THYROID DISEASE DURING PREGNANCY Chapter 1 (Section 1) - Gerard N Burrow, MD and Lauren H Golden, MD

October 28, 2002

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Numerous hormonal changes and metabolic demands occur during pregnancy, resulting in complex changes in maternal thyroid function. Despite these changes in thyroid function, normal pregnancy is considered to be a euthyroid state. Studies of thyroid function during pregnancy in women with marginal iodine intake, or in women with underlying autoimmune thyroid disease, have suggested that increased demand may result in thyroid "strain" during pregnancy. Whether there is any significant effect on normal thyroid function is not at all clear. As diseases of the thyroid are, in general, much more prevalent in women than in men, it is not surprising that thyroid disorders are relatively common among pregnant women. These disorders span the functional gamut from hyperthyroidism to hypothyroidism. Euthyroid pregnant women may exhibit a number of non-specific signs that mimic those of thyroid dysfunction, making clinical diagnosis difficult. For example, euthyroid pregnant women may manifest signs of a hyperdynamic state, including an increase in cardiac output, mild tachycardia, and a widened pulse pressure, signs commonly associated with the hyperthyroid state. They also experience progressive fatigue and de facto weight gain, which may mask underlying thyroid dysfunction. An understanding of the normal physiologic processes of the thyroid gland during gestation facilitates the understanding of pathologic processes in pregnancy. MATERNAL THYROID PHYSIOLOGY After conception, complex hormonal and metabolic changes ensue that help to ensure the continuation of pregnancy. These changes are directed by the production of polypeptide hormones by the placenta and fetal pituitary gland, as well as by steroid production in the fetal adrenals and gonads. Human chorionic gonadotropin (hCG) concentrations increase rapidly following implantation, ensuring sufficient progesterone concentrations to maintain the pregnancy until placental production is adequate. During pregnancy, maternal thyroid function is modulated by three independent but interrelated factors1,2 (Table 1): (1) an increase in hCG concentrations that stimulate the thyroid gland,3 (2) significant increases in urinary iodide excretion, resulting in a fall in plasma iodine concentrations, and (3) an increase in thyroxinebinding globulin (TBG) during the first trimester, resulting in increased binding of thyroxine. In the aggregate, these factors may be responsible for the increased thyroid demand, or thyroid "strain" observed during pregnancy. Reports that hypothyroid women require an increased dosage of L-thyroxine during pregnancy to maintain the euthyroid state (raise the question of whether normal women have difficulty in maintaining thyroid function during gestation. Table 1. Factors Affecting Maternal Thyroid Function hCG

Urinary iodide excretion TBG HCG As noted above, human chorionic gonadotropin is a peptide hormone responsible for the production of adequate concentrations of progesterone early in gestation, until progesterone production by the developing placenta is sufficient to subserve that function. Thus, hCG concentrations increase dramatically during the first trimester of pregnancy, and plateau gradually thereafter. Structurally, the hCG peptide is composed of two chains, an alpha chain and a beta chain, the same structural composition of TSH. Significantly, the alpha chain is identical to that of TSH, while the beta chains differ between the two molecules. This partial structural homology anticipates at least a partial overlap in function, and it has been established that hCG does possess intrinsic, weak thyroid-stimulating activity. In addition, homology exists between the TSH and LH/hCG receptors. TSH levels fall predictably during the first trimester, mirroring, in a reciprocal fashion, the concomitant rise in hCG (Fig 1). The overall effect of hCG on the degree of thyroid stimulation and TSH suppression reflects an integration of both the amplitude and the duration of the hCG peak. Despite hCG-mediated stimulation of the thyroid gland, free (unbound) serum hormone concentrations generally remain within, or slightly above, the normal range during the first trimester. The stimulatory effects of hCG on normal pregnancy are not significant and are normally confined to the first half of gestation. In certain pathological conditions, however, including hyperemesis gravidarum and trophoblastic tumors, hCG concentrations may increase into the range sufficient to induce biochemical hyperthyroidism.

