Thyroid Storm During Pregnancy

Thyroid disease, which is actually several different diseases, affects approximately 6% of the population. It may result from either subnormal or excessive levels of thyroid hormones. In this article, we focus on thyroid storm during pregnancy and a condition that leads to excess amounts of thyroid hormone, Graves disease.Graves disease is the most common form of hyperthyroidism1 and is characterized by 1 or more of the signs and symptoms listed in Table 1. Thyroid storm, a very rare complication of hyperthyroidism, can be fatal if untreated. It is often precipitated by a stressful event or trauma. Critical care nurses must recognize the signs and symptoms of thyroid storm to properly manage this condition and prevent further complications.2Thyroid diseases are common in women of childbearing age. In many cases, these diseases are first recognized during pregnancy or in the postpartum period. Some of the normal changes of pregnancy can be confused with signs and symptoms of various diseases, just as some signs and symptoms of a disease can be erroneously blamed on pregnancy. An example is hyperthyroidism, which occurs in approximately 1 in 500 pregnancies and is one of the most common endocrine disorders of pregnancy, second only to diabetes.3 Graves disease accounts for more than 85% of all cases of hyperthyroidism.4 Maternal and neonatal morbidity is significantly more common in women whose hyperthyroid state is not medically controlled. Thyroid storm is especially common in women who receive limited or no prenatal care and have medical or obstetric complications.2 Pregnant women with hyperthyroidism require careful management to prevent complications and adverse outcomes for both mother and infant.Thyroid hormones, triiodothyronine (T3) and thyroxine (T4), are synthesized within the follicles of the thyroid gland, and their synthesis requires iodide.5 Most T4 is transformed to T3 by the action of enzymes after T4 is released from the thyroid gland. Thyroid hormones are carried throughout the body by proteins, primarily thyroxine-binding globulin produced in the liver. Production of thyroid hormones is regulated by thyroid-stimulating hormone (thyrotropin or TSH) produced in the anterior lobe of the pituitary gland and released as a result of the activity of hypothalamic thyrotropin-releasing hormone (see FigureF1). Negative feedback mechanisms regulate the release of TSH from the pituitary gland. Stress and temperature changes can induce the synthesis of thyroid hormones, resulting in pronounced effects on the cardiovascular system (Table 2). Generalized vasodilatation results in increased cardiac output. Heart rate and contractility are increased, as is blood pressure. The need for oxygen is increased, and as a result the respiratory rate increases. Under the influence of thyroid hormones, muscles react more readily, and the central nervous system is stimulated. Because of this stimulation, sleep disturbances can occur when excess thyroid hormone is present. Endocrine gland function is stimulated by thyroid hormones, and gastric motility is increased.The normal, but reversible hormonal changes in pregnancy result in thyroid stimulation and increased levels of T3 and T4, although TSH levels remain normal. During normal pregnancy, the thyroid gland may enlarge up to 50% because of hyperplasia of the glandular tissue and increased vascularity. However, marked thyromegaly and goiter should be considered pathological changes.6 The basal metabolic rate increases by as much as 25%, resulting in increased cardiac output, increased pulse rate and heat intolerance.3,7(p129),8The maternal hypothalamic-pituitary thyroid hormone system is relatively independent of the fetal system. The human placenta is impermeable to the transfer of TSH and largely impermeable to the transfer of T3 and T4.9 Thyroid-stimulating immunoglobulins (TSIs), found in maternal hyperthyroidism, cross the placenta and stimulate production of thyroid hormones by the fetus and can result in fetal and neonatal hyperthyroidism.10Findings associated with the normal hypermetabolic state of pregnancy can overlap with the signs and symptoms of thyroid disease. Clinicians should be aware of other signs and symptoms of hyperthyroidism that indicate thyroid disease and are not common in pregnancy, such as weight loss, hyperemesis, diarrhea, heart rate greater than 100/min that does not decrease with the Valsalva maneuver, and/or lymphadenopathy.Graves disease is an autoimmune disorder in which a group of TSIs attach to and activate TSH receptors on the thyroid follicular cells. This activation leads to an increased production of thyroid hormones and the clinical findings associated with hyperthyroidism. Because the thyroid hormones control many bodily functions, this increase in the level of thyroid hormones causes these bodily functions, such as heart rate, or in some instances blood pressure, to increase, sometimes to very dangerous levels. High TSI levels confirm the diagnosis of Graves disease. If left untreated, hyperthyroidism during pregnancy can lead to maternal complications, including preterm delivery, perinatal morbidity, heart failure, and thyroid storm. The fetus and newborn can also be affected. Maternal TSI titers are used to predict the effect of maternal Graves disease on the fetus. The risk of thyrotoxicosis in the fetus and newborn is higher in women with high TSI titers.9 Careful assessment and monitoring of the fetus are important for early