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This chapter addresses several common endocrine emergencies that may be seen in pregnant women. While most endocrine conditions can become emergencies if ignored or untreated, the intention of this chapter is not to exhaustively review endocrine complications in pregnancy; rather, the conditions that might realistically be faced in an ICU situation have been highlighted. These include thyrotoxicosis and thyroid storm, hypothyroidism and myxedema coma, addisonian crisis, pheochromocytoma, primary hyperalderonism, and diabetes insipidus. Diabetes mellitus and ketoacidosis have been dealt with elsewhere.
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Thyroid disease is the second most common endocrine condition affecting women of reproductive age. It is now common for obstetricians to care for women who enter pregnancy with an established thyroid deficiency or overactivity state. Because pregnancy in and of itself affects thyroid function, even women who are well-controlled prepregnancy may become uncontrolled requiring continued monitoring and adjustment. In addition, it is important to remember that the developing fetus may be at significant risk from circulating maternal antibodies that are no longer an issue for the mother. Despite the fact that hyperthyroidism is uncommon during pregnancy (0.2% of pregnancies) and thyroid storm is considered rare, vigilance is important because of the potential for significant morbidity and mortality in these conditions.
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Thyrotoxicosis is a generic term referring to a clinical and biochemical state resulting from overproduction of, and exposure to, thyroid hormone. The most common cause of thyrotoxicosis in pregnancy is Graves disease. This disorder is an autoimmune condition characterized by production of thyroid-stimulating immunoglobulin (TSI) and thyroid-stimulating hormone-binding inhibitory immunoglobulin (TBII) that act on the thyroid-stimulating hormone (TSH) receptor to mediate thyroid stimulation or inhibition, respectively.
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Thyroid storm is characterized by an acute, severe exacerbation of hyperthyroidism.
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Hypothyroidism results from inadequate thyroid hormone production and myxedema coma is an extreme form of hypothyroidism.
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Thyroiditis is caused by an autoimmune inflammation of the thyroid gland and may occur for the first-time postpartum. It is usually painless and may present as de novo hypothyroidism, transient thyrotoxicosis, or as initial hyperthyroidism followed by hypothyroidism within 1 year postpartum.
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Thyroxine (T4) is the major secretory product of the thyroid. The majority of circulating T4 is converted in the peripheral tissues to triiodothyronine (T3), the biologically active form of this hormone. T4 secretion is under the direct control of the pituitary TSH. The cell surface receptor for TSH is similar to the receptors for luteinizing hormone (LH) and human chorionic gonadotrophin (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. Routine T4 measurements reflect total serum concentration and may be factitiously altered by increases or decreases in concentrations of circulating proteins. Plasma concentrations of TBG increase 2.5-fold by 20 weeks’ gestation, because of reduced hepatic clearance and an estrogen-induced change in the structure of TBG that prolongs the serum half-life. This TBG alteration causes significant changes in many of the thyroid 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 approximately 30% in the first trimester and by 50% to 65% later. In order to maintain the homeostasis of free T4, the thyroid gland produces more T4 until the new steady state has been reached, around mid-gestation. Thereafter, changes in peripheral thyroid hormone metabolism require persistently increased T4 production to maintain normal serum free T4 concentrations. TSH levels are transiently depressed in the first trimester due to hCG elevation, but they increase to normal in the second and third trimesters. Pregnancy affects other changes in the thyroid system and ultimately the interpretation of thyroid function tests (Table 10-1).
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The fetal hypothalamic-pituitary-thyroid axis develops independently of the maternal thyroid function. The fetus begins concentrating iodine between 10 and 12 weeks’ gestation. By 20 weeks’ gestation, the fetal pituitary TSH is functional. The human placenta acts as a significant barrier to circulating T4, T3, and TSH. Despite this, in cases of congenital hypothyroidism, there is still sufficient passage of maternal thyroid hormones across the placenta (cord levels 25%-50% of normal) to prevent overt hypothyroidism at birth. Immunoglobulin G (IgG) autoantibodies, iodine, thyrotropin-releasing hormone (TRH), and antithyroid medications (propylthiouracil [PTU], methimazole) can readily cross the placenta and interfere with fetal thyroid activity. Fetuses of women being treated with antithyroid drugs are at risk for hypothyroidism and goiter, and should be closely monitored. Targeted ultrasound for fetal growth abnormalities and thyroid size should be performed serially. Antepartum fetal heart rate monitoring and occasionally percutaneous fetal blood sampling (if ultrasound reveals an obvious goiter) should also be entertained. Because IgG autoantibodies can cross the placenta, it is important that women with a prior history of Graves disease are tested for TSI and TBII.
