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2002 Selected Articles

Thyroid Disease in Pregnancy

Gayle L. Olson, MD

Both functional and anatomic diseases of the thyroid gland are 5 to 10 times as common in women than in men. Abnormal thyroid function can significantly alter a woman’s ability to become pregnant, as well as the course of an established pregnancy, the health of the fetus, and the condition of both mother and neonate postpartum. Pregnancy also affects the course of autoimmune thyroid disease. This article focuses on the diagnosis and treatment of the three major forms of thyroid disease–hyperthyroidism, thyroid nodules, and hypothyroidism–in pregnant women.

The normal adult thyroid gland weighs 15 to 25 g. It consists of two lobes that are further subdivided into lobules and connected by an isthmus. The thyroid secretes two hormones: 80% is in the form of thyroxine (T₄) and 20% is in the form of triiodothyronine (T₃). Most of T₃, the biologically active thyroid hormone, is peripherally derived from T₄ by a deiodinase enzyme. Peripheral conversion of T₄ to T₃ is facilitated by type I 5’-deiodinase, which requires selenium. Along with selenium deficiency, other factors that may impair type I 5’-deiodinase activity include fasting, illness, and use of glucocorticoids, iodine contrast agents, high-dose propranolol, or propylthiouracil (PTU).¹

Iodine is also required for thyroid hormone synthesis. Iodine is ingested in the diet, reduced to iodide, and absorbed in the small intestine. Approximately 80% of circulating iodide is cleared by the kidneys and 20% by the thyroid. Iodide transport is controlled by thyrotropin (TSH). Nonpregnant women require approximately 150 µg of iodine daily to ensure adequate thyroid function. In pregnant and lactating women, however, the World Health Organization recommends a daily dose of 200 µg.² In the United States, the average amount of iodine consumed in the diet is substantially greater than that required.

PREGNANCY AND THYROID FUNCTION

During pregnancy, the thyroid increases slightly in volume as a result of increased vascularity and a small amount of glandular hyperplasia.³ Thyroid-binding globulin (TBG) levels increase during pregnancy (Table 1)⁴ in response to elevated estrogen levels, resulting in increased total T₄ and T₃ concentrations.⁵ The placenta deiodinates maternal T₄, contributing to increased T₄ turnover. Finally, decreased renal tubular iodide reabsorption and increased urinary excretion influence iodine steady state in pregnancy.³

Animal and human studies indicate that maternal T₄ can cross the placenta, as evidenced by detectable thyroid hormone in the cord blood of infants with congenital thyroid dysgenesis.^6,7 The fetal thyroid can form colloid, concentrate iodine, and synthesize thyroid hormone beginning at 10 to 12 weeks.^8,9 Thyroid hormone is crucial for many aspects of fetal brain development, including neurogenesis, neuronal migration, axon and dendrite formation, myelination, synaptogenesis, and neurotransmitter regulation.⁶ The second trimester is considered the most sensitive timeframe for this development.⁶

LABORATORY EVALUATION

Total T₄ and T₃ concentrations, which are increased in gravidas as a consequence of their elevated TBG levels, are not a useful measure of thyroid function in this population. By contrast, free T₄ and T₃ concentrations are unaffected by pregnancy, and accurately represent thyroid status. Serum TSH is also unaffected by pregnancy, and the negative feedback relationship between TSH and thyroid hormone production is preserved. The only confounding variable involving TSH is the first-trimester human chorionic gonadotropin (hCG) influence on TSH and thyroid hormone concentrations. Resin T₃ uptake (RT₃U) is normally decreased during pregnancy because of the increase in TBG.

In the past, the free T₄ index (FT₄I) was used to evaluate thyroid disease during pregnancy. However, the FT₄I is a calculated value, and equals total T₄ ¥ (patient’s RT₃U ÷ mean normal RT₃U), the components of which are affected by the physiologic changes of pregnancy. Modern methods of measuring free T₄ have replaced the FT₄I. Thus, physicians should measure serum TSH, free T₄, and free T₃ to assess thyroid function in gravidas. In fact, a second-generation TSH assay (detection limit, 0.05 mIU/L) is a sensitive screening test for both hyperthyroidism and hypothyroidism during pregnancy. Except for rare cases of thyrotropin hypersecretion, a normal TSH value excludes hyperthyroidism. An undetectable TSH on a second-generation assay or even a third-generation assay (detection limit, 0.005 mIU/L) suggests hyperthyroidism.¹⁰

HYPERTHYROIDISM

Hyperthyroidism is defined as hyperfunction of the thyroid gland.¹⁰ This term is not interchangeable with thyrotoxicosis, which is defined as any condition involving thyroid hormone excess (including overdosage of l-thyroxine in patients being treated for hypothyroidism). The incidence of hyperthyroidism in pregnancy is 0.2%.