Figure 1. Thyroid-stimulating hormone (TSH) and human chorionic gonadotropin (hCG) during gestation. Note the reciprocal relationship between TSH and hCG.

(Adapted from Glinoer D 1997 The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocrine Reviews 18:404-433)

Iodine Excretion During Pregnancy Plasma inorganic iodine concentrations decline during pregnancy, the result of an

increase in glomerular filtration rate. This increase in GFR results in a sustained rise in the renal clearance of iodine, beginning early in pregnancy. This is a major factor in the decreased plasma inorganic iodine concentration in pregnancy.4 The thyroid gland compensates by enlarging and increasing the plasma clearance of iodine to produce sufficient thyroid hormone to maintain the euthyroid state. Whether or not subsequent development of a goiter ensues depends upon the plasma concentration of inorganic iodide, as thyroid volume varies as a function of iodine intake.5,6 Numerous studies have evaluated changes in thyroid size and function during gestation. These have confirmed an increased prevalence of pregnancy-associated goiter in geographic regions of relative iodine deficiency.7 In a large study of 606 pregnant women in an area of marginal iodine intake (50 to 80 g/day), thyroid volume increased as determined by ultrasonography by an average increment of 20%.8 An inverse relationship has been found between iodine intake and thyroid blood flow. In a cross-sectional study done in Scotland, an area of relative iodine deficiency, 70% of pregnant women were diagnosed as having a goiter, in contrast to 38% of nonpregnant women.9 Goiters were also found in 39% of nulliparous women and 35% of nonpregnant parous women, suggesting that previous pregnancies did not affect the incidence of goiter. These investigators repeated the study in Iceland under the same experimental conditions. In an iodine-replete setting, they noted no increase in goiter during pregnancy,10 as goiter was found in 19% of nonpregnant and 23% of pregnant Icelandic women. A recent prospective study in the iodine-replete Netherlands also failed to demonstrate a significant change in thyroid volume/size during pregnancy.11 In iodine-deficient Belgium, Glinoer et al12 observed an 18% increase in thyroid volume during pregnancy. In a follow-up randomized, double-blind, placebocontrolled intervention study, they treated 180 pregnant women with placebo, 100g iodide (KI), or 100g iodide (KI) in addition to 100g L-thyroxine daily.13 Thyroid volume increased by 30% in the placebo group, compared to 15% in the group receiving iodide supplementation. The group receiving L-thyroxine therapy together with iodide supplementation noted the smallest change in thyroid volume, an increase of only 8%. These studies provide ample evidence that thyroid volume increases during pregnancy in regions of moderate or marginal iodine intake, while no significant changes in thyroid size or volume occur in iodine-replete conditions. Intervention studies suggest that thyroid enlargement during pregnancy is a physiological, compensatory adaptation to the increased demands for iodine associated with pregnancy. Iodine deficiency goiter is unlikely to occur at a plasma iodine concentration above 0.08 g/dl.14 In many regions of Europe, the plasma inorganic iodine concentration ranges from 0.10 to 0.15 g/dl, and during pregnancy may fall below 0.08 g/dl.15 In residents of North America and Iceland, on the other hand, the plasma inorganic iodine is approximately 0.30 g/dl, and remains above 0.08 g/dl, even during pregnancy. An iodine balance study done in the United States revealed no difference between pregnant and nonpregnant women.16 Despite the fact that pregnant women in North America manifest increased renal clearance of iodine, ample dietary intake prevents excess iodine loss. Iodized salt should be sufficient to supply the intake of 200 g of iodine needed during pregnancy, and the iodine in most prenatal vitamin

