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Thyroid disorders are among the most common endocrinopathies in young women of childbearing age. In large areas of the world, iodine defi ciency is the predominant cause of these disorders. In the Western Hemisphere, these disorders are most often related to altered immu-nity. The hormonal and immunologic perturbations of pregnancy and the postpartum period and the dependence of the fetus on maternal iodine and thyroid hormone have profound infl uences on maternal thyroid function and consequently on fetal well-being. Appropriate antepartum and postpartum care requires a basic knowledge of thyroid function, its alteration in pregnancy, and the more common thyroid diseases affl icting women in the setting of pregnancy, all of which are addressed in this chapter. The combination of thyroid disease and pregnancy has been the topic of several reviews,1,2 and the Endocrine Society’s guidelines for management of thyroid dysfunction during pregnancy and after delivery have recently been published.3

Maternal-Fetal Thyroid PhysiologyNormal Thyroid PhysiologyThe thyroid gland is located in the anterior neck below the hyoid bone and above the sternal notch. Consisting of two lobes and connected by the isthmus, it weighs approximately 20 to 25 g. Each lobe is divided into lobules, each of which contains 20 to 40 follicles. The follicle consists of follicular cells, which surround a glycoprotein material called colloid.

The hypothalamic-pituitary axis governs the production of thyroid hormone by the follicular cells. Tonic stimulation of thyrotropin-releasing hormone (TRH) is required to maintain normal thyroid function, and hypothalamic injury or disruption of the stalk results in hypothyroidism. TRH, a tripeptide, is produced in the paraventricular nucleus of the hypothalamus, and its local production as determined by mRNA is inversely related to concentrations of circulating thyroid hormones. Traversing the pituitary stalk, TRH is delivered to the pitu-itary thyrotroph by the pituitary portal circulation, and it affects the production and release of thyrotropin (i.e., thyroid-stimulating hormone [TSH]). A glycoprotein, TSH is composed of α and β sub-units, and the β subunit confers specifi city. Control of TSH secretion occurs by negative feedback (from circulating thyroid hormone, soma-tostatin, dopamine) or by stimulation by TRH.

Thyroid gland production of thyroxine (T4) and triiodothyronine (T3) is regulated by TSH. On binding to its receptor, TSH induces

thyroid growth, differentiation, and all phases of iodine metabolism from uptake of iodine to secretion of the two thyroid hormones. In the nonpregnant state, 80 to 100 μg of iodine are taken up by the gland daily. Dietary iodine is reduced to iodide, which is absorbed and cleared by the kidney (80%) and thyroid (20%). Iodide is actively trapped by the thyroid and is the rate-limiting step in hormone biosynthesis. The iodide is converted back to iodine and organifi ed by binding to tyrosyl residues, which are part of the glycoprotein thyroglobulin. This process requires the enzyme thyroid peroxidase. Iodination can give rise to monoiodotyrosine or diiodotyrosine, with the ratio depending on pre-vailing iodine availability. Coupling of two diiodotyrosine molecules forms T4, and one diiodotyrosine and one monoiodotyrosine form T3. Thyroglobulin is extruded into the colloid space at the center of the follicle, and thyroid hormone is stored as colloid.

Hormone secretion by thyroid cells, which is also under TSH control, involves digestion of thyroglobulin and extrusion of T4 and T3 into the capillaries. Daily secretion rates approximate 90 μg of T4 and 30 μg of T3. Both circulate highly bound to protein (mainly thyroxine-binding globulin [TBG]), with less than 1% in free form (0.3% of T3 and 0.03% of T4). Other binding proteins include thyroxine-binding prealbumin and albumin. It is the free hormone that enters cells and is active.

Whereas T4 is completely thyroidal in origin, only approximately 20% of T3 comes directly from the thyroid. Thyroxine is metabolized in most tissues (particularly in the liver and kidneys) to T3 by deiodin-ation. It is also metabolized to reverse T3, a metabolically inactive hormone. Removal of an iodine by 5′ monodeiodination from the outer ring of T4 results in T3, which is metabolically active. When iodine is removed from the inner ring, reverse T3 is produced (Fig. 47-1) Monodeiodinase type I and type II catalyze the formation of T3, whereas reverse T3 is catalyzed by monodeiodinase type III. Normally, approxi-mately 35% of T4 is converted to T3, and 40% is converted to reverse T3, but this balance is shifted in favor of the metabolically inert reverse T3 in illness, starvation, or other catabolic states.4,5 About 80% of cir-culating T3 is derived from peripheral conversion. The half-life of T4 is 1 week; 5 to 6 weeks are necessary before a change in dose of T4 therapy is refl ected in steady-state T4 values. The half-life of T3 is 1 day.

Free thyroid hormone enters the cell and binds to nuclear receptors and in this way signals its cellular responses.6 The affi nity of T3 for nuclear receptors is tenfold that of T4, which helps to explain the greater biologic activity of T3. Thyroid hormone receptors belong to a large superfamily of nuclear-hormone receptors that include the steroid hormone, vitamin D, and retinoic acid receptors. Thyroid hor-mones have diverse effects on cellular growth, development, and metabolism. The major effects of thyroid hormones are genomic,

Chapter 47

Thyroid Disease and PregnancyShahla Nader, MD

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996 CHAPTER 47 Thyroid Disease and Pregnancy

stimulating transcription and translation of new proteins in a concen-tration- and time-dependent manner.

Maternal Thyroid PhysiologyPregnancy alters the thyroidal economy, and the hormonal changes of pregnancy result in profound alterations in the biochemical parame-ters of thyroid function. This section reviews maternal thyroid physiol-ogy, the role of maternal hormones in fetal growth and development, and the development of the fetal hypothalamic-pituitary-thyroid axis. This topic was reviewed by Glinoer.7

Three series of events occur at different times during gestation. Starting in the fi rst half of gestation and continuing until term, there is an increase in TBG, a direct effect of increasing circulating estrogen concentrations. Basal levels increase twofold to threefold. This increase is accompanied by a trend toward lower free hormone concentrations (T4 and T3), which results in stimulation of the hypothalamic-pituitary-thyroid axis. Under conditions of iodine suffi ciency, the decrease in free hormone levels is marginal (10% to 15% on average). When the supply of iodine is insuffi cient, more pronounced effects occur, and these are addressed in later sections. There is usually a trend toward a slight increase in TSH between the fi rst trimester and term.