Causes

The most common causes of hyperthyroidism are Graves’ disease, toxic nodular goiter, and toxic solitary nodule. Other causes include hyperemesis gravidarum, gestational trophoblastic neoplasia, pituitary hypersecretion of TSH, metastatic follicular cell carcinoma, exogenous T₄ or T₃ ingestion, de Quervain’s thyroiditis, silent lymphocytic thyroiditis, and struma ovarii.

Evaluation

The history and physical examination will likely reveal clinical features such as heat intolerance, sweating, palpitations, fatigue, goiter, inadequate maternal weight gain, ophthalmopathy, tremor, change in bowel habits, visual changes, and poor concentration.^5,11 These signs and symptoms in the presence or absence of a palpable goiter may prompt laboratory evaluation of thyroid function, which should include measurement of TSH, free T₄, and free T₃. In hyperthyroidism, these values are low, high, and high, respectively. Radioisotope scanning, although commonly used in diagnosing thyroid disease, is contraindicated during pregnancy.

TSH-Receptor Antibody (TSHR-Ab) Levels

Graves’ disease and other autoimmune thyroid conditions are associated with the presence of TSHR-Ab. These antibodies may be pathogenic in the sense that they are capable of activating or blocking TSH-receptor function and of crossing the placenta and affecting fetal thyroid status.¹² They are present in 70% to 100% of patients with Graves’ disease; levels roughly parallel disease severity.¹² TSHR-Ab testing during pregnancy:^12,13

• is unnecessary in euthyroid gravidas with antecedent Graves’ disease in remission.
• is warranted in gravidas with antecedent Graves’ disease treated with radioiodine or surgery, irrespective of the degree of dysfunction at the time of pregnancy, as these women may still have circulating TSHR-Ab. If antibody levels are low or absent, the fetus is not at risk. If antibody levels are high, physicians should monitor for fetal signs of hyperthyroidism (eg, tachycardia, impaired growth, goiter, hydrops).
• should be undertaken during the third trimester in gravidas with active Graves’ disease who are receiving antithyroid medication, regardless of when treatment was initiated. High TSHR-Ab levels increase the risk for neonatal hyperthyroidism.

Transient Hyperthyroidism

Transient hyperthyroidism in the first trimester is generally ascribed to increased hCG. TSH, luteinizing hormone, follicle-stimulating hormone, and hCG contain a common alpha subunit. Also, a structural homology may exist at hCG- and TSH-receptor levels.¹⁴ Thus, hCG can stimulate the thyroid. This is commonly noted in gravidas with hyperemesis gravidarum. Along with changes in electrolytes and liver function, these patients have abnormal thyroid test results that resemble hyperthyroidism.

Distinguishing between transient hyperthyroidism and Graves’ disease may be difficult. However, in women with hyperemesis gravidarum-associated hyperthyroidism, thyroid test results generally normalize after vomiting subsides (usually by the middle of the second trimester). In addition, they do not have goiter, extrathyroidal signs (ie, heat tolerance, weight loss, unusual fatigue), symptoms antedating the pregnancy, or serum thyroid antibodies. Another important clue is their denial of hyperthyroidism symptoms before pregnancy. Two of the most supportive signs for new-onset hyperthyroidism in pregnancy are failure to gain weight despite a good appetite and regular meals, and persistent maternal tachycardia greater than 100 beats per minute.¹⁵ Outside the context of hyperemesis gravidarum, up to 15% of normal pregnancies in the first trimester may be associated with subclinical hyperthyroidism (suppressed TSH, normal free T₄) related to the hCG effect.¹⁴

