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Thyroid Storm: Critical Care In Obstetrics

WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).

Thyroid disease is the second most common endocrine disease affecting women of reproductive age, and appropriate management of the pregnant patient with thyroid disease is important. Thyrotoxicosis (thyroid storm) is a generic term referring to a clinical and biochemical state resulting in over-production of and exposure to thyroid hormone. Exacerbation of hyperthyroidism in pregnancy is an obstetric emergency. It demands accurate diagnosis and a prompt therapeutic response in order to minimize risk to mother and fetus. Only about 1% to 2% of women with hyperthyroidism who receive thionamide experience thyroid storm -- but it is a devastating complication (1). In years past, up to 25% of pregnant patients with thyrotoxicosis during pregnancy perished. Maternal mortality for this condition is currently approximately 3%. Nevertheless, obstetricians and gynecologists need to know how to spot a brewing "storm" and treat it promptly so as to ensure the best possible outcome for mother and fetus. Pregnancy is associated with significant but reversible changes in maternal thyroid physiology that can lead to confusion in the diagnosis of thyroid abnormalities. Further complicating the diagnosis of thyroid dysfunction during pregnancy are the effects that several abnormal pregnancy conditions such as gestational trophoblastic disease and hyperemesis gravidarum have on thyroid function studies.

The purpose of this document is to review evidence-based research and approaches for diagnosis and management of thyroid storm during pregnancy. Especially relevant is the intimate relationship between maternal and fetal thyroid function, particularly during the first half of pregnancy. Significant fetal brain development continues considerably beyond the first trimester, making thyroid hormone also important later in gestation. Importantly, although overt maternal thyroid failure during the first half of pregnancy has been associated with several pregnancy complications and intellectual impairment in offspring, it is currently less clear whether milder forms of thyroid dysfunction have similar effects on pregnancy and infant outcomes.

Background:

Thyrotoxicosis is a generic term referring to a clinical and biochemical state resulting from overproduction of the exposure to thyroid hormone. Overt hyperthyroidism complicates approximately 2 in 1,000 pregnancies. Pregnant women with hyperthyroidism are at increased risk for spontaneous pregnancy loss, congestive heart failure, thyroid storm, preterm birth, preeclampsia, fetal growth restriction, and associated with increased perinatal morbidity and mortality (2). Grave's disease, the most common cause of thyrotoxicosis in pregnancy, is an autoimmune condition characterized by production of thyroid-stimulating immunoglobulin (TSI) and thyroid-stimulating hormone binding inhibitory immunoglobulin (TBII). These two antibodies facilitate the thyroid-stimulating hormone (TSH) receptor in the mediation of thyroid stimulation and inhibition, respectively. Hyperthyroidism is thyrotoxicosis resulting from an abnormally functioning thyroid gland. Thyroid storm is an acute, severe exacerbation of hyperthyroidism. Although only 0.2% of pregnancies are complicated by hyperthyroidism and the thyroid storm is considered rare, but it can be life threatening if not diagnosed and managed early. In pregnant women with a history Grave's disease, however, thyroid-stimulating antibody activity may actually decline, leading to chemical remission during pregnancy (3). Other causes of overt hyperthyroidism include functioning adenoma or toxic nodular goiter, thyroiditis, and excessive thyroid hormone intake.

There is a unique form of hyperthyroidism associated with pregnancy called gestational transient thyrotoxicosis. It is typically associated with hyperemesis gravidarum, and can be due to high levels ofhuman chorionic gonadotropin (hCG) resulting from molar pregnancy. These high hCG levels lead to TSH receptor stimulation and temporary hypothyroidism. Women with gestational transient thyrotoxicosis are rarely symptomatic and treatment with antithyroxine drugs has not been shown to be beneficial (4). With expectant management of hyperemesis gravidarum, serum free T4 levels usually normalize in parallel with the decline in hCG concentrations as pregnancy progresses beyond the first trimester. Notably, TSH levels may remain partially depressed for several weeks after free T4 levels have returned to normal range. Gestational transient thyrotoxicosis has not been associated with poor pregnancy outcomes.