The second event takes place transiently during the fi rst trimester and is a consequence of thyroid stimulation by increasing concentra-tions of human chorionic gonadotropin (hCG). As hCG peaks late in the fi rst trimester, there is partial inhibition of the pituitary and tran-sient lowering of TSH between 8 and 14 weeks’ gestation (Fig. 47-2). In about 20% of women, TSH falls below the lower limit of normal, and these women often have signifi cantly higher hCG concentrations.8 The stimulatory action of hCG has been broadly quantifi ed; an increment of 10,000 IU/L is associated with a lowering of basal TSH of 0.1 mU/L. In most normal pregnancies, this is of minor consequence.9

In the third series of events, alterations in the peripheral metabo-lism of thyroid hormone occur throughout pregnancy but are more prominent in the second half. Three enzymes deiodinate thyroid hor-mones: deiodinase types I, II, and III. Type I is not signifi cantly modi-fi ed. Type II, which is expressed in the placenta, can maintain T3 production locally, which can be critical when maternal T4 concentra-tions are reduced. Type III is also found abundantly in the placenta, and it catalyzes the conversion of T4 to reverse T3 and conversion of T3 to T2; this abundance may explain the low T3 and high reverse T3 con-centrations characteristic of fetal thyroid hormone metabolism.10

These physiologic adaptations to pregnancy, depicted in Figure 47-3, are attained without diffi culty by the normal thyroid gland in a

state of iodine suffi ciency. This does not apply when thyroid function is compromised or iodine supply is insuffi cient.

Iodine Defi ciency and GoiterIncreased vascularity and some glandular hyperplasia can result in mild thyroid enlargement, but frank goiter occurs because of iodine defi ciency or other thyroidal disease. Although iodine defi ciency is usually not a problem in the United States, Japan, and parts of Europe, 1 to 1.5 billion people in the world are at risk, with 500 million living in areas of overt iodine defi ciency. The World Health Organization recommends 150 μg iodine per day for adults and 200 μg for pregnant women. There is increased renal iodine clearance during pregnancy, and in the latter part of gestation, a signifi cant amount of iodine is diverted toward the fetoplacental unit to allow the fetal thyroid to produce its own thyroid hormones. This physiologic adaptation occurs easily with minimal hypothyroxinemia and no goiter formation in areas of iodine suffi ciency. Through hypothalamic-pituitary feedback, borderline iodine intake chronically enhances thyroid stimulation. The iodine defi ciency manifests as greater hypothyroxinemia, which increases TSH and thyroglobulin levels and produces thyroid hyper-trophy (Fig. 47-4).

In a study of otherwise healthy pregnant women living under con-ditions of relative iodine restriction, thyroid volume, as assessed by ultrasonography, increased an average of 30% during pregnancy.11 In a selected group of these women with goitrogenesis, follow-up a year after delivery did not show a return of thyroid volumes to those found in early pregnancy. Iodine intake should also be increased after deliv-ery, especially in breastfeeding women. Ultrasonography of neonates revealed that thyroid volume was 38% larger in neonates of untreated mothers compared with neonates of mothers treated with iodine supplementation.12

Other than iodine defi ciency, goiter in pregnancy can be related to the following:

� Graves disease� Hashimoto thyroiditis� Excessive iodine intake� Lymphocytic thyroiditis� Thyroid cancer� Lymphoma� Therapy with lithium or thionamides

In the United States, clinical studies of pregnant women and non-pregnant controls have not revealed an increase in goiter during preg-

O CH2

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CH COOHHOT3

I I

I

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I I

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I

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FIGURE 47-1 Iodine removal. Removal of an iodine atom by 5′-monodeiodination from the outer ring of thyroxine (T4) results in the formation of metabolically active triiodothyronine (T3). Removal of an iodine atom from the inner ring results in formation of the metabolically inactive reverse triiodothyronine (rT3).

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997CHAPTER 47 Thyroid Disease and Pregnancy

nancy.13 Ultrasound studies from other areas replete with iodine have confi rmed these fi ndings.14,15

Iodine Metabolism in PregnancyAlthough radioactive iodine is absolutely contraindicated in preg-nancy, early studies using 132I showed a threefold increase in thyroidal iodine clearance in pregnant women. Another set of studies enrolling 25 pregnant women also revealed increased radioactive iodine uptake during pregnancy compared with the nonpregnant or postpartum state.16,17 The mean renal iodine clearance almost doubles because

of increased renal blood fl ow and an increase in glomerular fi ltration rate of as much as 50%.18 If iodine excretion is greater than 100 μg in a 24-hour period, the patient’s iodine intake is assumed to be suffi cient.19f

Placental-Fetal Thyroid PhysiologyThe thyroid gland forms as a midline outpouching of the anterior pharyngeal fl oor, migrates caudally, and reaches its fi nal position by 7 weeks’ gestation. Lateral contributions from the fourth and fi fth pha-ryngeal pouches give it its bilateral shape by 8 to 9 weeks’ gestation. Active trapping of iodide is detectable by week 12, and the fi rst indica-tion of T4 production is detectable by week 14. Hypothalamic TRH is detectable at weeks 8 to 9, and the pituitary portal circulation is func-

10 20

Free T3

Free T4

Free T4

Total T3

Total T4

Total T4

TBG

hCG

TBG

Week of pregnancy

30

Thyrotropin

Thyrotropin

40

Fetus

Mother

FIGURE 47-2 Relative changes in maternal and fetal thyroid function during pregnancy. The effects of pregnancy on the mother include a marked and early increase in hepatic production of thyroxine-binding globulin (TBG) and placental production of human chorionic gonadotropin (hCG). The increased level of serum TBG increases total serum thyroxine (T4) concentrations; hCG has thyrotropin-like activity and stimulates maternal T4 secretion. The transient hCG-induced increase in the serum level of free T4 inhibits maternal secretion of thyrotropin. (Reprinted by permission from Burrow GN, Fisher DA, Larsen PR: Maternal and fetal thyroid function. N Engl J Med 331:1072, 1994.)

Hypothalamus

TRH

TSH

hCG Thyroid

Pituitary

Liver

TBG Free hormones

Estrogen

Placenta Placental Deiodinases

T4, T3

T4 to T3Type II -T4 to reverse T3Type III -

FIGURE 47-3 Physiologic adaptation to pregnancy. Schematic representation of the physiologic adaptation to pregnancy shows increased thyroxine-binding globulin (TBG) concentrations, increased levels of human chorionic gonadotropin (hCG) with its thyrotropin-like activity, and alterations in the peripheral metabolism of thyroid hormones in the placenta. TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone, T4, thyroxine, T3, triiodothyronine. (Adapted from Glinoer D: What happens to the normal thyroid during pregnancy? Thyroid 9:631, 1999.)