Graves’ Disease

Manifestations of Graves’ disease in gravidas tend to increase in severity during the first trimester, decrease in severity during the second and third trimesters, and recur postpartum.¹⁴ In nonpregnant women, hyperthyroidism can be treated with antithyroid medication, radioactive iodine, or subtotal thyroidectomy. Radioactive iodine is contraindicated during pregnancy, as placental transfer of radioactive iodine has been noted as early as 8 weeks’ gestation. Berlin has suggested that the fetal thyroid, when compared with the maternal thyroid, has a 10- to 50-fold greater affinity for radioactive iodine uptake.⁹ In a series of gravidas who had received iodine-131 during the first or second trimester, 3% of liveborn infants exhibited hypothyroidism, and a smaller proportion demonstrated mental deficiencies.⁹ Administration of potassium iodide after inadvertent maternal treatment may reduce fetal thyroid uptake by a factor of 100.⁸

Antithyroid medications–that is, methimazole (MMI) and PTU–are first-line treatment for Graves’ disease during pregnancy. Some physicians prefer to use PTU because of animal data showing that it binds more tightly to albumin, traverses the placenta less readily, and is less likely to be transferred to the fetus. In addition, aplasia cutis congenita (localized failure of skin development) has been associated with MMI but not with PTU, although the incidence is low. Both drugs inhibit formation of thyroid hormone; however, PTU also blocks peripheral conversion of T₄ to T₃.

The goal of therapy is normalization of thyroid function using the least amount of drug possible. Mestman has suggested that, during pregnancy, free T₄ should be maintained in the upper one third of the normal range.¹⁴ Women with moderate hyperthyroidism may be started on PTU 100 mg every 8 hours.⁷ Dosing is guided by normalization of thyroid function, and may range from 100 to 800 mg daily.⁷ As euthyroidism is achieved, the dosage should be decreased. In some cases, serum TSH may return to normal and remain normal, thereby allowing discontinuation of antithyroid medication.⁷

Except in cases of poor drug compliance, intolerable drug side effects, or a symptomatic goiter not otherwise responsive to medicine, surgical treatment for Graves’ disease is usually avoided during pregnancy.

Complications

Hyperthyroidism during pregnancy can cause complications in both mother and fetus (Table 2).^4,14 It is also linked to an increased risk for gestational diabetes. Thyroid storm increases the risk for maternal heart failure, as well as for other forms of morbidity and even mortality. Physicians might consider using ultrasonography between 28 and 32 weeks’ gestation to assess fetal anatomy, presence of goiter, and growth.

THYROID NODULES

The risk for developing thyroid nodules is influenced by sex (higher in females), age (higher as people get older), and pregnancy (higher in gravidas). In the lattermost group, however, increased detection may simply be a result of increased access to health care during this time.⁷

Although thyroid nodules are usually benign, cancer must be excluded. Diagnostic options in gravidas include thyroid function testing, ultrasonography, and fine needle aspiration (FNA). FNA can be performed at any stage of pregnancy, and is associated with only minor complications (eg, pain, local hematoma).⁷ "Watchful waiting" can be instituted in gravidas whose nodules have benign cytologic findings; if growth is noted, FNA can be repeated. Nodules with cancerous components should be resected, optimally during the second trimester.⁷ Nodules with indeterminate cytologic findings may be evaluated with radionuclide scanning after delivery. Ultrasonography is useful for detecting nodules larger than 0.5 cm, and can help to distinguish between solid versus cystic masses. However, ultrasonographic features upon which to diagnosis malignancy are not well established.^7,15

HYPOTHYROIDISM

Hypothyroidism is defined as thyroid hormone deficiency. Prevalence of this condition in women ranges from 0.6% to 5.9%.⁷ During pregnancy, overt hypothyroidism occurs in fewer than 1% of women.⁶ Prevalence of subclinical hypothyroidism ranges from 3% to 15% in nonpregnant populations¹⁶ and from 2% to 3% in gravidas.^6,17

Causes

Autoimmune thyroid disease, especially chronic autoimmune thyroiditis (Hashimoto’s disease) is the most common cause of hypothyroidism during pregnancy.¹⁷ Other causes of primary hypothyroidism and of central hypothyroidism (pituitary—hypothalamic deficiency) are listed in Table 3.^7,16-18 In many cases, a history of Graves’ disease that has been treated with surgery or radioactive iodine therapy will be the clue to primary disease. By contrast, a history of a hypothalamic—pituitary tumor, cranial radiation, head trauma, or postpartum hemorrhage, along with clinical features of adrenocortical or growth hormone insufficiency, suggest central hypothyroidism.