Impact of Pregnancy on Thyroid:

Thyroxine (T4), the major secretory product of the thyroid gland, is converted in peripheral tissues to triiodothyronine (T3), the biologically active form of this hormone. T4 secretion is under the direct control of pituitary TSH. The cell surface receptor for TSH is similar to the receptors for luteinizing hormone (LH) and human chorionic gonadotropin (hCG). T4 and T3 are transported in the peripheral circulation bound to thyroxine-binding globulin (TBG), transthyretin (formerly called "prealbumin") and albumin. Less than 0.05% of plasma T4, and less than 0.5% of plasma T3, are unbound and able to interact with target tissues (4). Routine T4 measurements reflect total serum concentration and may be altered by increases or decreases in concentrations of circulating proteins. By 20 weeks' gestation, plasma TBG increases 2.5 folds because of reduced hepatic clearance and an estrogen-induced change in the structure of TBG that prolongs serum half-life (5). This TBG alteration causes significant changes in some of the test results in pregnancy. There is a 25% to 45% increase in serum total T4 (TT4) from a pregravid level of 5 to 12 mg to 9 to 16 mg. Total T3 (TT3) increases by about 30% in the first trimester and by 50% to 65% later (6).

The increase in available protein binding induced by pregnancy causes a transient change in free T4 (FT4) and free thyroxine index (FTI) in the first trimester (possibly related to an increase in hCG). Increased concentrations of TSH stimulate restoration of the free serum T4 level, such that FT4 and FTI levels are generally maintained within the normal non-pregnant range. Ultrasound evaluation of the thyroid gland during pregnancy shows an increase in volume, whereas its echo structure remains unchanged (4)(7). Plasma iodide levels decrease in pregnancy due to fetal use of iodide and increased maternal renal clearance. The result in many pregnant women is a 15% to 18% increase in size of the thyroid gland. The enlargement usually resolves after delivery and is not associated with abnormal thyroid function tests.

Diagnostic Approach:

Mild hyperthyroidism mimics symptoms of normal pregnancy, and can be present as fatigue, increased appetite, vomiting, palpitations, tachycardia, heat intolerance, increased urinary frequency, insomnia, and emotional instability. The suspicion increases if patient has tremor, nervousness, frequent stools, excessive sweating, brisk reflexes, muscle weakness, goiter, hypertension, or weight loss. Grave's ophthalmopathy (stare, lid lag and retraction, exophthalmos) and dermopathy (localized or pretibial myxedema) are diagnostic. The disease usually gets worse in the first trimester but typically moderates later in pregnancy. Untreated hyperthyroidism poses considerable maternal and fetal risks, including preterm delivery, severe preeclampsia, heart failure, and thyroid storm (8). Although nausea is common in early pregnancy, the occurrence of hyperemesis gravidarum together with weight loss can signify overt hyperthyroidism. Thyroid testing may be beneficial in these circumstances.

Potential Maternal and Fetal Complications in Uncontrolled Hyperthyroidism:

MaternalFetal
Pregnancy-induced hypertensionHyperthyroidism
Preterm deliveryNeonatal hyperthyroidism
Congestive heart failureIntrauterine growth restriction
Thyroid stormSmall for gestational age
Placental abruptionPrematurity
MiscarriageStillbirth
InfectionCentral hypothyroidism

Characteristics of Thyroid Storm:

The characteristics of thyroid storm, which is a hypermetabolic complication of hyperthyroidism, and hyperpyrexia (temperature >41C), cardiovascular compromise (tachycardia out of proportion to the fever, dysrhythmia, cardiac failure), gastrointestinal upset (diarrhea), and central nervous system changes (restlessness, nervousness, changed mental status, confusion, and seizures). Thyroid storm is a clinical diagnosis, and treatment should be initiated before confirmatory test results are available. In many patients there is absence of classic symptoms. Be alert for other signs of thyrotoxicosis in any patient with postpartum congestive heart failure, tachycardia, and severe hypertension (9). Occasionally, the diagnosis may be obfuscated by central nervous system (CNS) features, such as coma after cesarean section or seizures suggestive of eclampsia. The resulting delay in diagnosis can increase the risk of maternal mortality. Thyroid storm is usually seen in patients with poorly controlled hyperthyroidism complicated by additional physiologic stressors, such as infection, surgery, thromboembolism, preeclampsia, and parturition (10).

Laboratory Tests:

The laboratory profile of a mother with thyroid storm reveals leukocytosis, elevated hepatic enzymes, and occasionally hypercalcemia. Thyroid function test results are consistent with hyperthyroidism (elevated FT4/FT3 and depressed TSH) but they may not always correlate with the severity of the thyroid storm.  Laboratory investigations should include baseline electrolyte, glucose, renal and liver function testing, and the coagulation studies. If patient is unconscious or has focal CNS signs, it may be helpful to do a CT or MRI of the brain. Patients with focal CNS signs that do not respond to specific thyroid storm therapy are at risk of atrial fibrillation and CNS embolization, so investigate for cerebral emboli and prescribe anticoagulants if necessary. Tailor blood, uterine and wound cultures (as appropriate), and chest x-ray are essential. To define a patient's cardiac rhythm, do a 12-lead electrocardiogram (ECG) and continuous cardiac monitoring. An echocardiogram is helpful for management in cases where cardiac decompensation is suspected. Pulse oximetry should be used to monitor peripheral arterial oxygen saturation, and blood gas analysis will help acid-base balance assessment.

Management of Thyroid Storm:

Thyroid storm is a clinical diagnosis based on severe signs of thyrotoxicosis, with significant hyperpyrexia (>103F or >41C) and neuropsychiatric symptoms that are essential for the clinical diagnosis. Tachycardia with a pulse rate exceeding 140 beats/min is not uncommon, and congestive heart failure is a frequent complication. Gastrointestinal symptoms such as nausea and vomiting, accompanied by liver compromise, have been reported. Management of thyroid storm is best accomplished in an obstetric intensive care unit (ICU), or an ICU that has continuous fetal monitoring and can handle an emergent delivery. Therapy is designed to:

  • Reduce the synthesis and release of thyroid hormone;
  • Remove thyroid hormone from the circulation and increase the concentration of TBG;
  • Block the peripheral conversion of T4 to T3;
  • Block the peripheral actions of thyroid hormone;
  • Treat the complications of thyroid storm and provide support;
  • Identify and treat potential precipitating conditions.

Supportive adjunctive care for the patient in thyroid storm are:

  • IV fluids and electrolytes;
  • Cardiac monitoring;
  • Consideration of pulmonary artery catheterization (central hemodynamic monitoring to guide beta-blocker therapy during hyperdynamic cardiac failure);
  • Cooling measures: blanket, sponge bath, acetaminophen, avoid salicylates (risk of increased T4). Acetaminophen is the drug of choice;
  • Oxygen therapy (consider arterial line to follow serial blood gases);
  • Nasogastric tube if patient is unable to swallow (may be only avenue for propylthiouracil administration).

Medication to reduce synthesis of thyroid hormones are: thionamides (propylthiouracil (PTU) and methimazole); iodide and glucocorticoids. These drugs should be started as soon as diagnosis of thyroid storm is made. PTU and methimazole inhibit iodination of tyrosine -- leading to reduce synthesis of thyroid hormones and block peripheral conversion of T4 to T3 (11). These drugs alone can reduce the T3 concentration by 75%. Iodide can be in the form of Lugol's iodine, SSKI (Strong Solution of Potassium Iodide), sodium iodide, orografin, or lithium carbonate (for use in patients allergic to iodine). These drugs function by inhibiting proteolysis of thyroglobulin and thereby blocking the release of stored hormone. Because one of the side effects is an initial increase in production of thyroid hormone, it is therefore very important to start PTU before you give iodides. Glucocorticoids block release of stored hormone (as do iodides), and peripheral conversion of T4 to T3 (as do thionamides). They may also bolster adrenal function, and prevent adrenal insufficiency, although data in support of this particular benefit are few (12). Start PTU before giving iodides.