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tional by weeks 10 to 12. Until mid-gestation, fetal TSH and T4 con-centrations remain low. At 18 to 20 weeks’ gestation, the fetal thyroid gland’s iodine uptake and serum T4 concentrations begin to increase.20 Concentrations of T4 increase from 2 μg /dL at 20 weeks to 10 μg/dL at term, with increasing TBG concentrations contributing to this rise. Similarly, free fetal T4 concentrations increase from 0.1 ng/dL at 12 weeks’ gestation to 1.5 ng/dL near term. Increases in T3 and free T3 are smaller, presumably because of the availability of placental type III deiodinase, which converts T4 rapidly to reverse T3. Fetal serum T3 increases from 6 ng/dL at 12 weeks’ gestation to 45 ng/dL near term. Fetal serum TSH increases from 4 to 8 mU/L between weeks 12 and term.21,22 In summary, most fetal T4 is inactivated to reverse T3. The T3 (from T4 conversion or direct fetal thyroid secretion) has limited avail-ability. Fetal tissues that depend on T3 for development (e.g., brain structures) are supplied by local T4 to T3 conversion by means of deio-dinase type II.22

Placental Transfer of Thyroid HormonesAlthough earlier studies suggested only limited T4 and T3 transfer through the placenta, later studies have shown that T4 can be found in fi rst-trimester celomic fl uid by 6 weeks’ gestation. Nuclear T3 receptors can be identifi ed in the brain of 10-week-old fetuses, and they increase tenfold by 16 weeks’ gestation before the fetal thyroid becomes fully functional.24 These studies suggest that maternal T4 transfer occurs early in gestation and that low levels of T4 are sustained in the fetus at this time.25 Vulsma and colleagues26 reported that cord serum T4 levels in hypothyroid neonates with glandular agenesis represented as much as 30% of normal circulating values, a strong indication of maternal T4 transfer, although this has not been a uniform fi nding.27

It appears that the fi rst phase of maximum growth velocity of developing brain structures—neuronal multiplication and organiza-tion occurring during the second trimester—corresponds to a phase during which the supply of thyroid hormones to the fetus is almost exclusively of maternal origin.20 In the second phase of maximum fetal brain growth velocity, occurring from the third trimester to 2 to 3 years postnatally, the supply of thyroid hormone is of fetal and neonatal origin. Low maternal thyroxine concentrations in the second trimester can result in irreversible neurologic defi cit in offspring. When it occurs later, the damage to the fetal brain is less and is partially reversible. The need for T3 by mid-gestation for development of the human cerebral cortex was also demonstrated by Kester and associates.28 Concentra-tions of TSH, T4, T3, and reverse T3 are measurable in the amniotic fl uid and correlate with the fetal rather than maternal serum.

Neonatal Thyroid FunctionImmediately after birth, there is a surge of TRH and TSH that is fol-lowed by an increase in T3 (from increased T4 to T3 conversion) and a moderate increase in T4.

10 Within a few days, the increased TSH falls to adult levels through T4 and T3 negative-feedback inhibition. Neona-tal T4 and T3 concentrations return to normal adult levels within 4 to 6 weeks.29 The transient hyperthyroxinemia can be triggered by neo-natal cooling and may represent an adaptation of thermogenesis to extrauterine life.30,31

In premature neonates, free T4 levels are low, TSH levels are normal (adult), and T4 levels are related to gestational age. The clinical conse-quence of this transient hypothalamic hypothyroidism is unknown, but it has been associated with impaired neurologic and mental development.32-34

Placental Transfer of Drugs Affecting Thyroid FunctionThe potential infl uence of the placenta on fetal thyroid and neurologic development is evident by the ready transfer of several agents that affect thyroid function.35,36 These agents include the following:

� Iodine� Thionamides� β-Adrenergic receptor blockers� Somatostatin� Exogenous TRH� Dopamine agonists and antagonists� Thyroid-stimulating immunoglobulins and other antibodies

TSH does not cross the placenta. TRH and corticosteroid adminis-tered antenatally before 32 weeks’ gestation stimulates T4 release and decreases the frequency of chronic lung disease among neonates.37 Intra-amniotic administration of T4 in the preterm setting increases fetal maturation, as refl ected by an increase in the lecithin-to-sphingomyelin ratio and decrease in respiratory distress syndrome of the newborn.38

Pregnancy, the Immune System, and Thyroid DiseaseChapter 6 offers a detailed review of pregnancy immunology. The fetus, with its complete set of paternal antigens, survives because of

�5 �5 �10 �10

Urinary iodide (μg/dL)

0

5

Thy

roid

hyp

ertr

ophy

(%

)

10

15

20

FIGURE 47-4 Iodine defi ciency can manifest as thyroid hypertrophy. The percentage of maternal thyroid hypertrophy (thyroid volume > 18 mL) is plotted against the urinary iodine concentration measured during the fi rst trimester of pregnancy. (Reprinted by permission from Caron P, Hoff M, Bassi S, et al: Urinary iodine excretion during normal pregnancy in healthy women living in the southwest of France: Correlation with maternal thyroid parameters. Thyroid 7:749, 1997.)

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adjustments in the maternal-placental-fetal immune systems. This immunologic compromise of pregnancy is orchestrated primarily by the placental tissues and passaged fetal cells that are able to modulate the local and systemic maternal immune responses.39,40 Autoimmune responses are usually reduced in pregnancy, as evidenced by ameliora-tion of Graves disease, rheumatoid arthritis, and multiple sclerosis.41-43 Although there is a shift from proinfl ammatory TH1 cytokines to TH2 cytokines, driven perhaps by progesterone,44 it is occurring against a background of reduced B-cell reactivity. The reduced B-cell responses are likely orchestrated by placental sex steroids, which are powerful negative regulators of B-cell activity. Whereas most of the immune changes in pregnancy return to normal by 12 months after delivery, there is a marked increase after most pregnancies in many different types of autoantibody secretion and an exacerbation of autoimmune disease. In most studies, total immunoglobulin G and autoantibody levels rise above pre-pregnancy levels during the fi rst 6 months after delivery, suggesting continuing nonspecifi c immune stimulation.39

Laboratory Evaluation of Thyroid Function during PregnancyThyrotropin and Thyroid HormonesTotal T4 and total T3 are elevated because of increased TBG production and reduced clearance induced by the hyperestrogenic state of preg-nancy.45 The normal reference range for total T4 should be adjusted by a factor of 1.5 for pregnant patients.2 The T3 resin uptake (i.e., indirect laboratory measure of available TBG binding sites) is reduced in preg-nancy because increased TBG binding sites take up more of the added T3, leaving less to bind to resin. The free thyroxine index, which is a product of the total T4 and T3 resin uptake, usually falls to within the normal range in pregnancy. Because free T4 can be determined, however, third-generation TSH and free T4 assessments are the best ways to evaluate thyroid function in pregnancy. However, automated free T4 assays are sensitive to alternations in binding proteins as occurs in pregnancy. Because these proteins change, they can falsely elevate or lower the free T4 assay result. The free T4, as measured by equilibrium dialysis, is not affected by these protein changes. Trimester-specifi c normative data for iodine-suffi cient women using specifi c commer-cially available assays is not available. This topic is discussed further in the section on Subclinical Hypothyroidism and Hypothyroxinemia.

