Chapter 10: Thyroid and Other Endocrine Emergencies

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.

Thyroid Disease

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.

Definitions

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.

Thyroid storm is characterized by an acute, severe exacerbation of hyperthyroidism.

Hypothyroidism results from inadequate thyroid hormone production and myxedema coma is an extreme form of hypothyroidism.

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.

Physiology

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).

Fetal Effects

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.

Hyperthyroidism

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).

Fetal and Neonatal Implications

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.

Laboratory Diagnosis

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).

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.

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.

Treatment of Hyperthyroidism During Pregnancy

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.

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.

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.

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.

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.

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.

Thyroid Storm

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

1. Reduce the synthesis and release of thyroid hormone

2. Remove thyroid hormone from the circulation and increase the concentration of TBG

3. Block the peripheral conversion of T₄ to T₃

4. Block the peripheral actions of thyroid hormone

5. Treat the complications of thyroid storm and provide support

6. Identify and treat the potential precipitating conditions

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:

1. 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.

2. Iodide initiated 1 to 2 hours after PTU administration:

   1. Oral SSKI to block T₄ release (2-5 drops orally every 8 hours)

   2. Intravenous (IV) sodium iodide, 500 to 1000 mg every 8 hours

   3. Oral Lugol iodine solution (8 drops every 6 hours)

   4. 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.

   5. Oral lithium carbonate, 300 mg every 6 hours (therapeutic level = 1 mEq/L)

3. 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).

4. 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:

   1. Reserpine, 1 to 5 mg IM every 4 to 6 hours

   2. Guanethidine, 1 mg/kg orally every 12 hours

5. Phenobarbital, 30 to 60 mg orally every 6 to 8 hours, is needed to control restlessness.

6. Iodides and glucocorticoids may be discontinued after initial clinical improvement.

7. Plasmapheresis or peritoneal dialysis to remove circulating thyroid hormone is an extreme measure reserved for patients who do not respond to conventional therapy.

8. An algorithm for the management of thyroid storm is presented in Fig 10-2.

Hypothyroidism

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.

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.

Fetal and Neonatal Implications

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.

Treatment of Hypothyroidism During Pregnancy

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.

Myxedema coma represents the extreme expression of severe hypothyroidism and is considered a medical emergency with a 20% mortality rate. It is very rare in pregnancy and usually affects older patients. It is characterized by hypothermia, hypotension, hypoventilation, hyponatremia, and bradycardia. Primary objectives in treating myxedema coma are restoration of normal thyroid hormone levels, correction of electrolyte disturbances, and identification and treatment of any underlying infection. Because of the inherently high mortality rate, treatment should be started immediately and should include appropriate supportive therapy and corticosteroids to prevent adrenal insufficiency (Table 10-12). Possible precipitating factors should also be identified and treated. Levothyroxine sodium may be given via a nasogastric tube, but the preferred route of administration is intravenous. A bolus dose of levothyroxine sodium is given as quickly as possible to increase the peripheral pool of T₄. This should usually be between 300 and 500 μg. Although such a dose is usually tolerated well, rapid IV administration of large doses of levothyroxine sodium should be cautiously undertaken in patients with cardiac compromise. Clinical judgment in this situation may dictate smaller IV doses of levothyroxine sodium. The initial dose is followed by daily IV doses of 75 to 100 μg until the patient is stable and oral administration is feasible. Normal T₄ levels are usually achieved within 24 hours, followed by progressive increases in T₃. Improvement in cardiac output, blood pressure, temperature, and mental status generally occur within 24 hours, with further improvement in the other manifestations of hypothyroidism in 4 to 7 days.

