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 intensive care unit (ICU) situation have been highlighted. These include thyrotoxicosis and thyroid storm, hypothyroidism and myxedema coma, Addisonian crisis, pheochromocytoma, primary hyperaldosteronism, and diabetes insipidus. Diabetes mellitus and ketoacidosis have been dealt with elsewhere.
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.
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.
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 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. 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 of 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).
Normal hypothalamic-pituitary-thyroid axis First-trimester TSH depression due to hCG, normalized thereafter First trimester: 0.24-2.99 Second trimester: 0.46-2.95 Third trimester: 0.43-2.78 Increased renal iodide clearance (increased glomerular filtration rate) Goiter—minimal in regions of iodine sufficiency; 30% increase in size in regions with dietary iodine deficiency Increased serum TBG; decreased T3 resin uptake Increased total serum T4 and total serum T3 Normal serum free T4 and free T3 |
The fetal hypothalamic-pituitary-thyroid axis develops independently of the maternal thyroid function. The fetus begins concentrating iodine between 10 and 12 weeks of gestation. By 20 weeks of 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 thyroid autoantibodies. Thyrotropin receptor antibodies (TRAb) may be used to help determine the etiology of hyperthyroidism in pregnant patients without nodular goiter and without obvious clinical manifestations of Graves’ disease other than a diffuse goiter. Graves’ disease is known to be caused by autoantibodies to the TSH (thyrotropin) receptor that activate the receptor, and stimulate thyroid hormone synthesis and secretion as well as thyroid growth. Detecting TRAb in the patient’s serum allows the diagnosis of Graves’ disease and helps to differentiate her disorder from other etiologies of hyperthyroidism. At a technical level it is important to understand that there are two methods for measuring TRAb, and these assays may be called any of the following names: TBI (thyrotropin-binding inhibiting) immunoglobulin, TBII, or TSI assays. Third-generation TBI/TBII assays are competition-based assays that measure inhibition of binding of a labeled, monoclonal, anti-human TRAb (or labeled TSH) to recombinant TSH receptor. TSI assays are performed differently and measure immunoglobulin-stimulated increased cAMP production, for example, from Chinese hamster ovary cells transfected with human TSH (hTSH) receptor. Measuring the maternal serum TRAb between 24 and 28 weeks may enable prediction of which infants are at a higher risk for the development of fetal and neonatal Graves’ disease. One approach is to measure the antibodies during the first trimester, and if they are elevated, to repeat the testing again at 18 to 22 weeks of gestation. For patients in remission after treatment with thionamides, it is not usually necessary to measure antibodies although their neonates remain at risk for hyperthyroidism from the TRAb. In pregnant women who are currently hyperthyroid it is recommended that TRAb be measured at diagnosis, and, if elevated, again at 18 to 22 weeks. In those patients where TRAb is persistently elevated the level should be checked again at 30 to 34 weeks of gestation. If TRAb levels are significantly elevated (>3 times upper limit of normal) increased fetal monitoring is indicated, since the neonate is likely to have Graves hyperthyroidism and should be closely monitored for this after delivery. Fetal venous blood sampling may be indicated in cases where maternal Graves’ disease is being treated with thionamides, the fetus has a goiter, and there is uncertainty as to whether the baby is hyper- or hypothyroid. In those cases where TRAb falls and the Graves’ disease resolves during pregnancy thionamide therapy may be tapered or even discontinued.
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 immunoglobulin [TSI]—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).
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 thionamide 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 thionamide therapy during pregnancy remain at significant risk for neonatal Graves’ disease because of the persistence of the thyrotropic antibodies.
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.
Increased stroke volume and cardiac output Increased pulse rate Reduced peripheral vascular resistance Increased blood volume Impaired myocardial contractility Electrocardiographic changes: Left ventricular hypertrophy (15%) Atrial fibrillation (21%) Wolff-Parkinson-White syndrome |
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.
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 the two thionamide agents currently available in the United States. In Europe and Asia, the methimazole derivative carbimazole is also used. Because carbimazole is rapidly metabolized to methimazole, these drugs are essentially the same, although an approximately 40% higher dose of carbimazole is needed to yield an equivalent dose of methimazole. 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 an increased teratogenic profile (including aplasia cutis in infancy). Some significant congenital malformations (including choanal atresia, tracheoesophageal fistula, patent vitellointestinal duct, omphalocele, and omphalomesenteric duct anomaly, have been reported following maternal use of methimazole and carbimazole, but not with PTU. For these reasons, PTU at one time was the preferred medication for treating hyperthyroidism throughout pregnancy in the United States. The pendulum has swung in recent years based on reports of severe liver failure associated with PTU and methimazole is now the first line drug in pregnancy except in the first trimester (because of concerns about an increased teratogen profile). In patients needing thionamide therapy in the first trimester, or in the preconceptional period, PTU is recommended with a switch to methimazole at approximately 16 weeks. There are trade-offs with the switching of drugs—avoiding PTU does decrease the risk of liver toxicity, but since methimazole is 20 to 30 times more potent than PTU switching from PTU to methimazole increases the risk of maternal and fetal hypothyroidism. A 200-mg dose of PTU would be roughly equivalent to 5 or 10 mg of methimazole. Monitoring of thyroid function tests should occur 2 weeks after switching to make sure that thyroid function is stable and that dose adjustment is not needed.