supplements ensures an adequate intake.17 In areas of marginal iodine intake (i.e., 50 g/day), supplementary iodine (160 g/day) given to pregnant women reduced neonatal goiter from 33% to 7%.18 An excessive iodine intake because of unusual dietary practices (e.g., 2000g/day) may cause difficulties for both mother and child and is discussed later. TBG As noted above, an increase in thyroxine-binding globulin (TBG), resulting in increased binding of thyroxine, is a third modulating factor that influences thyroid function during pregnancy. It is discussed in further detail below. DETERMINATION OF THYROID FUNCTION IN PREGANCY The physiologic hormonal changes and alterations in metabolic demand that occur in the pregnant woman complicate the determination of thyroid function. These same changes make the clinical diagnosis of thyroid disease difficult and increase the need to rely on laboratory determinations. Basal Metabolic Rate Prior to the development of accurate biochemical determinations of thyroid function, basal metabolic rate (BMR) was monitored as a reflection of overall thyroid function. Early studies indicated that the BMR was elevated in pregnant women, increasing 15%-20% by the eighth month of gestation. Under scrupulously basal conditions, it was demonstrated that the uterus and its contents could account for 70% to 80% of the rise in oxygen consumption above those of nonpregnant values. Although clinical laboratory tests are now the standard method of appraisal of thyroid function, a true BMR is still a good indicator of integrated thyroid function. However, measurements of BMR correlate with the final clinical appraisal in only about half of patients. Discrepancies reflect the difficulty in separating basal from total metabolism, which also includes increases in oxygen consumption from digestive and muscular activity. Only the true basal metabolism is a measure of thyroid activity, and most errors in the interpretation of the BMR are due to a failure to recognize this distinction. Total Serum Thyroxine And Triiodothyronine Radioimmunoassays measure the total T4 and T3 content in the serum and are elevated in pregnancy because of increased thyroid hormone binding to TBG. Serum T- and T3 concentrations rise significantly early in pregnancy. T4 concentrations rise sharply between 6 and 12 weeks of gestation, stabilizing by mid-gestation. It is estimated that serum T4 concentrations increase by 1-3% per day over the trimester to compensate for the above-mentioned increase in TBG.19 Thus, in areas of iodine sufficiency, the T4/TBG molar ratio remains stable during pregnancy, as both T4 TBG concentrations rise in tandem. The rise in serum T3 is more gradual, although it also stabilizes at approximately 20 weeks gestation.20 Once mid-gestation plateaus have been reached, serum T4 and T3 concentrations remain elevated throughout gestation, returning to normal shortly after delivery.21,22,23 Free Thyroid Hormone

Although the bound T4 and T3 are increased, the unbound, or free thyroid hormone concentrations generally remain within the normal range for nonpregnant women, although they tend to decrease by 10-15% in late pregnancy.24,25,26 However, variation has been reported in a large series in which decreases in mean serum free T4 and T3 concentrations were reported in an area of marginal iodine intake.27 Less than 0.05% of the circulating T4 and less than 0.5% of the circulating T3 is unbound. The reference method of equilibrium dialysis is expensive and laborious. Commercially available measurements of unbound thyroid hormone reflect indirect calculations, and may not be reliable in pregnancy. Radioimmunoassays for free thyroid hormones are now available, but there is significant variability among the different tests. This is particularly true in the presence of the large amounts of TBG found in pregnancy. The most common measure of unbound thyroid hormone is the free T4 index, an arithmetic product of the total serum T4 determination and a measure of thyroid hormone binding.28 Most binding methods that are commonly used underestimate the large increases in TBG concentration and may result in falsely high free T4 index values in some euthyroid pregnant women.29 When accurate measurements of serum T4 and T3 concentrations are used, most thyrotoxic women have elevated values and most women with moderate to severe hypothyroidism have low serum T4 values. Many of the latter have normal serum T3 concentrations. Women with mild hypothyroidism may have low-normal free T4 values. The diagnostic accuracy of some T4 index methods may be less during pregnancy, and it is therefor important to understand the function of the test used. Thyroxine Production And Metabolism After free thyroid hormones enter the cell, they exert their effect by binding to nuclear receptors and initiating new protein synthesis. Thyroid hormone is subsequently degraded, and this degradation can be measured with radioisotopelabeled T4. In the steady state, T4degradation is a measure of thyroid hormone production. Serum T4 has an approximate volume of distribution of 10 L. With a normal serum T4 of 8 g/dl, the entire thyroidal pool of T4 is approximately 800 g. T4 disappears from the serum of a euthyroid nonpregnant adult with a half-life of 6 to 8 days, which results in a fractional turnover of approximately 10% per day. Therefore, approximately 10% of the extrathyroidal pool of T4, or approximately 80 g, turns over per day. In a steady state, 80 g of T4 is produced daily. Peripheral metabolism of thyroid hormones in human tissues is accomplished by three deiodinase enzymes (Fig 2). Type I deiodinase is responsible for the production of the majority of circulating T3, by outer ring deiodination of circulating T4. Inner ring deiodination of T4 by type I deiodinase produces reverse T3 (r T3), and these levels may be elevated in pregnancy in proportion to the increase in serum T4. There is no direct evidence for upregulation of type I deiodinase activity in pregnancy30,31,32 T4 and rT3 are the preferential substrates for type II deiodinase, which acts on the outer ring to produce T3. There is evidence that this enzyme is expressed in the placenta, and that its activity increases if maternal concentrations of T4 are reduced. It may thus play a role in maintenance of local T3 production in the setting of relative maternal hypothyroxinemia.33 Type III deiodinase converts T4 to rT3 and T3 to T2. It too is expressed in the placenta, and may be responsible for the low concentrations of T3 and high concentrations of rT3 seen in fetal thyroid hormone metabolism.