Evaluation

Clinical features of hypothyroidism, whether primary or central, include cold intolerance, weight gain, fluid retention, paresthesias, depression, constipation, dry skin, brittle hair, relaxed and delayed return of deep tendon reflexes, slowing of maternal pulse, and goiter. Primary hypothyroidism is confirmed by measuring serum TSH (will be high) and free T₄ (may be normal [subclinical hypothyroidism] or low [overt hypothyroidism]). Additional findings of antithyroid peroxidase (TPO) antibodies suggest autoimmune thyroiditis.

Treatment

Hypothyroidism is treated with thyroid hormone replacement, usually in the form of l-Thyroxine at a daily dose of 1 µg per pound (or 1.6 µg/kg) of maternal body weight.¹⁶ Thyroxine replacement is usually continued for life, with special attention during pregnancy to maintain TSH in the normal range and free T₄ in the upper half to upper third of the normal range. Physiologic changes during pregnancy, in addition to placental metabolism of thyroid hormone, may heighten the need for an l-thyroxine dosage increase as pregnancy progresses (this occurs in 40%-70% of gravidas so treated).¹⁷

TSH should be checked 4 to 6 weeks after therapy is initiated or following a change in dosage. It is also reasonable to repeat thyroid studies at the beginning of each trimester in case the l-thyroxine dosage needs to be adjusted. After delivery, the dosage can be reduced to that used prepregnancy.¹⁷ l-thyroxine is best taken in the morning on an empty stomach.¹⁷ Ferrous sulfate and calcium can form insoluble complexes with l-thyroxine; thus, these minerals should be ingested at least 2 hours before or after l-thyroxine.¹⁷ Likewise, bran, antacids, and sucralfate can impair l-thyroxine absorption, and should not be taken at the same time.¹⁰ Drugs inducing hepatic microsomal oxygenases, (rifampin, phenytoin, carbamazepine) may increase l-thyroxine clearance.

Gravidas in whom a euthyroid state is expeditiously restored experience improved outcomes.

Complications

Anemia is noted in 30% to 40% of gravidas with hypothyroidism. In addition, chronic hypertension, pre-eclampsia, preterm delivery, placental abruption, postpartum hemorrhage, and fetal distress have occurred with increased frequency in pregnancies complicated by hypothyroidism in the first trimester and/or near term.¹⁷ Neonatal effects of maternal hypothyroidism during pregnancy may include low birth weight, stillbirth, and congenital hypothyroidism. Antenatal testing, including ultrasonography, should be tailored for disease severity.

Subclinical Hypothyroidism

Patients with slightly increased TSH and normal free T₄ have subclinical hypothyroidism. They are generally asymptomatic or have vague symptoms; thus, many cases go undetected. Prevalence is about 2.5% in gravidas.^16,18,19 Causes are similar to those of hypothyroidism (Table 3). Patients with subclinical thyroid dysfunction have a 4% lifetime risk for overt hypothyroidism (vs a 1% risk in the general population).^16,18 Risk is even greater in patients in whom thyroid antibodies are detected.^16,18

Neurointellectual development of offspring of gravidas with hypothyroidism (overt or subclinical) is also of concern, and raises the issue of universal screening. One study suggested that decreased maternal thyroxine in the first, but not third, trimester may increase the risk for impaired psychomotor development in infants.²⁰ In another study, maternal TPO antibodies identified during gestation, even in the presence of normal maternal thyroid parameters, were the most important predictor of decreased scores on General Cognitive Scale examinations.²¹ A review showed that siblings born before the onset of maternal hypothyroidism, relative to those born after disease onset, did not differ in intelligence quotient (IQ) at a 4- to 10-year follow-up.¹⁷ However, Haddow et al found decreased IQs in offspring of gravidas with untreated hypothyroidism as compared with offspring of a treated hypothyroid group and a control group.²² Finally, hypothyroidism has been associated with maternal depression, which may also affect infant development. Gravidas in whom subclinical thyroid dysfunction is identified require relatively low l-thyroxine replacement doses. Regardless, the goal of maintaining TSH in the normal range and free T₄ in the upper half to upper third of normal is the same.