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The causes of hyperthyroidism in pregnancy are listed in Table 10-2. Hyperthyroidism occurs in 0.2% of pregnancies and Graves disease accounts for more than 90% of these cases. Autoantibodies against TSH receptors (thyroid-stimulating antibody [TSAb]—formerly known as LATS [long-acting thyroid stimulator]) act as TSH agonists, thereby stimulating increased production of thyroid hormone. The clinical presentation of mild hyperthyroidism is similar to the symptoms of normal pregnancy (fatigue, increased appetite, vomiting, palpitations, tachycardia, heat intolerance, increased urinary frequency, insomnia, emotional lability) and may confound the diagnosis. More specific symptoms and signs highly suggestive of hyperthyroidism include tremor, nervousness, frequent stools, excessive sweating, brisk reflexes, muscle weakness, goiter, hypertension, and weight loss. Graves 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 moderates later in pregnancy. Untreated hyperthyroidism poses considerable maternal and fetal risks, including intrauterine growth restriction (IUGR), preterm delivery, severe preeclampsia, and heart failure (Table 10-3).
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Fetal and Neonatal Implications
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Perinatal risks include IUGR, prematurity, cardiac dysrhythmias, and intrauterine death. Fetal thyrotoxicosis should be considered in any pregnancy with Graves disease. Neonates of women with thyrotoxicosis are at risk for immune-mediated hypothyroidism and hyperthyroidism secondary to autoantibodies that may cross the placenta (Graves disease and chronic autoimmune thyroiditis). TBII can cause transient neonatal hypothyroidism and TSI can result in neonatal hyperthyroidism. The incidence is low (<5%) because thioamide treatment frequently decreases the titers of these antibodies. Maternal autoantibodies are cleared slowly in the neonate sometimes resulting in delayed presentation of neonatal Graves disease. Neonates of women with prior Graves disease who have been treated with surgery or radioactive iodine and who do not need thioamide therapy during pregnancy remain at significant risk for neonatal Graves disease because of the persistence of the thyrotropic antibodies.
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Laboratory diagnosis of hyperthyroidism is confirmed with a suppressed serum TSH in the setting of elevated free T4 levels (or FTI) without the presence of a nodular goiter or thyroid mass. In rare circumstances, the serum total T3 may demonstrate greater (or earlier) elevation than T4 (T3 toxicosis).
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Hyperthyroidism may also result from elevated serum levels of hCG, as seen with trophoblastic diseases and hyperemesis gravidarum. In these circumstances, treatment is seldom required, as the disease spontaneously resolves after the trophoblastic tissue is evacuated or vomiting is resolved. Biochemical hyperthyroidism is seen in up to 66% of women with severe hyperemesis gravidarum (undetectable TSH level or elevated FTI, or both), but this usually resolves by 18 weeks. If therapy is needed, efforts should be directed toward uncovering an underlying thyroid condition as clinical hyperthyroidism (as opposed to biochemical hyperthyroidism) is extremely unusual with hyperemesis gravidarum. Cardiac decompensation in pregnancy usually occurs only in poorly controlled hyperthyroid patients with anemia, infection, or hypertension. Reversible dilated cardiomyopathy, congestive cardiac failure, and ventricular fibrillation have been reported with thyroid storm. The hemodynamic changes associated with hyperthyroidism during pregnancy are outlined in Table 10-4.
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β-Adrenergic blockade is theoretically contraindicated with congestive heart failure, as adrenergic stimulation of the heart is the major compensating mechanism against cardiac failure. The negative inotropic effect imposed by β-adrenergic blockade may depress myocardial contractility. These drugs, however, are very effective for treating atrial fibrillation and supraventricular tachycardia that may accompany hyperthyroidism. Thus, cautious use of β-blocker therapy is recommended, as congestive heart failure during pregnancy is often rate related. A pulmonary artery catheter is an important adjunct to the effective and safe use of β-blocker therapy in these critical situations. Other helpful therapeutic modalities include diuretic therapy, digoxin, and bed rest. Cardiac dysfunction may linger for months after restoration of normal thyroid function.