Figure 2. Thyroxine (T4) Concentrations During Gestation

(Adapted from Burrow GN, Fisher D, Larsen PR: Maternal and fetal thyroid function. N Engl Med 331:1072, 1994. Copyright1994 Massachusetts Medical Society. All rights reserved.)

One study showed a decrease in the fractional rate of T4 turnover when TBG capacity was increased by estrogen administration.34 However, the absolute rate of thyroid hormone disposal was unchanged, because the total serum T4 concentration increased. In another study, net T4 turnover and presumably thyroid hormone requirements were unchanged in normal human pregnancy.35 Net T4 turnover was 90 g/day in the nonpregnant women and 97 g/day in the pregnant women. The two values were identical when expressed as the daily turnover per square meter of body surface. These findings are for one period in pregnancy, but because of necessary restrictions on the use of radioisotopes in pregnant women, further data will not be available. Increased T4 turnover has been reported during pregnancy in monkeys. Triiodothyronine Sulfate. Studies indicate that sulfation of iodothyronines plays a significant role in thyroid hormone metabolism. Despite the fact that T3 sulfate binds to TBG, values are in the low normal range in pregnant women.36 Interestingly, T3 sulfate binds poorly to nuclear receptors and is not an active hormone. If an active T3 or T4 sulfatase were present, T3 or T4 sulfate could serve as an active hormone. The reason why the serum T3 sulfate concentration is not increased in pregnancy is unclear. Factors such as decreased production, increased clearance, or increased fetal transfer may play a role singly or in combination. The elevated serum T3 sulfate in the neonate may reflect increased production or decreased metabolism by fetal tissue. In any case, the values represent another example of the changes in thyroid hormone metabolism that occur in pregnancy. Thyroxine-Binding Globulin Thyroid hormone transport in serum is accomplished by non-covalent binding to three thyroid hormone transport proteins: thyroxine-binding globulin (TBG), albumin, and transthyretin (thyroxine-binding prealbumin or TBPA). The least abundant of the three transport proteins, thyroxine-binding globulin (TBG), binds thyroxine with the highest affinity37 In steady state conditions, the bound hormone