POSTPARTUM DISEASE

Prevalence of postpartum thyroid dysfunction ranges from 5% to 30%, with the higher rate noted in women with antithyroid antibodies.²³ This dysfunction takes one of five forms: persistent thyrotoxicosis, transient thyrotoxicosis, destructive thyrotoxicosis, transient hypothyroidism, or persistent hypothyroidism.²⁴ Persistent or transient thyrotoxicosis typically occurs 4 to 6 months postpartum, is associated with high radioactive iodine uptake, and is likely to represent Graves’ disease.²⁴ By comparison, destructive thyrotoxicosis usually occurs 1 to 6 months postpartum, is associated with low radioactive iodine uptake, and is likely to represent postpartum thyroiditis.^24,25

Postpartum Thyroiditis

Two percent to 15% of women experience postpartum thyroiditis,^25,26 with the highest rate occurring in those who have had it previously. Diagnosis is based on the following: no previous history of a thyroid abnormality, abnormal TSH in the first year postpartum, no toxic nodules identified, and negative TSHR-Ab.²⁵ Some thyroid autoantibodies may be detected during the hyperthyroid phase, but if a TSH receptor antibody is positive then Graves’ disease is considered. The presence of microsomal and thyroglobulin antibodies are strongly associated with the occurrence of postpartum thyroiditis.^26-27 During the thyrotoxic phase, postpartum thyroiditis is differentiated from Graves’ disease by low thyroid uptake of radioactive iodine or technetium and negative TSH-receptor antibody testing. Clinical presentation is usually subtle and may include palpitations, heat intolerance, nervousness, lack of energy, and increased irritability.

In most cases of postpartum thyroiditis, thyroid function goes through phases, starting with hyperthyroidism, which is usually self-limited. Thyrotoxicosis is secondary to hormone release from the damaged gland, as opposed to increased synthesis and secretion. Antithyroid medication is usually not required. A short course of propranolol (eg, 20 mg orally, every 8 hours²⁷ ) usually suffices for severe symptoms. The second phase is hypothyroidism, which is usually transient. Treatment is dictated by symptoms and by persistently elevated TSH. Women with moderate or severe symptoms may be given l-thyroxine 0.05 to 0.10 mg daily.^25-27 As a spontaneous return to a euthyroid state usually occurs within 1 year postpartum, it is reasonable to attempt weaning of l-thyroxine after 6 months of therapy. Physicians should check patients annually for the development of permanent primary hypothyroidism. It should be noted that some women with postpartum thyroiditis experience only the hyperthyroid or hypothyroid phase.

Breast-Feeding

Many women with thyroid dysfunction wish to nurse their infants. PTU is considered the drug of choice to treat hyperthyroidism during pregnancy, but questions regarding its use during lactation remain. Momotani et al investigated the effects of this agent on nursing infants’ thyroid status.²⁸ Their mothers were receiving high-dose PTU (300-750 mg/day) following a relapse or exacerbation of Graves’ disease. TSH binding inhibiting antibody levels were elevated in two infants shortly after birth, but they normalized by 19 weeks of age. TSH values were initially elevated in three infants, but they normalized despite continued maternal PTU ingestion. Other investigators have suggested that the amount of PTU excreted in breast milk is too low to affect infant thyroid status, especially if nursing is undertaken 2 or more hours after PTU ingestion.^29,30

CONCLUSION

To accurately evaluate thyroid disease during pregnancy, the physiologic changes of pregnancy need to be considered. In women with thyroid dysfunction, achieving a euthyroid state during pregnancy can favorably impact maternal and neonatal outcome. Radioiodine scanning should be avoided during pregnancy. Postpartum thyroid dysfunction often goes undetected. Increased awareness of the many symptoms and risk factors can aid in identifying thyroid disease.

Gayle L. Olson, MD, is assistant professor, University of Texas Medical Branch, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Galveston. She can be reached by telephone (409-747-4905), fax (409-772-5297), or email (golson@utmb.edu).

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