detection of effects, with particular attention given to elevated resting heart rate and poor fetal growth pattern.Thyroid storm is a rare, life-threatening endocrinologic emergency that can lead to cardiac arrest and death. A total of 20% to 30% of all cases are fatal.11 Patients can have a wide range of signs and symptoms (Table 3). The tachycardia is often out of proportion to the hyperthermia. Blood pressure is commonly normal, although a widened pulse pressure is common. Patients with thyroid storm usually appear confused and disoriented. Thyroid storm can be precipitated by surgery, infection, trauma, or labor and delivery.3,12 Patients with thyroid storm require assessment and management in an intensive care unit where they can be monitored for cardiac status, fluid and electrolyte balance, and control of hyperthermia.6 The underlying cause of thyroid storm must be identified and treated.Thyroid storm requires prompt recognition, aggressive reversal of thyroidotoxins with antithyroid drugs (ATDs), and supportive management of signs and symptoms (Table 4). Antithyroid agents are propylthiouracil and methimazole. These agents inhibit the synthesis of thyroid hormones.13 Propylthiouracil has been the drug of choice in pregnancy because it was thought that it did not cross the placenta as readily as methimazole does and because it blocks conversion of peripheral T4 to T3.2,14 Recent studies suggest that this notion may be incorrect. In a study15 in which the suppressive effect of maternal ingestion of propylthiouracil on fetal thyroid status was compared with that of methimazole, the occurrence of low T4 levels or high fetal TSH levels did not differ significantly between the 2 groups. The standard practice is to give an initial loading dose of 300 mg to 600 mg propylthiouracil enterally and then 150 mg to 300 mg every 6 hours.14 If a patient cannot take the solution by mouth, propylthiouracil can be administered via the nasogastric tube or can be compounded by the pharmacy and given as a rectal suppository. Iodides are also commonly given because they rapidly inhibit the release of thyroid hormones. Iodides are administered several hours after propylthiouracil therapy is initiated to avoid the buildup of hormones stored in the thyroid gland. A saturated solution of potassium iodide is given orally in dosages of 2 to 5 drops every 8 hours, or sodium iodide is given intravenously in dosages of 0.5 to 1 g every 8 hours. β-Blockers such as propranolol should also be given to help decrease some of the thyrotoxic effects on the cardiovascular system. Additional supportive measures include administration of intravenous fluids for dehydration, antipyretics for control of hyperthermia (a cooling blanket may be necessary), nutritional support, correction of possible electrolyte imbalances, and use of glucocorticoids, which also inhibit conversion of T4 to T3 and prevent adrenal insufficiency. If sedation is required, barbiturates are most often used because they lower the levels of thyroid hormones by increasing the catabolism of the hormones.14 Oxygen should be used as needed for possible increased oxygen demands.14,16,17 Because of the hypermetabolic state of thyroid storm, medications are metabolized faster than normal. Therefore, higher and more frequent doses may be required to control the thyrotoxicosis.18 Patients in thyroid crisis require close assessment and monitoring of cardiovascular status, including continuous cardiac monitoring and frequent monitoring of vital signs. Significant changes should be reported immediately. During this period, careful monitoring of the fetus is also a critical element of management. Current recommendations are to avoid delivery during thyroid storm unless the condition of the fetus demands prompt delivery.19The gold standard of treatment of thyroid storm is primary prevention. Prevention of thyroid storm requires careful control and management of the hyperthyroidism. Standard treatment options for Graves disease include therapy with radioactive iodine, ATDs, and thyroid surgery.20 However, pregnancy limits these treatment options. Because of possible destruction of the thyroid gland in the fetus, radioactive iodine cannot be given, and surgery is avoided because of the increased risk for miscarriage or preterm delivery.As a result, the standard treatment during pregnancy is the use of ATDs to inhibit the biosynthesis of thyroid hormones. Because of the immunosuppressive effect of pregnancy, ATDs can be given in lower doses in pregnant patients than in nonpregnant patients. Every attempt should be made to treat with the lowest possible effective dose of ATDs because these drugs can cross the placenta, enter the fetal circulation, and affect the thyroid gland of the fetus.Even though propylthiouracil is the drug of choice during pregnancy, it is not given without careful observation, because it results in drug reactions in up to 5% of treated patients. These reactions include fever, rash, urticaria, arthralgias, and leukopenia. A rare adverse effect, agranulocytosis, an acute condition distinguished by a deficit or absolute lack of granulocytes, usually is manifested by fever and sore throat. If fever and sore throat occur, a complete blood cell count should be done, and if agranulocytosis is diagnosed, treatment with thiopropyluracil should be stopped.19The starting dose is typically 300 to 450 mg per day divided into 3 doses. If methimazole is used, the starting dose is 20 mg twice a day. Results of laboratory