If the TSH is suppressed, suggesting overproduction of thyroid hormones, free T3 can be determined. The third-generation TSH assays can differentiate profound from marginal suppression. Trimester-specifi c TSH concentrations were obtained by Dashe and colleagues,46 who determined these concentrations at each point during gestation in singleton and twin pregnancies. They constructed nomograms for both using regression analysis and showed signifi cantly lower TSH concentrations in the fi rst trimester. These levels were lower in twin pregnancies, as would be expected from the known effects of hCG. Values were converted to multiples of the median for singleton preg-nancies at each week of gestation, and they suggested that values expressed this way might facilitate comparison across laboratories and populations. In another study, using sensitive TSH assays, 9% of non-symptomatic fi rst-trimester women were found to have TSH values higher than 0.05 mU/L (i.e., lower limit of assay detection) but less than 0.4 mU/L, and another 9% had TSH values below the detection limit.8 Free T3 and T4 concentrations can be in the high-normal range

early in pregnancy because of the stimulatory effects of hCG. Free T4 levels tend to fall through the rest of pregnancy and occasionally to levels below those of nonpregnant women.2 Free hormone levels then fall through the rest of the pregnancy but usually not below the lower limit of normal.47 Table 47-1 outlines factors that infl uence TBG and therefore total hormone concentrations.

Resistance to thyroid hormone is a rare condition encompassing a number of different defects. The pituitary and other peripheral tissues can manifest this resistance. These patients present with an increased free T4 concentration along with an inappropriately elevated or non-suppressed TSH, and they may have goiters. Whereas patients with thyroid hormone resistance have normal α-subunit concentrations, patients with TSH-secreting tumors (i.e., differential diagnosis of thyroid hormone resistance) often have elevated serum α-subunit levels.48 In a case reported by Anselmo and colleagues,49 transient thy-rotoxicosis occurred during pregnancy in a woman with resistance to thyroid hormone caused by a mutation in the thyroid receptor β gene. This thyrotoxicosis manifested clinically by hypermetabolic features and paralleled the rise and peak of hCG concentrations. Symptoms ameliorated and thyroid hormone concentrations declined as preg-nancy progressed and hCG concentrations fell.

Concern has been raised regarding unaffected fetuses of mothers with thyroid hormone resistance. Outcomes of pregnancies in an extended Azorean family with resistance to thyroid hormone were analyzed; miscarriages were found to be more common, and unaf-fected infants born to affected mothers had lower birth weights, dem-onstrating a direct toxic effect of thyroid hormone excess on the fetus.50

Thyrotropin Receptor AntibodiesSeveral functional types of TSH receptor antibodies are recognized. Some antibodies promote gland function (i.e., thyroid-stimulating immunoglobulins [TSIs]), some inhibit binding of TSH to its receptor (i.e., thyroid-binding inhibitory immunoglobulins [TBIIs]), and some enhance or inhibit thyroid growth. These antibodies can be measured by a variety of bioassays and receptor assays. For example, maternal production of TSIs causes maternal Graves disease, is transferred across the placenta, and can lead to neonatal Graves disease. Excess TBIIs can cause maternal and neonatal hypothyroidism.

Antithyroid AntibodiesPatients with autoimmune thyroid disease commonly develop anti-bodies to thyroid antigens. The two most commonly determined antibodies are those to thyroglobulin and to thyroid peroxidase (anti-TPO).51 Among nonpregnant women, the incidence of anti-TPO

TABLE 47-1 FACTORS INFLUENCING THYROXINE-BINDING GLOBULIN

Factors Increasing TBG Levels Factors Decreasing TBG Levels

Oral contraceptives TestosteronePregnancy Nephrotic syndromeEstrogen CirrhosisHepatitis GlucocorticoidsAcute intermittent porphyria Severe illnessInherited defect Inherited defect

TBG, thyroxine-binding globulin.

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antibodies is about 3%, with the incidence ranging from 5% to 15% among pregnant women. A substantial proportion of women with positive anti-TPO antibodies in early pregnancy develop postpartum thyroiditis.52,53

Drugs and Thyroid FunctionTable 47-2 outlines drug effects on thyroid function and metabolism, absorption of thyroid hormones, and interpretation of thyroid func-tion tests. Iodine and lithium inhibit thyroid function. Propranolol and ipodate block T4 to T3 conversion, as do glucocorticoids; however, glucocorticoids also reduce release of TSH from the pituitary, as do dopamine, dopamine agonists, and somatostatin. The antiseizure med-ication phenytoin reduces total T4 levels (up to 30%) by inhibiting the binding of thyroid hormones to binding proteins and increasing T4 clearance. Ferrous sulfate, aluminum hydroxide, and sucralfate may inhibit thyroid hormone absorption substantially—an important interaction in pregnant women who are taking both iron and thyroid hormones.

Amiodarone, an iodine-rich drug, has been used in pregnancy for maternal or fetal tachyarrhythmias. Amiodarone and the iodine are transferred across the placenta, exposing the fetus to the drug and iodine overload. This iodine overload can cause fetal or neonatal hypothyroid-ism and goiter, because the fetus acquires the capacity to escape from the acute Wolff-Chaikoff effect (i.e., decrease in peroxidase activity and organifi cation that follow iodine excess) only late in gestation. Among 64 pregnancies in which amiodarone was given to the mother, 17% of progeny developed hypothyroidism (goitrous and nongoitrous). Hypo-thyroidism was transient, although a few of the infants were treated

short term with thyroid hormones. Only two newborns had transient hyperthyroxinemia. Although breastfeeding resulted in substantial infant amiodarone ingestion, it did not cause major changes in neonatal thyroid function. The study authors concluded that amiodarone should be used only when tachyarrhythmias are unresponsive to other drugs and are life threatening and that hypothyroid neonates (and perhaps the fetus in utero) should be treated. It is prudent to monitor the infants of breastfeeding mothers who continue to use the medication.54