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Treatment of Hyperthyroidism During Pregnancy
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The primary objective of treatment is to effectively control thyroid dysfunction until after delivery. Protecting the fetus from the effects of the disease and the side effects of the medical regimen is a secondary yet important objective. Basic treatment options are outlined in Table 10-5.
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Observation alone may be a reasonable treatment plan for mild clinical disease without cardiovascular compromise. For overt disease, antithyroid medications are the mainstay of treatment. PTU and methimazole (Tapazole) are two of the thioamide agents currently available in the United States. In Europe, the methimazole derivative carbimazole is used. Because carbimazole is rapidly metabolized to methimazole, these drugs are essentially the same. Both methimazole and PTU effectively block intrathyroid hormone synthesis, but PTU also blocks extrathyroid conversion of T4 to T3. Both agents readily cross the placenta and may inhibit fetal thyroid function. Methimazole was believed to be approximately 4 times more bioavailable to fetal tissue than PTU and has also been associated with aplasia cutis in infancy. For these 2 reasons, PTU has become the preferred medication for treating hyperthyroidism in pregnancy in the United States. Both of these beliefs have recently been disputed with studies showing no differences in mean umbilical cord TSH or FT4 levels between PTU- and methimazole-treated neonates and no increased incidence of cutis aplasia. Twice-daily doses of 150 to 200 mg PTU or a dosage of 100 mg tid will usually control hyperthyroidism within 4 to 8 weeks. Lack of response is usually due to noncompliance and may require hospitalization. The goal of treatment is to use the smallest dose that maintains maternal free T4 levels at or just above the upper limit of normal. Clinical and laboratory follow-up (TSH, free T4, free T3) should occur every 2 to 4 weeks. Most women (90%) will have a significant improvement within 2 to 4 weeks. Rapid improvement necessitates a decrease in dosage. Improvement commonly occurs in the second trimester, and as many as 40% of mothers may discontinue therapy. It may, however, be reasonable to continue giving small doses to ameliorate the risks of fetal thyrotoxicosis imposed by transplacental passage of TSAb and to reduce the general overall incidence of thyroid storm during labor and delivery.
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Baseline white blood cell (WBC) and liver function tests should be obtained before initiating antithyroid therapy, as hyperthyroidism itself may also cause liver enzyme elevations and leukopenia. The incidence of agranulocytosis with thioamides is about 0.1% to 0.4%. This is usually heralded by a fever and sore throat, and these symptoms should precipitate immediate discontinuation of the drug and checking for leukopenia. Antithyroid medications should also be discontinued if liver function values become extremely abnormal. These medications may be restarted during the postpartum period as disease activity dictates, but the clinician should be aware that treatment with other thioamides carries a high risk for cross reaction. Other major side effects of thioamides, which include a lupus-like syndrome, thrombocytopenia, hepatitis/hepatic infarction, and vasculitis, occur in fewer than 1% of patients. Minor side effects include rash, argthralgias, nausea, anorexia, fever, and a loss of taste or smell may occur in up to 5% of cases. Breast-feeding is permissible while taking PTU because little is passed into breast milk with standard doses. Breast-feeding is also acceptable with methimazole therapy despite the fact that it is present in a higher ratio than PTU in breast milk.
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β-Adrenergic blockers may be used as adjunctive therapy to control the symptoms of tremor and palpitations until the thioamides decrease thyroid hormone levels. Propranolol is the most commonly used β-blocker for this purpose. Relative contraindications to the use of β-adrenergic blockers include obstructive lung disease, heart block, heart failure, and insulin use. Although unusual, there may be adverse fetal effects such as bradycardia, growth restriction, and neonatal hypoglycemia. It is advisable to minimize the duration of β-adrenergic blocker therapy during gestation.
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Subtotal thyroidectomy is reserved for patients with severe antithyroid drug side effects or failed medical suppression of thyroid function. To minimize pregnancy complications, surgery is usually performed during the second trimester. Preoperatively, hyperthyroidism should be controlled with antithyroid medication for 7 to 10 days, a β-adrenergic blocker (propranolol, 20 mg, 3-4 times daily), and inorganic iodide (Lugol solution, 3 drops twice daily) for 4 to 5 days. The latter two can be discontinued 48 hours postoperatively. Iodide must be used cautiously to minimize the risk of severe fetal hypothyroidism and goiter.