Acute adrenocortical insufficiency or addisonian crisis can occur in pregnancy when a patient with chronic adrenal insufficiency is stressed, or in one who is undiagnosed. Normal levels of total and free cortisol, urinary free cortisol, and adrenocorticotrophic hormone (ACTH) in pregnancy are shown in Table 10-13. It may also result from an obstetric complication that results in disseminated intravascular coagulopathy (DIC), such as severe preeclampsia or eclampsia, abruptio placentae, amniotic fluid embolus, or postpartum hemorrhage. In such cases, bilateral massive adrenal hemorrhage may occur and constitute an acute emergency. This condition usually presents with nausea, vomiting, abdominal pain, and shock, and is frequently fatal. Early recognition and treatment are paramount to avoiding a bad outcome. A similar presentation has been noted in the third trimester of pregnancy or in the postpartum period in association with acute pyelonephritis, gram-negative bacillemia, and fulminant meningococcal infection (Waterhouse-Friderichsen syndrome). Therapy for acute adrenocortical insufficiency in pregnancy should include an initial IV bolus of 200 mg hydrocortisone succinate (Solu-Cortef) followed by 100 mg in 1 L of normal saline solution given over 30 minutes. One hundred milligrams of hydrocortisone succinate should be placed in each subsequent liter of normal saline infused, until the patient is adequately hydrated. This may take up to 5 L. Hypoglycemia may be prevented by instituting a 50-gm glucose infusion. Because the patient will receive up to 600 mg of hydrocortisone succinate with this protocol, no added mineralocorticoid is required.

Pheochromocytoma in Pregnancy

Pheochromocytoma is a rare endocrine tumor. When associated with pregnancy, it can be very dangerous for both the mother and the fetus. The main sign of the disease is hypertension, which is common in pregnancy and can be easily mistaken for pregnancy-induced hypertension. Differentiation from preeclampsia should, however, be straightforward as the edema, proteinuria, and hyperuricemia found in preeclampsia are absent in pheochromocytoma. Plasma and urinary catecholamines may be modestly elevated in preeclampsia and other serious pregnancy complications requiring hospitalization, though they remain normal in mild preeclampsia and pregnancy-induced hypertension. Catecholamine levels may, however, be 2 to 4 times the normal level after an eclamptic seizure and this can be confusing.

An unrecognized pheochromocytoma can be lethal because a fatal hypertensive crisis may be precipitated by anesthesia or even normal delivery. As the uterus enlarges and an actively moving fetus compresses the adrenal neoplasm, maternal complications such as severe hypertension, hemorrhage into the neoplasm, hemodynamic collapse, myocardial infarction, cardiac arrhythmias, congestive heart failure, and cerebral hemorrhage may occur. Extra-adrenal tumors, which occur in 10%, such as in the organ of Zuckerkandl at the aortic bifurcation, are particularly prone to hypertensive episodes with changes in position, uterine contractions, fetal movement, and Valsalva maneuvers. Unrecognized pheochromocytoma is associated with a maternal mortality rate of 50% at induction of anesthesia or during labor. A recent review of 41 pregnant women with known pheochromocytoma by Ahlawat et al, however, showed a much lower maternal mortality rate of 4% and a fetal mortality rate of 11%. Antenatal diagnosis of pheochromocytoma reduced the maternal mortality rate to 2%. These mortality rates are significantly lower than those of prior studies and can be attributed to increased awareness of the condition and more reliable testing modalities (see Table 10-13).

There is minimal placental transfer of catecholamines. Adverse fetal effects, such as hypoxia, are a result of catecholamine-induced uteroplacental vasoconstriction and placental insufficiency, as well as maternal hypertension, hypotension, or vascular collapse. Pheochromocytoma can also occur as part of multiple endocrine neoplasia type 2 (MEN2) in association with medullary carcinoma of the thyroid gland and parathyroid adenomas. Identification of the RET protooncogene mutations that cause MEN2 can be used to screen family members of MEN2 kindred and to monitor those who are at risk. The women at risk should be monitored very closely during pregnancy. Patients with MEN2A are more likely to have paroxysmal hypertension and have higher rates of bilateral neoplasms than those with sporadic pheochromocytoma. Examination for associated evidence for MEN2 may be difficult in pregnancy, with the expected pregnancy alterations in calcium, PTH, and calcitonin. Clinical thyroid examination should be assisted by fine-needle aspiration of any suspicious nodules so that overt medullary carcinoma can be treated immediately.

Most pregnant patients with pheochromocytoma will initially complain of symptomatic hypertension that is severe and fluctuating, and which is often associated with severe headache, perspiration, palpitation, and tachycardia (Table 10-14). Other possible signs and symptoms include arrhythmias, postural hypotension, chest or abdominal pain, visual disturbance, convulsions, or sudden collapse. Symptoms may occur or worsen during pregnancy because of the increased vascularity of the tumor and mechanical factors such as pressure from the expanding uterus or fetal movement. The coexistence of diabetes mellitus, possible hyperthyroidism, and myocardial infarction are important and should prompt a search for pheochromocytoma. Individuals with neurofibromatosis, von Hippel-Lindau disease, or retinal angiomatosis should also be screened for pheochromocytomas prior to pregnancy as these conditions are associated with an increased risk of pheochromocytoma.