Nonthyroidal Illness and Thyroid FunctionNonthyroidal illness has been the topic of various reviews and com-mentaries.4,5,55 Severely ill patients can manifest thyroid function test abnormalities that may correlate with functional inhibition of the hypothalamic-pituitary-thyroid axis, impaired T4 to T3 conversion (a constant accompaniment of nonthyroidal illness), and abnormalities in binding and clearance of thyroid hormone. Reverse T3 levels are substantially elevated because of increased T4 to reverse T3 conversion and impaired metabolic clearance of reverse T3. TSH concentrations can be low, normal, or elevated, although seldom higher than 20 mU/L.55 The more severe the illness, the lower the T4 values, and this rela-tionship has been used as a prognostic indicator, because a high cor-relation has been found between a low T4 value and a fatal outcome.56 The best test for assessing thyroid function in severely or chronically ill patients is the free T4 concentration. Despite the low T3 and total T4 state, this situation does not represent true hypothyroidism, but rather an adaptation to stress, and it should not be treated.

Thyroid Dysfunction and Reproductive DisordersThyroid hormones are important for normal reproductive function. Defi ciency of thyroid hormone can result in delayed sexual develop-ment. As reviewed by Winters and Berga57 and Krassas,58 all women with infertility and menstrual disturbances should have thyroid func-tion tests, usually T4, T3, and TSH. Women with type 1 diabetes, who have a relatively high incidence of hypothyroidism, should probably undergo screening before conception. This topic has been reviewed by Trokoudes and coworkers.59

HyperthyroidismHyperthyroidism has been linked to oligomenorrhea, hypomenorrhea, amenorrhea, and infertility, although many thyrotoxic women remain ovulatory. In one survey, only 21.5% of 214 thyrotoxic patients had menstrual disturbances, compared with 50% to 60% in older series.60 Thyroxine upregulates the production of sex hormone–binding globu-lin. Elevated levels of circulating testosterone and estrogen may be observed, and the clearance of testosterone is reduced. Gonadotropin concentrations can be tonically elevated.61,62 The substantial weight loss seen in some hyperthyroid patients can affect the hypothalamic-pituitary-gonadal axis and can contribute to the infertility of severe hyperthyroidism.

HypothyroidismHypothyroidism in fetal life does not affect the development of the reproductive tract, but during childhood, it leads to sexual immaturity

TABLE 47-2 EFFECTS OF DRUGS ON THYROID HORMONES AND FUNCTION TEST RESULTS

Inhibition of thyroid function Iodine LithiumInhibition of T4 to T3 conversion Glucocorticoid Ipodate Propranolol Amiodarone PropylthiouracilIncreased level of TSH Iodine Lithium Dopamine antagonistsDecreased level of TSH Glucocorticoids Dopamine agonists SomatostatinInhibition of T4 and T3 binding to binding proteins Phenytoin Salicylates SulfonylureasInhibition of gastrointestinal absorption of thyroid hormone Ferrous sulfate Sucralfate Cholestyramine Aluminum hydroxide

TSH, thyroid-stimulating hormone; T3, l-triiodothyronine; T4,

l-thyroxine.

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and usually a delay in puberty, followed by anovulatory cycles. Almost 25% of women with untreated hypothyroidism have menstrual irregu-larities. Menorrhagia occurs frequently and can refl ect interference with the endometrial maturational process and response to ovarian steroids; it usually responds to thyroxine treatment.63 The increased miscarriage rate seen in hypothyroid patients may refl ect disrupted endometrial maturation. Hypothyroidism, through increased TRH, can be associated with hyperprolactinemia, which itself can disrupt reproductive function and menstrual cyclicity,64 leading to oligomen-orrhea or amenorrhea. Galactorrhea can sometimes be seen in this setting, as can elevated levels of luteinizing hormone, possibly through diminished dopamine secretion.65

Women with hypothyroidism have diminished rates of metabolic clearance of androstenedione and estrone and an increase in peripheral aromatization. Whereas plasma concentrations of testosterone and estradiol are decreased because of diminished binding activity, their unbound fractions are actually increased. Several studies have sug-gested increased risk of miscarriage in the presence of thyroid anti-bodies, even in the face of a euthyroid status. Although previous studies did not demonstrate benefi t in using T4 to treat euthyroid women with recurrent spontaneous abortions,66-68 benefi t was shown by Negro and colleagues69 in a group of 115 antibody-positive women, one half of whom received thyroxine. Treatment decreased miscarriages and pre-maturity by 75% and 69%, respectively. In a thoughtful accompanying editorial, Glinoer70 stated that the statistical strength of the association between miscarriages and autoimmune thyroid disease has been largely confi rmed, with a threefold increase in the overall miscarriage rate. Because there is no reason to believe that thyroxine treatment altered autoimmunity, it was thought that the subtle defi ciency in thyroid hormone concentration or reduced ability of maternal thyroid func-tion to adapt adequately in women with autoimmune thyroid disease was the main reason for the benefi cial effects of thyroid hormone administration.

Radioiodine and Gonadal FunctionThe prevalence of infertility, premature births, miscarriage, and genetic damage in the offspring of women treated with radioactive iodine for thyrotoxicosis does not seem to be increased.71,72 Although thyroid cancer doses of 131I may be associated with subsequent menstrual irregularities, exposure to radioiodine does not appear to reduce fecundity.73 In a study of 32 women who conceived after 131I treatment for thyroid cancer (resulting in 60 term deliveries), two children conceived within a year of 131I therapy had birth defects, but no anomalies were seen in the remaining 58.74 Contraception has been recommended for 1 year after 131I treatment. In a large study, Schlumberger and associates75 obtained data on 2113 pregnancies conceived after exposure to 30 to 100 mCi of radioiodine given for thyroid cancer. The incidences of stillbirths, preterm labor, low birth weight, congenital malformations, and death during the fi rst year of life were not signifi cantly different between pregnancies conceived before or after radioiodine therapy. Miscarriages were more common for the women treated with 131I in the year preceding conception (40%).