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Radioactive iodine administration is contraindicated during pregnancy because of the risk of fetal thyroid ablation. It is recommended that women avoid pregnancy or breast-feeding for 4 months after iodine 131 (131I) therapy. This agent readily crosses the placenta and may cause permanent damage to the fetal thyroid if used after 10 to 12 weeks of gestation. Inadvertent use of 131I in very early pregnancy (up to 10 weeks) is usually not associated with any long-term fetal/neonatal thyroid side effects.
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Thyroid storm is a rare but potentially fatal hypermetabolic complication of hyperthyroidism characterized by cardiovascular compromise (tachycardia out of proportion to the fever, dysrhythmia, cardiac failure), hyperpyrexia, and central nervous system changes (restlessness, nervousness, changed mental status, confusion, and seizures) (Table 10-6). Thyroid storm is estimated to occur in 1% to 2% of pregnancies complicated by hyperthyroidism. This rare but devastating complication is usually seen in patients with poorly controlled hyperthyroidism complicated by additional physiologic stressors such as infection, surgery, thromboembolism, preeclampsia, and parturition. Precipitating events for thyroid storm are presented in Table 10-7. Diagnosis can be difficult, and if delayed, the patient may lapse into shock and/or coma. Diagnostic scoring systems have been developed and one is shown in Table 10-8. The laboratory profile of the 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 do not always correlate with the severity of the thyroid storm. Treatment should, however, be initiated on the suspicion of the condition and the clinician should not wait for laboratory confirmation before starting therapy. Management is best accomplished in an obstetric ICU. Table 10-9 reviews basic supportive adjunctive care for patients in thyroid storm. The basic goals of therapy are 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 the potential precipitating conditions
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To these ends the following drugs are available: (1) PTU and methimazole, both of which inhibit iodination of tyrosine (leading to reduced synthesis of thyroid hormones), and block peripheral conversion of T4 to T3. These drugs alone can reduce the T3 concentration by 75%. (2) For thyroid storm, Lugol iodine, SSKI (saturated solution of potassium iodide), sodium iodide, orografin, and lithium carbonate. These drugs function by blocking the release of stored hormone by inhibiting the proteolysis of thyroglobulin. One of the side effects of such agents is to initially increase the production of thyroid hormone, and it is therefore very important to start PTU prior to giving iodides. The mainstay of therapy are glucocorticoids that should be started as soon as the condition is recognized, and act by blocking the release of stored hormone (as do iodides), and by blocking peripheral conversion of T4 to T3 (as do the thioamides). Figure 10-1 describes the action of antithyroid medications. Specifics of the medical therapy are detailed as follows:
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Oral PTU (or by nasogastric tube if necessary) with a 300- to 600-mg loading dose followed by 150 to 200 mg orally every 4 to 6 hours.
Iodide initiated 1 to 2 hours after PTU administration:
Oral SSKI to block T4 release (2-5 drops orally every 8 hours)
Intravenous (IV) sodium iodide, 500 to 1000 mg every 8 hours
Oral Lugol iodine solution (8 drops every 6 hours)
Oragrafin (62% iodine) can be used if other solutions are not available. Three grams given orally will suppress thyroid hormone release for 2 to 3 days.
Oral lithium carbonate, 300 mg every 6 hours (therapeutic level = 1 mEq/L)
Adrenal glucocorticoids: This may be in the form of dexamethasone, 2 mg intravenously or intramuscularly every 6 hours for 4 doses (or hydrocortisone, 300 mg/d IV or prednisone, 60 mg/d orally).
Propranolol (20-80 mg orally or by nasogastric tube every 4-6 hours or 1-2 mg/min IV for 5 minutes for a total of 6 mg, followed by 1-10 mg IV every 4 hours) is effective for controlling tachycardia. If the patient has a history of severe bronchospasm, reserpine or guanethidine may be used:
Reserpine, 1 to 5 mg IM every 4 to 6 hours
Guanethidine, 1 mg/kg orally every 12 hours
Phenobarbital, 30 to 60 mg orally every 6 to 8 hours, is needed to control restlessness.