The diagnosis is confirmed by an accurate 24-hour urine collection for both epinephrine, norepinephrine, and their metabolites. The assays should preferably be performed on specimens collected during or after a hypertensive episode. Laboratory diagnosis of pheochromocytoma is unchanged from the nonpregnant state as catecholamine metabolism is not altered by pregnancy per se. If possible, methyldopa and labetalol should be discontinued prior to the investigation as these agents may interfere with the quantification of the catecholamines and vanillylmandelic acid (VMA). Provocative testing should be avoided because of the increased risk of maternal and fetal mortality.

Efforts to localize the tumor should be made once a biochemical diagnosis is made. Magnetic resonance imaging (MRI) and ultrasound are the preferred methods for localization of tumors in pregnant patients because they avoid exposing the fetus to ionizing radiation. Metaiodobenzylguanidine scans are contraindicated in pregnancy, but they may be necessary if other tumor localization methods fail.

Initial medical management involves α-blockade with phenoxybenzamine, phentolamine, prazocin, or labetalol (Table 10-15). All of these agents are well tolerated by the fetus, but phenoxybenzamine is considered the preferred agent as it provides long-acting, stable, noncompetitive blockade. Placental transfer of phenoxybenzamine occurs, but it is generally safe. If hypertension remains inadequately controlled, metyrosine has also been used successfully to reduce catecholamine synthesis in a pregnancy complicated by malignant pheochromocytoma, but it may potentially adversely affect the fetus. β-Blockade is reserved for treating maternal tachycardia or arrhythmias that persist after complete α-blockade and volume repletion. β-Blockade without prior α-blockade is contraindicated because the unopposed α-adrenergic activity may lead to vasoconstriction and hypertensive crisis. Propranolol has been successfully used after appropriate α-blockade in pregnancy. β-Blockers may be associated with fetal bradycardia and intrauterine fetal growth restriction when used early in pregnancy. All of these potential fetal risks are small compared to the risk of fetal wastage from unblocked high maternal levels of catecholamines. Hypertensive emergencies should be treated with phentolamine or nitroprusside. The definitive treatment of pheochromocytoma is surgical removal of the tumor(s) and this should ideally be accomplished before 24 weeks of gestation, and only after achieving adequate α-blockade. Successful laparoscopic excision of a pheochromocytoma has been described in the second trimester of pregnancy. After 24 weeks of gestation, uterine size makes abdominal exploration and access to the tumor difficult, and it is generally recommended that surgery be delayed until fetal maturity is reached. To that end, steroid therapy may be used to hasten fetal lung maturity. Once delivery is entertained, adequate α-blockade should be instituted and elective cesarean delivery may be performed, followed immediately by adrenal exploration. Cesarean section is recommended for delivery based on the work of Schenker and Granat who reported higher maternal mortality rates with vaginal delivery (31%) compared to cesarean delivery (19%). Labor may result in uncontrolled release of catecholamines secondary to pain and uterine contractions. Severe maternal hypertension may lead to placental ischemia and fetal hypoxia. However, in the well-blocked patient, vaginal delivery may be possible if cesarean section is not possible, as long as there is intensive pain management with epidural anesthesia, avoidance of mechanical compression, passive descent, and instrumental delivery.

There is no available information regarding the impact of maternal use of phenoxybenzamine on the nursing neonate. Malignant pheochromocytoma may recur in pregnancy. Lifelong monitoring is necessary in all patients, with extra caution in those who are pregnant.

Primary hyperaldosteronism is a rare cause of hypertension in pregnancy. Occasionally, this hypertension can be severe and confusing with preeclampsia. In addition, the degree of hypertension can be variable and can significantly worsen in the first 6 weeks of the postpartum period.