All women need pregnancy tests before 131I treatment. Treatment late in the fi rst trimester and in the second trimester may result in irreversible hypothyroidism in the fetus. Lactating mothers who have received diagnostic or therapeutic doses of 131I should not breastfeed their infants. These topics are reviewed by Gorman76 and Berlin.77

Hyperthyroidism and PregnancySigns and SymptomsThe prevalence of hyperthyroidism in pregnant women ranges from 0.05% to 0.2%.78 The signs and symptoms of mild to moderate hyper-thyroidism—heat intolerance, diaphoresis, fatigue, anxiety, emotional lability, tachycardia, and a wide pulse pressure—can be mimicked by the hypermetabolic state of normal pregnancy. However, weight loss, tachycardia greater than 100 beats/min, and diffuse goiter are features that may suggest hyperthyroidism. Graves ophthalmopathy can be helpful but does not necessarily indicate active thyrotoxicosis.79 Gas-trointestinal symptoms such as severe nausea and excessive vomiting can accompany thyrotoxicosis in pregnancy, as can diarrhea, myopathy, lymphadenopathy, and congestive heart failure.

DiagnosisBiochemical confi rmation of the hyperthyroid state can be obtained through laboratory measurement of free T4, free T3, and TSH. Typi-cally, elevated values of free T4 and T3 and greatly suppressed TSH values are found, but a normal free T4 level can be seen in cases of T3 toxicosis. Other laboratory features include normochromic, normocytic anemia; mild neutropenia; elevated levels of liver enzymes and alkaline phosphatase; and mild hypercalcemia. Patients may test positive for anti-thyroid antibodies (i.e., antithyroglobulin and antithyroid peroxidase), but they are not specifi c to Graves disease. TSIs are considered to be the antibodies specifi c to Graves disease and can be measured by bioas-says or receptor assays.80

Differential DiagnosisCauses of hyperthyroidism are outlined in Table 47-3. Approximately 90% to 95% of hyperthyroid pregnant women have Graves disease, and this can be diagnosed with certainty in a thyrotoxic pregnant woman who has diffuse thyromegaly with a bruit and ophthalmopathy. Whereas excess circulating thyroid hormones cause lid retraction and lid lag, proptosis and external ocular muscle palsies refl ect infi ltrative ophthalmopathy of Graves disease. Graves disease is an autoimmune disease mediated by antibodies (i.e., TSIs) that activate the TSH recep-

TABLE 47-3 CAUSES OF HYPERTHYROIDISM IN PREGNANCY

Graves diseaseToxic adenomaToxic multinodular goiterHyperemesis gravidarumGestational trophoblastic diseaseTSH-producing pituitary tumorMetastatic follicular cell carcinomaExogenous T4 and T3

De Quervain (subacute) thyroiditisPainless lymphocytic thyroiditisStruma ovarii

TSH, thyroid-stimulating hormone; T3, l-triiodothyronine; T4,

l-thyroxine.

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tor and stimulate the thyroid follicular cell. It affects 3% of women of reproductive age.81

TreatmentThe outcome of treatment before pregnancy is better than that of treatment in pregnancy,82 and hyperthyroidism is therefore best treated before conception. If untreated or treated inadequately, women may have more complications during pregnancy and delivery. Very mild cases of hyperthyroidism, with adequate weight gain and appropriate obstetric progress, may be followed carefully, but moderate or severe cases must be treated. In a retrospective study of 60 thyrotoxic preg-nant women, preterm delivery, perinatal mortality, and maternal heart failure were signifi cantly increased among women who remained thy-rotoxic. Thyroid hormone status at delivery correlated directly with pregnancy outcome.82 In another study by Momotani and Ito,83 hyper-thyroidism at conception was associated with a 25% rate of abortion and 15% rate of premature delivery, compared with 14% and 10%, respectively, for euthyroid patients. Preeclampsia has also been associ-ated with uncontrolled hyperthyroidism.84

Thionamide TherapyThionamide therapy has been reviewed by Cooper85 and Clark and associates.86 The thionamides inhibit the iodination of thyroglobulin and thyroglobulin synthesis by competing with iodine for the enzyme peroxidase. Propylthiouracil (PTU) is more frequently prescribed in the United States. Carbimazole (a drug metabolized to methimazole) and methimazole itself are used often in Europe and Canada. PTU (but not methimazole) also inhibits the conversion of T4 to T3. The goal of therapy is to control the hyperthyroidism without causing fetal or neonatal hypothyroidism.87 Maternal free T4 should be maintained in the high-normal range. PTU is given every 8 hours at doses of 100 to 150 mg (300 to 450 mg total daily dosage) according to thyrotoxicosis severity. The occasional patient may require higher doses (e.g., 600 mg or more) because the risk of uncontrolled maternal hyperthyroidism is greater than that of high-dose PTU.82 It can take 6 to 8 weeks for major clinical effects to manifest. After the patient is euthyroid (refl ected by monthly free T4 and free T3 values), the dose of PTU should be tapered (e.g., halved), with further reduction as the preg-nancy progresses. For many patients, PTU can be discontinued by 32 to 36 weeks’ gestation, because remission of Graves disease during pregnancy is commonly observed, often with relapse after delivery. It has been suggested that a change from stimulatory to blocking anti-body activity may contribute to this remission.88

Maternal side effects of PTU treatment can include rash (≈5%), pruritus, drug-related fever, hepatitis, a lupus-like syndrome, and bronchospasm. An alternative thionamide can be used, although cross-sensitivity occurs in 50% of patients. Agranulocytosis, which is the most serious side effect, develops in only 0.1%, occurring especially in older women and those receiving higher doses.89 All patients experi-encing fever or unexpected sore throat on therapy should discontinue the drug and have white blood cell count monitoring. Agranulocytosis is a contraindication to further thionamide therapy; the blood count gradually improves over days or weeks.

Methimazole is not used in the United States. Although the trans-placental passage is similar,90 methimazole may cause cutis aplasia, a scalp deformity.91-93 Although rare, there are reports of methimazole and carbimazole embryopathy, with choanal atresia, tracheoesopha-geal fi stula, and facial anomalies.94-97

The risks of untreated hyperthyroidism need to be considered in relation to the risk of antithyroid medications. They appear to relate

directly to the control and severity of the hyperthyroidism. In a study of hyperthyroid pregnant women, the odds ratio for low birth weight was 2.4 for those treated during pregnancy and 9.2 for those uncon-trolled during pregnancy compared with a group who was euthyroid and remained so. Similarly, prematurity was more common in the hyperthyroid group; the odds ratio was 2.8 for the controlled group and 16.5 for the uncontrolled group. Similar fi ndings related to pre-eclampsia, with an odds ratio of 4.7 for the controlled group.84 This was confi rmed by a later study.98 In other reports, higher frequencies of small-for-gestational-age births, congestive heart failure, and stillbirths have been found.82,99 It is uncertain whether untreated Graves disease is associated with a higher frequency of congenital malformation.87,100

Infants of mothers receiving thionamides should be evaluated ultrasonographically for signs of hypothyroidism, such as goiter, bra-dycardia, and intrauterine growth restriction. If needed, cordocentesis may be performed and fetal thyroid function determined; reference ranges have been reported.101 Doses of PTU should be adjusted to keep free T4 level in the upper normal range and TSH level less than 0.5 mU/L during pregnancy to avoid hypothyroidism in the fetus. PTU often can be stopped in late gestation.