tests should be monitored carefully, and once a patient becomes euthyroid, the dose can be tapered gradually. Many patients need only 50 mg per day, and some patients may not need any medication by the third trimester; however, the dosage may vary from 50 to 200 mg of propylthiouracil every 8 hours, or methimazole 10 to 60 mg a day, depending on the patient’s signs and symptoms and laboratory values.4,8 Biochemically, the aim is to keep the serum level of total T4 between 154 and 193 nmol/L (12–15 μg/dL) and the serum level of free T4 within the reference range for the laboratory test used. (These values will vary from one laboratory to another.8)Fetal and neonatal hypothyroidism, as well as the occurrence of goiters, may occur from passage of thionamides across the placenta.2 During the first trimester, transfer of ATDs transplacentally can affect thyroid development in the fetus. Fetal exposure to ATDs can produce hypothyroidism and fetal growth restriction.21Methimazole therapy may be associated with aplasia cutis (a localized lesion in the parietal area of the scalp, characterized by congenital absence of the skin, punched-out “ulcer” lesions, that usually heal spontaneously) in the offspring of treated women and is another reason that propylthiouracil has become the drug of choice during pregnancy.22 The therapeutic goal is to control the mother’s hyperthyroidism by using the smallest possible amount of medication, to avoid suppressing the thyroid gland in the fetus.23Transplacental passage of TSIs can result in fetal and neonatal thyrotoxicosis, although this complication is rare. It occurs in only 1% of babies born to women with a history of Graves disease, but it may have serious consequences if not recognized.24 Potential fetal and neonatal complications are listed in Table 5.The level of TSIs should be measured in the third trimester in all pregnant women with active or inactive Graves disease. High TSI levels, more than 5 times the reference range, are common in the mothers of babies with neonatal hyperthyroidism.24 The activity of the mother’s disease, however, does not necessarily correlate with fetal or neonatal disease. In cases of quiescent Graves disease, the prediction of neonatal Graves disease on the basis of the maternal clinical status is not always possible because the mother may not manifest signs or symptoms. In some infants, both stimulating and blocking antibodies are acquired from the mother, and the blocking antibodies block the effect of the stimulating antibodies for 4 to 6 weeks such that late-onset neonatal Graves disease develops in an infant in whom the disease was not previously diagnosed.9 In all pregnancies considered to be high risk, the fetus should be closely monitored. Fetal thyrotoxicosis is suggested by a resting heart rate that is elevated (>160/min) and poor fetal growth.10,25In many cases, neonatal thyrotoxicosis is not evident at birth when the mother has been treated with thionamides. As thionamide levels decrease in the neonate, clinical signs of thyrotoxicosis occur, usually 5 to 10 days after birth (Table 6). Common signs are irritability, tachycardia, poor feeding, and failure to gain weight. The disease is usually self-limiting over 1 to 3 months as the circulating levels of maternal immunoglobulins decrease. In severe cases, clinical manifestations may include goiter with resultant respiratory distress, hyperthermia, exophthalmos, tachycardia, hypertension, poor weight gain, thrombocytopenia, and jaundice. Arrhythmias, cardiac failure, and death may occur if the thyrotoxicosis is severe and treatment is inadequate. High levels of total T4, free T4, and T3 in postnatal blood confirm the diagnosis.Treatment of neonatal thyrotoxicosis is similar to the methods used in treating the mother. Thionamides, β-blockers, and iodine are most commonly used. In the most severe cases, digitalis, glucocorticoids, and sedatives many be necessary to prevent cardiovascular collapse.24 Hyperthyroidism results in increased metabolic demands, and infants with hyperthyroidism require careful attention to nutritional needs and a high caloric intake to maintain growth. Fatigue and exhaustion can also result from the hypermetabolic state, and measures to conserve energy stores are essential to the well-being of these infants. The half-life of immuno-globulins received from the mother is 8 to 20 days, and as the circulating level of the antibodies decreases in the infant, the disease wanes and the infant shows signs of improvement. Complete resolution of the hyperthyroidism occurs within 3 to 12 weeks.24Breast-feeding in women with hyperthyroidism remains controversial, primarily because of passage of ATDs in breast milk. Propylthiouracil is excreted in breast milk in relatively small amounts, whereas methimazole is excreted in slightly larger amounts. Most sources2,26 suggest that breast-feeding should not be routinely contraindicated in women taking these medications if the women are carefully monitored.Thyroid storm is the major risk to pregnant women with thyrotoxicosis. This life-threatening condition is more likely to occur with another precipitating factor such as labor and delivery, surgical delivery, infection, or trauma. Thyroid storm most often occurs in patients with under-treated or undiagnosed hyperthyroidism. As many as 20% to 30% of cases can end in maternal and fetal mortality.11 Therefore, critical care nurses must be able to recognize and initiate proper medical and nursing interventions promptly.