Propylthiouracil (PTU) followed at least 1 hour later by iodides to block T4 release (IV sodium iodide or oral Lugol's):

  1. PTU orally or via nasogastric tube, 300-800 mg loading dose followed by 150-300 mg every 6 hours;
  2. One hour after instituting PTU give: Sodium iodide, 500 mg every 8-12 hours or oral Lugol's solution, 30-60 drops daily in divided doses.

Iodides may be discontinued after initial improvement.

Give adrenal glucocorticoids to inhibit peripheral conversion of T4 to T3. Consider any of the following options as appropriate:

  1. Hydrocortisone, 100 mg IV every 8 hour, or
  2. Prednisone, 60 mg PO every day, or
  3. Dexamethasone, 8 mg PO every day

Glucocorticoids may be discontinued after initial improvement.

Medications to control maternal tachycardia: beta-blocker agents -- propranolol can be used to control autonomic symptoms (especially tachycardia). Beta-adrenergic blockade may have some effect on inhibition of peripheral conversion of T4 to T3, but will not alter thyroid hormone release nor prevent thyroid storm. Use propranolol with caution because it has a tendency to increase pulmonary diastolic pressure, and cardiac failure is a frequent presentation of thyroid storm. Treatment with a beta-blocker to control tachycardia is usually reserved for heart rates of 120 beats per minute or higher. Propranolol, labetalol, and esmolol have all been used successfully in pregnancy (13).

Commonly following dosages are used:

  1. Propranolol, 1-2 mg/min IV or dose sufficient to slow heart rate to 90 bpm; or 20-80 mg PO or via nasogastric tube every 4-6 hourly;
  2. Esmolol, a short-acting beta-acting antagonist given IV with a loading dose of 250 to 500 g/kg of body weight followed by a continuous infusion at 50 to 100 g/kg/min may also be used.
  3. Consider a echocardiogram and/or pulmonary artery catheter to help guide management, especially in cardiac failure;
  4. If patient has severe bronchospasm -- give 1-5 mg reserpine every 4-6 hours or 1 mg/kg orally of guanethidine every 12 hours.

Heart failure due to cardiomyopathy from excessive thyroxine in women with uncontrolled hyperthyroidism is more common in pregnant women (14). Treatment of thyroid storm or thyrotoxic heart failure is similar. They both should be treated as medical emergencies.

Phenobarbital: 30 to 60 mg orally every 6-8 hours as needed to control restlessness.

After initial clinical management, iodides and glucocorticoids can be discontinued. Reserve plasmapheresis or peritoneal dialysis to remove circulating thyroid hormone for patients who do not respond to conventional therapy. Prescribe anticoagulants if appropriate. If conventional therapy is unsuccessful: consider subtotal thyroidectomy (during second-trimester pregnancy) or radioactive iodine (postpartum). 

Postpartum Care:

Women with Grave's disease should be followed up closely after delivery, because recurrence or aggravation of symptoms is not uncommon in the first few months of postpartum. Most asymptomatic women should have a TSH and free T4 performed approximately 6 weeks postpartum. Both PTU and methimazole are excreted in breast milk, but PTU is largely protein bound and does not seem to pose a significant risk to the breastfed infant. Methimazole has been found in breastfed infants of treated women in amounts sufficient to cause thyroid dysfunction. However, at low doses (10-20 mg/d) it does not seem to pose a major risk to the nursing infant. The American Academy of Pediatricians considers both compatible with breastfeeding (9)(15).

