidism. The diagnosis of hyperthyroidism is confirmed by the presence of an elevated free T 4 level. Maternal hyperthyroidism may result in either fetal hyperthyroidism or hypothyroidism. Failure to identify fetal thyrotoxicosis can result in nonimmune hydrops and fetal demise. For this reason, it is important to screen women in their prenatal screen for TSH levels. If the TSH is borderline or a more definitive diagnosis is sought, then free T 4 is a good follow-up test.

21.3 B. Overall, the most common cause of hyperthyroidism in the United States is Graves disease. H owever, in the postpartum period, women with hyperthyroidism are more likely to have destructive lymphocytic thyroiditis. This is because the high corticosteroid levels in pregnancy suppress the autoimmune antibodies, and a flare occurs postpartum when the corticosteroid levels fall after the placenta delivers. Often, antimicrosomal and antiperoxidase antibodies are present. Thus, the postpartum patient is unique in that the cause of hyperthyroidism is usually lymphocytic thyroiditis rather than Graves disease.

21.4 C. With hypothyroidism, the TSH level is elevated and the free T 4 is decreased. With hyperthyroidism, the TSH is decreased and the free T 4 is increased. Normally, with pregnancy, the only physiologic change is increased total T 4. With early or mild hypothyroidism, one may occasionally find the TSH level as normal (upper limits of normal) and free T 4 as low; however, the findings most consistent with hypothyroidism would be elevated TSH and low T 4.

REFERENCES

American College of Obstetricians and Gynecologists. Thyroid disease in pregnancy. ACOG Practice

Bulletin 148. Washington, DC; 2015.

American College of Obstetricians and Gynecologists. Subclinical hypothyroidism in pregnancy. ACOG

Committee Opinion 381. Washington, DC; 2007.

Castro LC, Ognyemi D. Common medical and surgical conditions complicating pregnancy. In: H acker

NF, Gambone JC, H obel CJ, eds. Essentials of Obstetrics and Gynecology. 5th ed. Philadelphia, PA:

Saunders; 2009:191-218.

Cunningham FG, Leveno KJ, Bloom SL, H auth JC, Dwight JR, Spong CY. Thyroid and other endocrine

disorders. In: Cunningham FG, Leveno KJ, Bloom SL, H auth JC, Gilstrap LC III, Wenstrom KD,

eds. Williams Obstetrics. 24th ed. New York, N Y: McGraw-H ill; 2014:1126-1144.