Methimazole should be started at 5 to 10 mg daily and increased to as much as 30 mg daily as needed. Initial dosing of PTU should be 50 mg 2 to 3 times daily, increasing as needed to as much as 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 the trimester-specific normal range for pregnancy, or the smallest dose that keeps the total T4 and T3 at 1.5 times above the nonpregnant reference range. The serum TSH concentration should be below the reference range for pregnancy (eg, goal TSH approximately 0.1-0.3 mU/L).
Treatment of hyperthyroidism is not required when there is:
Transient, subclinical hyperthyroidism (normal serum total or free T4 and T3 concentrations for pregnancy with a subnormal TSH level) in the first trimester of pregnancy. This is regarded as a normal physiologic adaptation.
hCG-mediated, overt hyperthyroidism (gestational transient thyrotoxicosis). This is usually transient and mild.
Hyperemesis gravidarum-associated hyperthyroidism which generally disappears as hCG production falls (16-18 weeks of gestation).
Subclinical and mild, asymptomatic, overt hyperthyroidism due to Graves’ disease, toxic adenoma, or toxic multinodular goiter. Subclinical hyperthyroidism (a low TSH level combined with a free T4 level that is within the trimester-specific reference range, or a total T4 and T3 level that is <1.5 times above the upper limit of normal for nonpregnant patients) should generally not be treated during pregnancy. Even when the patient has biochemical, overt hyperthyroidism (subnormal TSH and free T4 above the trimester-specific reference range or total T4 and T3 >1.5 times above the upper limit of normal for nonpregnant patients) she may not require treatment if the hyperthyroidism is mild and asymptomatic (or minimally symptomatic), since the goal of treatment is to maintain mild maternal hyperthyroidism.
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 TRAb 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 thionamides 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 thionamides carries a high risk for cross reaction. Other major side effects of thionamides, which include a lupus-like syndrome, thrombocytopenia, hepatitis/hepatic infarction, and vasculitis, occur in fewer than 1% of patients. Minor side effects include rash, arthralgias, nausea, anorexia, fever, and a loss of taste or smell may occur in up to 5% of cases. About 50% of neonates who are exposed to thionamides (either PTU or methimazole) will have low thyroid function at birth and all exposed babies should all be tested. 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. Given that Graves’ disease frequently resolves to some extent in the third trimester it is important to monitor thyroid function tests and TRAb during pregnancy, and if TRAb levels fall and thyroid functions remain stable thionamides can be tapered and even discontinued (in up to one third of patients). It must be remembered that in the postpartum period Graves’ hyperthyroidism can again worsen and so close follow-up is needed.
β-Adrenergic blockers may be used as adjunctive therapy to control the symptoms of tremor and palpitations until the thionamides decrease thyroid hormone levels. Metoprolol (25-50 mg daily) is the most commonly used β-blocker for this purpose, but propranolol (20 mg q 6-8 hours) is also an appropriate alternative. Atenolol is avoided because of possible growth restriction effects. 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, and to wean the patient off these agents once the thionamides are controlling the hyperthyroid symptoms.
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 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
| Hypermetabolism |
| Fever >100°F |
| Perspiration |
| Warm, flushed skin |
| Cardiovascular |
| Tachycardia |
| Atrial fibrillation |
| Ventricular fibrillation |
| Congestive heart failure |
| Reversible dilated cardiomyopathy |
| Central nervous system |
| Irritability |
| Agitation |
| Tremor |
| Mental status change (delirium, psychosis, coma) |
| Gastrointestinal |
| Nausea, vomiting |
| Diarrhea |
| Jaundice |
| Supporting laboratory evidence |
| Leukocytosis |
| Elevated liver function values |
| Hypercalcemia |
| Low TSH, high free T4 and/or T3 |
| Criteria | Points | Criteria | Points |
|---|---|---|---|
| Thermoregulatory dysfunction | Gastrointestinal-hepatic dysfunction | ||
| Temperature (°F) | Manifestation | ||
| 99.0-99.9 | 5 | Absent | 0 |
| 100.0-100.9 | 10 | Moderate (diarrhea, abdominal pain, nausea/vomiting) | 10 |
| 101.0-101.9 | 15 | Severe (jaundice) | 20 |
| 102.0-102.9 | 20 | ||
| 103.0-103.9 | 25 | Central nervous system disturbance | |
| >104 | 30 | Manifestation | |
| Absent | 0 | ||
| Cardiovascular | Mild (agitation) | 10 | |
| Tachycardia (beats/min) | Moderate (delirium, psychosis, extreme lethargy) | 20 | |
| 100-109 | 5 | Severe (seizure, coma) | 30 |
| 110-119 | 10 | ||
| 120-129 | 15 | Precipitant history | |
| 130-139 | 20 | Status | |
| >140 | 25 | Positive | 0 |
| Negative | 10 | ||
| Atrial fibrillation | |||
| Absent | 0 | ||
| Present | 10 | ||
| Congestive heart failure | |||
| Absent | 0 | ||
| Mild | 5 | ||
| Moderate | 10 | ||
| Severe | 20 |
Intravenous fluids and electrolytes Cardiac monitoring Consideration of central hemodynamic monitoring (invasive or noninvasive) to guide β-blocker therapy during hyperdynamic cardiac failure Cooling measures: blanket, sponge bath, acetaminophen Oxygen therapy (consider arterial line to follow serial blood gases) No salicylates (increased T4) Nasogastric tube if patient is unable to swallow (may be the only avenue for PTU administration) Cholestyramine (4 g orally four times daily) can be given in severe cases to reduce enterohepatic recycling of thyroid hormones |
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