Patients with classic hyperaldosteronism present with hypertension, hypokalemia, and elevated urine potassium levels. Before biochemical diagnosis, hypokalemia should be corrected because low potassium levels may suppress aldosterone. When the diagnosis is performed, potassium replacement should be initiated, all diuretics should be discontinued for at least 2 weeks, and high doses of β-blockers should be reduced because they reduce renin production. Calcium channel blockers should not be used for at least 2 to 3 hours before testing.

The measurement of plasma aldosterone levels may not be useful in the diagnosis of hyperaldosteronism in pregnant women because of the physiologic increase in aldosterone levels in pregnancy. The levels measured during normal pregnancy are often within the primary hyperaldosteronism range. Pregnant women may have less urinary potassium wasting than patients with primary hyperaldosteronism because of the antagonizing effects of progesterone. Another factor that may complicate the diagnosis during pregnancy is the increase in plasma renin levels in normal pregnancy. In primary hyperaldosteronism, plasma renin levels are usually decreased, and in pregnancy, the decrease may be attenuated. Outside of pregnancy, salt-loading studies are desirable to confirm the autonomous secretion of aldosterone, but during pregnancy, there are concerns about volume overload, worsening of hypokalemia, and the lack of specific reference ranges for pregnancy. One test that can be used in pregnancy involves prolonged positioning of the patient in an upright posture. This usually causes a modest increase in plasma renin activity. However, if there is primary hyperaldosteronism, the renin activity remains suppressed.

Ultrasonography and MRI are the preferred imaging methods in pregnant women for localizing the tumor, but if necessary, any appropriate imaging modality should be used to confirm the presence of a tumor.

If an adrenal adenoma is detected, the preferred treatment is unilateral adrenalectomy. Cases of successful adrenalectomy in the second trimester have been reported. Early delivery may need to be considered in the third trimester as spironolactone and angiotensin-converting enzyme inhibitors are generally avoided in pregnancy. The goals of therapy are to reduce blood pressure and replace potassium, and while α-methyl dopa, β-blockers, and calcium channel blockers can be used, they have variable success rates.

Diabetes insipidus in pregnancy is caused by either an abnormality of vasopressin secretion, an abnormality of vasopressin action, or vasopressin degradation. The presenting features are polydipsia, polyuria, and dehydration. Three types of diabetes insipidus can be found in pregnancy: central, nephrogenic, and transient vasopressin resistant (Table 10-16).

Central Diabetes Insipidus

Central diabetes insipidus is caused by decreased production of vasopressin by the paraventricular nuclei of the hypothalamus. It complicates 1 in 15,000 deliveries. The most common presentation is that of a woman who has central diabetes insipidus before conception, arising from a pituitary tumor or another invasive disease such as histiocytosis X. Central diabetes insipidus often worsens during pregnancy due to an increase in the clearance of endogenous vasopressin by placental vasopressinase. Vasopressinase concentration increases during pregnancy in proportion to the placental weight. It is metabolized by the liver; thus its activity is increased in liver disease. Subclinical central diabetes insipidus may be unmasked for the first time during pregnancy, because of the need for vasopressin release, low serum osmolality, and increased clearance of vasopressinase. During pregnancy, 60% of established cases of central diabetes insipidus worsen, but 25% improve, and 15% remain the same.

The diagnosis of central diabetes insipidus during pregnancy has been seen following development of Sheehan syndrome and as a result of the enlargement of a prolactinoma, histiocytosis X, and lymphocytic hypophysitis. It has also been reported as a complication of ventriculoperitoneal shunt during pregnancy.

The diagnosis of central diabetes insipidus that occurs for the first time during pregnancy requires modification of the standard water deprivation test. Nonpregnant patients normally need to lose up to 5% of their total body weight before the induced dehydration adequately stimulates vasopressin release. Such dehydration can be dangerous in pregnancy and should not be used. The use of desmopressin (DDAVP) as a test of urinary concentrating ability has been described and is currently the preferred method. Maximum urine osmolality over 11 hours after administration of DDAVP is assessed. Any value greater than 700 mosmol/kg is considered normal.

The treatment of central diabetes insipidus in pregnancy is with DDAVP, 2 to 20 μg intranasally twice daily. This treatment can be given parenterally after cesarean section, but IV dosing is 5- to 20-fold more potent than the intranasal spray, and the dose should be adjusted accordingly. DDAVP is not degraded by vasopressinase and no further adjustment is needed in patients with increased vasopressinase activity. Transfer of DDAVP to breast milk is minimal, and breast-feeding is not contraindicated. Treatment of central maternal diabetes insipidus with DDAVP throughout pregnancy does not pose a risk to the infant.