Fetal Hyperthyroidism:

In mothers with a history of Grave's disease previously treated with ablation therapy, either surgery or radioactive iodine, concentrations of TSI may remain elevated, in spite of maternal euthyroidism. The concentration of these IgG immunoglobulins is low early in normal pregnancy, reaching a level in the fetus similar to that of the mother around 30 weeks of gestation. Therefore, the symptoms of fetal hyperthyroidism are not evident until 22 to 24 weeks of gestation. When TSI levels are present in high concentrations, fetal hyperthyroidism may result, characterized by fetal tachycardia, intrauterine growth restriction, oligohydramnios, and occasionally, a goiter identified on ultrasonography (16). The diagnosis may be confirmed by measuring thyroid hormone levels in cord blood obtained by cordocentesis. Serial cordocentesis for monitoring drug therapy has been proposed, but its value has been questioned (16)(17). Fetal goiter can be detected by ultrasonography. Treatment consist of antithyroid medication given to the mother, PTU 100 to 400 mg/day or Tapazole (MM) 10 to 20 mg/day. The dose is guided by the improvement and resolution of fetal tachycardia and normalization of fetal growth, both of which are indicators of good therapeutic response.  

Neonatal Hyperthyroidism:

It is infrequent, with an incidence of less than 1% of infants born to mothers with Grave's disease, therefore affecting 1 in 50,000 neonates. In the vast majority of cases, the disease is caused by the transfer of maternal immunoglobulin antibodies to the fetus. These stimulating thyroid antibodies to the TSH receptor (TSIs), when present in high concentrations in maternal serum, cross the placental barrier, stimulate the fetal thyroid gland, and may produce fetal or neonatal hyperthyroidism (15)(17). When the mother is treated with antithyroid medications, the fetus benefits from maternal therapy, remaining euthyroid during pregnancy. However, the protective effect of the antithyroid drug is lost after delivery, and neonatal hyperthyroidism may develop within a few days after birth. High titers of TSI receptor antibodies, a three- to five-fold increase over baseline, in the third trimester of pregnancy are predictors of neonatal hyperthyroidism. If neonatal hyperthyroidism is not recognized and treated properly, neonatal mortality may be as high as 30%. Because of half-life of the antibodies is only a few weeks, complete resolution on neonatal hyperthyroidism is the rule (17). A few cases of familial neonatal Grave's disease have been reported. The pathogenesis is not clearly understood. This condition may persist for several years. Sporadic cases of neonatal hyperthyroidism without evidence of the presence of circulating TSI in mother or infant have recently been published. Activation of mutations in the TSH receptor molecule are the cause of this entity (1)(15)(17). It is inherited as an autosomal dominant trait, and in contrast to Grave's neonatal hyperthyroidism, the condition persists indefinitely. Treatment with antithyroid medications followed by thyroid ablation therapy are eventually needed.

Teratogenic effects of Antithyroid Medications:

PTU, methimazole and whole category -- there is general consensus among clinicians that the lowest dose needed to keep T3 and T4 within the upper normal range for these women should be used (18). Because women previously ablated with either radioactive iodine or thyroidectomy may still be producing thyroid-stimulating antibodies (even though they are themselves euthyroid), the fetus remains at risk and should be monitored with serial ultrasonography for growth and early detection of goiter. No deleterious effects on neonatal thyroid function or on physical and intellectual development of breastfed infants have been described (19).

PTU: it is first-line treatment for Grave's disease in pregnancy due to lower risks of teratogenicity than methimazole. It crosses the human placenta and associated with fetal hypothyroidism, and rarely aplasia cutis. Cordocentesis is sometimes recommended to test fetal thyroid function. It does not readily crosses membranes and milk concentrations are quite low.

Methimazole (Thiamazole, Mercazole, Tapazole): it is the second-line treatment of Grave's disease. It crosses the human placenta and can induce fetal goiter and even cretinism in a dose-dependent fashion. It is also commonly associated with fetal anomalies such as aplasia cutis, esophageal atresia, and choanal atresia (20). Long-term follow-up studies of exposed children reveal no deleterious effects on their thyroid function or physical and intellectual development with doses up to 20 mg/d (19). It is excreted in breast milk.