PTU is not signifi cantly concentrated in breast milk (10% of serum) and does not appear to affect the infant’s thyroid hormone levels in any major way. Methimazole also does not appear to affect subsequent somatic or intellectual growth in children exposed to it during lacta-tion.87,102,103 Antithyroid medication should be taken just after breast-feeding, allowing a 3- to 4-hour interval before the woman lactates again.

b-Blockersβ-Blockers are useful for the control of adrenergic symptoms, particu-larly maternal heart rate. Propranolol is commonly used in doses of 20 to 40 mg two or three times daily, and it inhibits T4 to T3 conversion. Alternatively, atenolol (50 to 100 mg daily) may be used, and in an emergency, esmolol, an ultra-short-acting cardioselective intravenous β-blocker, has been used successfully.104 Prolonged therapy with β-blockers can be associated with intrauterine growth restriction, fetal bradycardia, and hypoglycemia.

IodidesIodides decrease circulating T4 and T3 levels by up to 50% within 10 days by acutely inhibiting the release of stored hormone. Their use is appropriate in combination with thionamides (which should be started before the iodide) and β-blockers in patients with severe thyrotoxicosis or thyroid storm. Potassium iodide (SSKI, 5 drops every 8 hours) is given. Sodium ipodate, a radiographic contrast agent, is an alternative and has the added benefi t of inhibiting conversion of T4 to T3. Its safety in pregnancy has not been documented.

Because iodides cross the placenta readily, they should be used for no longer than 2 weeks, or fetal goiter can result. Inadvertent use of iodides also follows use of Betadine cleansing solutions, iodine-con-taining bronchodilators, and the drug amiodarone.

131I thyroid ablation is contraindicated in pregnancy because the radioactive iodine is concentrated in the fetal thyroid after 10 to 12 weeks’ gestation. If a woman inadvertently receives 131I during preg-nancy, SSKI should be given immediately, along with PTU, to block organifi cation and reduce radiation exposure to the fetal thyroid by a factor of 100 and to the fetal whole body by a factor of 10. To be of benefi t, SSKI and PTU treatment must be given within 7 to 10 days of exposure.76

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SurgeryIn select cases of thyrotoxicosis with severe complications or noncom-pliance, surgery can be performed in the pregnant patient. Two weeks of low-dose iodine therapy, such as one or two drops of SSKI daily, can reduce gland vascularity preoperatively. Surgery is best performed in the second trimester, although it can be done in the fi rst or third tri-mester.105 The risks are those of anesthesia, hypoparathyroidism, and recurrent laryngeal nerve paralysis.

Thyroid StormThyroid storm is a life-threatening exacerbation of thyrotoxicosis. Cri-teria for its diagnosis have been introduced,106 and the classic fi ndings are various degrees of thermoregulatory dysfunction, central nervous system effects (e.g., agitation, delirium, coma), gastrointestinal dys-function, and cardiovascular problems manifesting as tachycardia or heart failure. For example, a patient with a temperature of 102°F who is agitated and tachycardic with a pulse rate exceeding 130 beats/min would be diagnosed with thyroid storm. Although rare in pregnancy, it may be seen and can be precipitated by labor and delivery, cesarean section, infection, or preeclampsia.107 Thyrotoxic cardiomyopathy may also lead to heart failure in pregnancy.108 Intensive care treatment with fl uid and nutritional support is necessary for thyroid storm and heart failure. A loading dose of PTU of 600 mg may be given orally or through a nasogastric tube, and 200 to 300 mg of PTU is continued every 6 hours. An hour after the initial dose of PTU, iodine is given as fi ve drops of SSKI every 8 hours (or 500 to 1000 mg of intravenous sodium iodide every 8 hours) to inhibit thyroid hormone release. If the patient is iodine allergic, lithium (300 mg every 6 hours) is an alternative. Dexamethasone (2 mg every 6 hours) is also given to block T4 to T3 conversion. For tachycardia exceeding 120 beats/min, β-blockers such as propranolol, labetalol, or esmolol may be used.1 Table 47-4 summarizes the management of thyroid storm.

Subclinical HyperthyroidismSubclinical hyperthyroidism, as defi ned by suppressed TSH and normal free T4 and free T3 levels, is also seen in pregnancy. In a study by Casey and associates,109 1.7% of women screened had subclinical hyperthy-roidism, which they defi ned as TSH values at or below the 2.5th per-centile for gestational age and a free T4 level of 1.75 ng/dL or less. Pregnancy complications, morbidity, and mortality were not increased

among these women, and it was recommended that treatment in preg-nancy was unwarranted.

Fetal and Neonatal HyperthyroidismThe topic of fetal and neonatal hyperthyroidism has been reviewed by Zimmerman.110 Hyperthyroidism in fetuses and neonates is usually produced by transplacental passage of TSIs. Although they are a common component of active Graves disease, the antibodies can con-tinue to be present in the maternal circulation after surgical (Fig. 47-5) or radioactive iodine ablation or even in patients with Hashimoto thyroiditis. Fetal hyperthyroidism occurs when TSIs cross the placenta and activate the fetal thyroid; this occurs in 1% of infants born to these women.

Maternal TSI levels in excess of 300% of control values are predictive of fetal hyperthyroidism99 and should be measured at 28 to 30 weeks. The assay used should be a functional one, because TSH-receptor antibodies are heterogeneous and can stimulate or block the TSH receptor.99,111 Neonatal syndromes have been caused by transpla-cental passage of stimulating and blocking antibodies.112

Fetal ThyrotoxicosisFeatures of fetal thyrotoxicosis include a heart rate greater than 160 beats/min, growth retardation, advanced bone age, and craniosynos-tosis, all of which can be detected by ultrasound examination.113 Occa-sionally, nonimmune fetal hydrops and fetal death occur with associated diminished subcutaneous fat and thyroid enlargement. In utero, most cases are likely treated by the PTU given to the mother. This problem can arise if the mother is euthyroid but has elevated levels of TSIs.114 Cordocentesis can be used for diagnosis and for monitoring therapy. A combination of PTU and T4 treats the fetal hyperthyroidism while keeping the mother euthyroid.