Iodides and glucocorticoids may be discontinued after initial clinical improvement.
Plasmapheresis or peritoneal dialysis to remove circulating thyroid hormone is an extreme measure reserved for patients who do not respond to conventional therapy.
An algorithm for the management of thyroid storm is presented in Fig 10-2.
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Most cases of hypothyroidism in pregnancy are the result of a primary thyroid dysfunction or are iatrogenic from prior thyroid surgery or radioactive iodine. A few cases are caused by hypothalamic abnormalities. The most common causes of hypothyroidism in pregnant or postpartum women include Hashimoto disease (chronic thyroiditis or chronic autoimmune thyroiditis), subacute thyroiditis, thyroidectomy, radioactive iodine therapy and iodine deficiency, and drugs that interfere with thyroid function (Table 10-10). Hashimoto disease is the most common etiology in developed countries and is characterized by production of antithyroid antibodies. These include thyroid antimicrosomal and antithyroglobulin antibodies. Hashimoto disease may be associated with thyroid enlargement (as is iodine deficiency that is rare in the United States). Hashimoto disease is more common in patients with diabetes mellitus; in one study of 100 diabetic women, 20% of patients with type 1 diabetes also had Hashimoto disease. Subacute thyroiditis is not associated with goiter. Goiter is generally thought to be a sign of compensatory TSH production in the face of low circulating T4. On a worldwide basis, the most common cause of hypothyroidism is iodine deficiency. Patients recently arrived in the United States from a region where iodine deficiency is endemic and who have features of hypothyroidism, as well as those with malnutrition, should be considered as candidates for iodine replacement.
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The symptoms of hypothyroidism are common to all of the underlying etiologies (Table 10-11). Patients complain of constipation, cold intolerance, cool, dry skin, coarse hair, irritability, and inability to concentrate. Of note, however, is a significant overlap with complaints common to euthyroid pregnant women, making the clinical diagnosis difficult. The presence of paresthesias may be helpful, as it is an early symptom in approximately 75% of patients with hypothyroidism. The presence of delayed deep tendon reflexes is also suggestive of hypothyroidism. In addition, signs of gross myexedma, including a low body temperature, large tongue, hoarse voice, and periorbital edema, are not found in normal pregnancy, and their presence should prompt an immediate evaluation for hypothyroidism. Patients may complain of excessive fatigue. Gestational hypertension is common. Postpartum amenorrhea and galactorrhea associated with hyperprolactinemia may be indicative of hypothyroidism.
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Fetal and Neonatal Implications
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Laboratory diagnosis, an elevated TSH in association with a low serum free T4 concentration, is the most sensitive indicator of primary hypothyroidism. Because TBG is elevated in pregnancy, the total serum T4 level may not be as low as would be expected and may appear inappropriately high in the setting of an elevated TSH. Positive-thyroid autoantibodies support the diagnosis of hypothyroidism, particularly in the absence of a past history of thyroidectomy or radioactive iodine therapy. Elevated serum cholesterol concentration is useful in nonpregnant patients, but is not helpful in pregnancy, as serum cholesterol concentration increases by up to 60% above prepregnancy values during gestation.
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Treatment of Hypothyroidism During Pregnancy
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Once a diagnosis of hypothyroidism is made in a pregnant patient, full replacement doses of T4 should be instituted, regardless of the degree of thyroid function. This will minimize further fetal exposure to a hypothyroid environment. Therapy can be titrated rapidly in young pregnant women with no other comorbid conditions starting with 0.1 mg of T4 daily for 3 to 5 weeks. Thereafter, dosage adjustments can be made depending on the thyroid function test results. Because T4 has a long half-life, it can be given once a day. With adequate treatment, the serum TSH concentration should decrease to values below 6 U/mL within 4 weeks, and the serum free T4 concentration should increase to normal values for pregnancy in the same timespan. The optimal range for TSH during pregnancy is less than 3.0 U/mL. It is important to note that normal total serum T4 concentrations in pregnancy are higher than the normal range for nonpregnant women due to an increase in thyroxine binding and increases in serum TBG concentration. The free T4 concentration is ideally in the upper range of normal value. If the values do not return to normal, the dose of T4 should be increased by 0.05 mg increments. The serum TSH concentration may take longer to return to normal values.