Propranolol, labetalol and whole category: approximately 3% of women take an antihypertensive during pregnancy. The American College of Obstetricians and Gynecologists (ACOG) recommends treatment for women with a systolic blood pressure higher than 170 mmHg and/or diastolic blood pressure above 109 mmHg. There is no consensus whether lesser degrees of hypertension require treatment during pregnancy because antihypertensive therapy improves only the maternal, not the fetal, outcome in women with mild to moderate chronic hypertension (22).

Radioactive iodine (iodine-131; I-131): it is contraindicated in pregnant women. It is cost-effective, safe, and reliable treatment for hyperthyroidism in non-pregnant women (21). Although excreted from the body within 1 month, the ACOG recommendation is that women should avoid pregnancy for 4-6 months following treatment. No adequate reports or well-controlled studies in human fetuses are available. Detrimental effects on the thyroid of the developing fetus as a result of I-131 treatment for thyrotoxicosis of the mother in the first trimester of pregnancy are reported. Breast-feeding should be avoided for at least 120 days after treatment.

Summary:

Thyroid storm is a life-threatening condition, requiring early recognition and aggressive therapy in an intensive care unit setting. During gestation, women with hyperthyroidism should have their thyroid function checked every 3-4 weeks. Grave's disease represents the most common cause of maternal hyperthyroidism during pregnancy. Fetal reaction is often unpredictable and different than the maternal response. Only 0.2% of gestations are complicated by thyroid storm and more than 90% of cases are caused by Grave's disease. Increased production of thyroid hormone occurs when autoantibodies (thyroid-stimulating antibody [TSAb] -- formerly known as LATS [long-acting thyroid stimulator]) against TSH receptors -- acts as TSH agonists. The diagnosis of fetal hyperthyroidism should be suspected in the presence of fetal tachycardia with or without Grave's disease treated by ablation therapy and with high titers of serum TSI antibodies. Fetal ultrasonography in experts' hands may be a valuable diagnostic tool. The diagnosis may be confirmed by the determination of fetal thyroid hormones by cordocentesis. Whether to prescribe a drug to a pregnant or breast-feeding woman is a decision that must be made in consideration of many factors, including, but not limited to, gestational age of the embryo or fetus, route of administration, absorption rate of the drug, whether the drug crosses the placenta or is excreted in breast milk, the necessary effective dose of the drug, molecular weight of the drug, whether monotherapy is sufficient or if multiple drugs are necessary to be effective, and the mother's genotype. However, accurate weighing benefit against risk requires a thorough understanding of the benefits and risks.

References:

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  2. Millar LK, Wing DA, Leung AS et al. Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 1994;84:946-949
  3. Kung AW, Jones BM. A change from stimulatory to blocking antibody activity in Grave's disease during pregnancy. J Clin Endocrinol Metab 1998;83:514-518
  4. Stagnaro-Green A, Chen X, Bogden JD et al. The thyroid and pregnancy: a novel risk factor for very preterm delivery. Thyroid 2005;15:351-357
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  10. Ecker JL, Musci TJ. Thyroid function and disease in pregnancy. Curr Probl Obstet Gynecol Fertil 2000;23:109-122
  11. Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001;86:2354-2356
  12. Luton D, Le Gac I, Vuillard E et al. Management of Grave's disease during pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab 2005;90:6093-6098
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  15. American Academy of Pediatricians, Committee on Drugs. American Academy of Pediatricians 2001;108:776-789
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  17. Mestman JH. Thyroid and parathyroid diseases in pregnancy. In Obstetrics normal and abnormal pregnancies; 5th ed. Publishers: Churchill, Livingstone, Elsevier 2007; p.1025
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Published: 2 June 2010

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