fraction is in equilibrium with the unbound, free, fraction. In non-pregnant patients, approximately two-thirds of serum thyroxine is bound by TBG. Normal pregnancy is considered to be a state of TBG excess. TBG concentrations rise to about twice normal values during pregnancy. The increase in TBG concentration is a direct effect of increased estrogen levels during gestation. Estrogens stimulate increased sialylation of TBG, prolonging circulatory half-life and resulting in increased serum TBG concentrations. Estrogens also stimulate hepatic synthesis of TBG and cause a fall in transthyretin binding capacity.38,39 As a result, the proportion of circulating thyroxine bound to TBG increases during pregnancy, and may be in excess of 75%. The maximum binding capacity of TBG and transthyretin can be determined by the addition of saturating concentrations of thyroxine. TBG has a normal binding capacity that ranges from 19 to 30 g/dl of T4 and increases to 40 to 60 g/dl of T4 during pregnancy. TBG concentration can also be measured directly by radioimmunoassay and has a normal range of 12 to 30 g/L, which increases to 30 to 50g/L during pregnancy.40 The maximum binding capacity for transthyretin has been determined to be 219 to 393 g/dl of T4.41 Although transthyretin has a greater binding capacity for T4, TBG has a greater affinity and actually binds more T4 in vivo. T4 binds more tightly to TBG than does T3. The role of the increased TBG in pregnancy has also been studied by examining pregnant patients with partial or total TBG deficiency.42 There was no increase or only a minimal increase in TBG in these patients during pregnancy, and no significant changes in thyroid function occurred. That is, serum T4 does not increase unless there is a concomitant increase in TBG. Conversely, there must be adequate amounts of thyroid hormone produced to maintain normal thyroid function in the presence of increased binding. In a study of 606 women, the rise in serum T3 and T4 concentrations during gestation did not increase as much as would be predicted by the increase in serum TBG.43 This relative hypothyroxinemia was accompanied by a serum TSH concentration that was increased, although well within the normal range. Whether TBG saturation can be studied without taking serum albumin concentrations into account is a matter of controversy.44 Nevertheless, the sample size is impressive. In addition to changes in TBG concentration, mutations in the transthyretin and the albumin gene may alter T4/T3 binding.45The most frequent disorder, familial dysalbuminemic hyperthyroxinemia, is the result of a mutation in albumin with increased affinity for T4, but not T3. The serum total T4 concentration is elevated, with a normal serum T3 concentration and normal serum TSH concentration. Serum free T4determined by the resin T4 uptake method is not accurate in these patients. Determination Of Serum TSH The low sensitivity of serum TSH determinations in the past has resulted in conflicting reports about TSH values in pregnancy. Current availability of specific, ultrasensitive, third-generation immunoradiometric assays of serum TSH has brought clarity.46,47 These assays can accurately detect TSH values as low as 0.002 mU/L. During the first trimester, serum TSH values decrease slightly, in response to elevations in hCG, and its intrinsic thyroid-stimulating activity (Fig 1). During the remainder of a normal pregnancy, serum TSH values increase but remain