Labor proceeds normally in women with central diabetes insipidus, and surges of oxytocin can be detected during labor and the puerperium. This suggests that women with central diabetes insipidus, although they are vasopressin deficient, still secrete oxytocin normally. Lactation is not impaired.

Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus is a rare X-linked disorder. At least 6 mutations in this gene have been identified, and direct mutation analysis can now be used for carrier detection and early prenatal diagnosis. Nonpregnant women with nephrogenic diabetes insipidus are usually treated with thiazide diuretics or chlorpropamide. Chlorpropamide stimulates vasopressin release and enhances its action on the renal tubule, but it may cause fetal hypoglycemia and neonatal diabetes insipidus, and therefore should not be used in pregnancy. Thiazide diuretics are the treatment of choice for nephrogenic diabetes insipidus during pregnancy.

Transient Vasopressin-Resistant Diabetes Insipidus

Transient vasopressin-resistant diabetes insipidus is probably the most common form of diabetes insipidus seen in pregnancy. It is caused by increased vasopressinase activity due to either increased placental production of the enzyme or decreased hepatic vasopressinase metabolism as a result of liver damage. Transient disturbances of liver function may be seen in acute fatty liver of pregnancy, preeclampsia, HELLP (hemolysis, elevated liver transaminases, low platelets) syndrome, and hepatitis.

The treatment of transient vasopressin-resistant diabetes insipidus in pregnancy requires DDAVP because DDAVP is not degraded by vasopressinase. Electrolyte and fluid balance should be closely monitored during the postpartum period. The symptoms of transient vasopressin-resistant diabetes insipidus resolve in a few days to a few weeks after delivery, when hepatic function returns to normal.

Severe hemorrhage, shock, or prolonged hypotension during or after delivery may lead to postpartum pituitary necrosis or the Sheehan syndrome. This condition is rare (1:10,000 deliveries) and its pathogenesis is still unclear. It is believed to be the result of spasm in the arterial supply to the anterior lobe of the pituitary gland leading to ischemia and edema and ultimate necrosis and thrombosis in the portal sinuses and capillaries. A second theory as to the etiology is based on the development of DIC and intrapituitary bleeding. Sheehan syndrome usually involves only anterior pituitary function because the posterior pituitary and hypothalamus are supplied by the inferior hypophyseal artery and the circle of Willis, which makes them less vulnerable to ischemic necrosis. In rare cases, however, some women with Sheehan syndrome may develop partial or overt diabetes insipidus due to reduced vasopressin (antidiuretic hormone [ADH]) secretion. There is frequently poor correlation between the severity of the postpartum hemorrhage and the occurrence of Sheehan syndrome, and patients suspected of this complication should be investigated regardless of the severity of their postpartum/intrapartum bleed.

The presentation of Sheehan syndrome is highly variable. It is estimated that 95% to 99% of the anterior pituitary gland needs to be destroyed before the characteristic postpartum failure of lactation, secondary amenorrhea, loss of axillary and pubic hair, genital and breast atrophy, increasing signs of secondary hypothyroidism, and adrenocortical insufficiency occur. The most specific early postpartum sign will be failure of lactation. Because mineralocorticoid secretion is not impaired, there are usually no electrolyte disturbances. However, hyponatremia has been reported in conjunction with Sheehan syndrome and appears to be on the basis of syndrome of inappropriate ADH secretion (SIADH).

Less extensive pituitary destruction (50%-95%) is associated with an atypical form of the disease with loss of one or more trophic hormones. Postpartum diagnosis of Sheehan syndrome requires dynamic provocative testing of both anterior and posterior lobes of the pituitary gland. The anterior pituitary gland function is best assessed with pituitary hormone response to standard stimulatory tests in conjunction with pituitary imaging with axial computed tomography (CT) or MRI. Posterior pituitary function in Sheehan syndrome can be studied with plasma vasopressin response to osmotic stimuli either during 5% hypotonic saline infusion or following a water deprivation test. Spontaneous recovery from hypopituitarism due to postpartum hemorrhage has also been reported.