well within the normal range.48,49 With the widespread institution of ultrasensitive TSH assays into clinical laboratory usage, normal pregnant women can be readily distinguished from pregnant women with thyrotoxicosis, as the latter manifest suppressed TSH values. Although more expensive than T4 determinations, the sensitive TSH determination is the best measure of thyroid function in pregnancy.50 Radioactive Iodine Uptake Due to the potentially harmful effects of radiation on the fetus, the use of radioisotopes in the pregnant woman is avoided. Whether radiation effects depend on a threshold dose is not clear, and all radiation to the fetus should be regarded as harmful.51 Administration of radioactive iodine to a pregnant woman is therefore contraindicated. However, when pregnant women have been studied in the past, the radioactive iodine thyroid uptake has been increased. In a small study performed in the 1950's, three of five women had an elevated radioactive iodine thyroid uptake at 12 weeks of pregnancy.52 In a second study, 132 I, a short-lived isotope, was administered to 25 pregnant women and the 2-hour thyroid uptake measured at 12, 24, and 36 weeks' gestation as well as 1 and 6 weeks post partum. The thyroid uptakes during pregnancy and at least 1 week post partum were significantly elevated compared with both nonpregnant values and those at 6 weeks post partum. The reasons for this elevation in radioactive iodine thyroid uptake become clear if one recalls that thyroid radioiodine uptake depends upon both the size of the iodine pool and thyroid-stimulating activity. As noted above, plasma inorganic iodine concentrations decline during pregnancy, a result of an increase in glomerular filtration rate and a sustained rise in the renal clearance of iodine. Decreased plasma inorganic iodine concentrations result in a smaller iodine pool and an increased thyroid clearance of iodine. Thyroid-stimulating activity is also enhanced during pregnancy, particularly during the first trimester. As a result of both increased thyroid clearance of iodine and enhanced thyroid-stimulating activity, radioactive iodine thyroid uptake is elevated in pregnancy. Two pregnant patients also had a triiodothyronine (T3) suppression test with this isotope, and thyroid uptake was suppressed to the same extent as in four nonpregnant women. The same worker also compared the effect of a single injection of TSH in three pregnant and three nonpregnant women and found a similar response in both groups. The uptake doubled 22 hours after the administration of TSH and returned to normal on the third day. These studies suggest that the thyroid-pituitary axis functions normally during pregnancy. Urinary excretion of radioactive iodine is also useful as an indirect reflection of thyroid uptake. Indeed, in 22 women in the third trimester, the mean urinary excretion of radioiodine was in the range between normal and thyrotoxic values.53 However, this method does not distinguish maternal and fetal thyroid uptake. Hypothalamic- Pituitary-Thyroid Axis Thyroid hormone secretion depends on stimulation by TSH, and TSH secretion in turn depends on the circulating thyroid hormone concentration. Thyroid function is therefore an example of the classic negative feedback mechanism. The level of thyroid hormone - particularly pituitary T3 - at which TSH secretion is inhibited, is determined by thyrotropin-releasing hormone (TRH), a tripeptide, L-pyroglutamyl-L-

histidyl-L-proline-amide. This hypothalamic releasing hormone determines the set point at which circulating thyroid hormone suppresses TSH secretion of the pituitary. There are conflicting reports about the responsiveness of the hypothalamic-pituitarythyroid axis during pregnancy. In a study performed in 1952, two pregnant women given 80 g of T3 for 1 week had depression of the thyroid uptake similar to that in nonpregnant control subjects.54 The increase in 131I uptake with TSH was also similar in pregnant and nonpregnant women. Pregnant women in the second and third trimesters were suppressed with 75 to 125 g T3 daily for 7 days. Thyroid uptakes were suppressed to the same extent as in nonpregnant women. Serum protein-bound iodine (PBI) values, reflective of thyroid hormone suppression, fell more than 1 g/dl at all time periods studied, but more T3 was needed to lower the serum PBI concentration in the latter months of pregnancy. In addition, some patients failed to suppress, regardless of the dose of T3. One group found that only one of five pregnant women who received 150 to 200g T3 daily had a serum PBI determination consistent with complete suppression. Thus, overall, 131I uptake appears to be normally responsive to thyroid hormone suppression during pregnancy, but the serum PBI concentration is not. Part of this apparent lack of responsiveness may be due to the increase in TBG during pregnancy. We administered TRH to patients in different stages of pregnancy who were to undergo therapeutic abortion.55 Women between 16 and 20 weeks of pregnancy had an increased TSH response to TRH compared with patients in the 6th to 12th week of pregnancy. This increase may have been an estrogen-mediated effect, because nonpregnant women on oral contraceptive steroids showed a comparable increase in TSH response to TRH. Other workers, however, have not found an increased TSH response to TRH in pregnant women.56,57,58 The discrepancies in these findings may be due to differences in iodine-sufficiency among the subjects studied. That is, the failure to find an increase in the TSH response to TRH may be due to iodine deficiency,59 although the mechanism is not clear. TRH has been shown to cross the placenta and stimulate the fetal pituitary in animal studies.60 TRH activity was found in the human placenta, and lower levels of TRH61 degrading activity were found in both cord and maternal sera, compared with sera from euthyroid nonpregnant adults. These data all suggest that TRH may play a role in the modulation of thyroid function during pregnancy. However, fetal pituitary TSH secretion appears to be controlled independently of both the maternal and the fetal hypothalamus.