Neonatal ThyrotoxicosisFeatures of thyrotoxicosis in the neonate include hyperkinesis, diar-rhea, poor weight gain, vomiting, exophthalmos, arrhythmias, cardiac failure, hypertension (systemic and pulmonary), hepatosplenomegaly,

TABLE 47-4 TREATMENT OF THYROID STORM

Treatment Rationale and Cautions Dosage

General care Intensive management achieved with intravenous fl uid hydration and nutritional support

Propylthiouracil Initial: 600 mg orally or crushed and given by NG tubeMaintenance: 200-300 mg every 6 hr given orally or by NG tube

Iodide Initial dose to be given 1 hr after start of PTU 5 drops of supersaturated solution of potassium iodide every 8 hr or500-1000 mg of intravenous sodium iodide infusion every 12 hr

Lithium carbonate Used if patient is allergic to iodine 300 mg every 6 hrDexamethasone Given to block T4 to T3 conversion 2 mg every 6 hr for four dosesβ-Blockers Given to control tachycardia ≥ 120 beats/min

(use cautiously if patient in heart failure)IV propranolol at 1 mg/min up to several doses until blockade is

achieved and concurrent 60 mg of propranolol (PO or NG tube) every 6 hours or

IV loading dose of 250-500 μg/kg of esmolol, followed by infusion at 50-100 μg/kg/min

IV, intravenous; NG, nasogastric; PO, orally; PTU, propylthiouracil.

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thrombocytopenia, and craniosynostosis. The infant should be exam-ined immediately after birth. Cord blood refl ects the in utero environ-ment, and by day 2 of life, the maternal antithyroid drug effects have receded. Affected neonates are treated with PTU, β-blockers, iodine, and glucocorticoids and digoxin, as needed. Ipodate may be preferable because it blocks T4 to T3 conversion. Remission by 20 weeks is common, and it usually occurs by 48 weeks; occasionally, there is persistent disease when there is a strong family history of Graves disease.

Other mechanisms of fetal and neonatal hyperthyroidism include activating mutations of the stimulatory G protein in McCune-Albright syndrome and activating mutations of the TSH receptor.115,116

Hyperthyroidism Related to Human Chorionic GonadotropinWhen hyperthyroidism is diagnosed during the fi rst trimester, the physician has a challenging differential diagnosis, usually that of Graves disease versus hCG-mediated hyperthyroidism. The hCG has TSH-like stimulatory activity, which can result in overproduction of thyroid hormone when the concentrations are high or when there is a change in its molecular structure. Molecular variants of hCG with increased thyrotropic potency include basic molecules with reduced sialic acid content, truncated molecules lacking the C-terminal tail, or molecules in which the 47-48 peptide bond in the β-subunit loop is nicked.117 This relationship is further complicated by differences in clearance rates of different hCG glycoforms.118 In vivo thyrotropic activity is regulated by the glycoforms and the plasma half-life.

The hCG concentrations peak at 6 to 12 weeks and then decline to a plateau after 18 to 20 weeks. The stimulation of thyroid hormone

production can suppress the TSH to low or suppressed values in up to 20% of normal pregnancies. Twin pregnancies can be associated with biochemical hyperthyroidism,9 as may pregnancies complicated by trophoblastic disease. Several clinical scenarios can arise and are described in the following sections.

Gestational Transient ThyrotoxicosisGestational transient thyrotoxicosis (GTT) occurs in the fi rst trimester in women without a personal or family history of autoimmune disease. It results directly from hCG stimulation of the thyroid. Glinoer and colleagues8 found an overall prevalence of GTT in 2.4% in a prospec-tive cohort study between 8 and 14 weeks’ gestation. Symptoms com-patible with thyrotoxicosis were often present, and elevated free T4 concentrations were found. The GTT was transient, paralleled the decline in hCG, and usually did not require treatment. The thyroid gland was not enlarged. Occasionally, β-blockers were used. GTT was not associated with a less favorable outcome of pregnancy.

Hyperemesis GravidarumHyperemesis gravidarum is a serious pregnancy complication associ-ated with weight loss and severe dehydration, often necessitating hos-pitalization.119 Biochemical hyperthyroidism is found in most women with this condition.120,121 Whereas Goodwin and colleagues120,121 found that the severity of disease varied directly with the hCG concentration, Wilson and associates122 did not fi nd such a correlation. As in the case of GTT, certain hCG fractions may be more important than total hCG as thyroid stimulators.123 The duration of the hyperthyroidism varies widely from 1 to 10 weeks but is usually self-limited. Vomiting and normalization of T4 levels occur by 20 weeks, though TSH may remain suppressed a little longer. Treatment is usually supportive, with correction of dehydration, antiemetics, and occasionally, parenteral nutrition. The vomiting may not be controlled by normalization of

FIGURE 47-5 Graves disease. A, Hypothyroid 21-year-old woman who developed Graves disease at age 7 was treated by subtotal thyroidectomy. She was given maintenance therapy with thyroid hormone (0.15 mg of Synthroid) throughout pregnancy. B, Her daughter was born at term with severe Graves disease, goiter, and exophthalmos that persisted for 6 months. C, The child was normal at 20 months old.

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thyroid hormones. In patients who require treatment, PTU therapy can be attempted if tolerated; methimazole suppositories can also be used.

Gestational Trophoblastic DiseaseBoth hydatidiform mole and choriocarcinoma can be associated with hCG levels that are greater than 1000 times normal and thus can cause hyperthyroidism (biochemically seen in approximately 50% of such women). The thyroid is usually not enlarged. Treatment of the hyda-tidiform mole or choriocarcinoma restores thyroid function to normal. Treatment with antithyroid drugs and β-blockers is frequently neces-sary, however, before surgical treatment of the mole.124

Recurrent Gestational HyperthyroidismCases of recurrent gestational hyperthyroidism have been described.125,126 In the case described by Rodien and colleages,126 the hyperthyroidism was caused by a mutant TSH receptor that was hypersensitive to hCG.

Other Causes of HyperthyroidismMuch less common causes of hyperthyroidism include thyrotoxicosis factitia (i.e., ingestion of exogenous hormone surreptitiously); in such cases, serum thyroglobulin, which is produced by the thyroid, is sup-pressed.127 Women with large nodular goiters may have hyperthyroid-ism from autonomously functioning nodules within such goiters. Alternatively, women can have hyperthyroidism from a single toxic

adenoma. If either of these entities is diagnosed during pregnancy, the correct treatment is control of hyperthyroidism with antithyroid drugs until defi nitive treatment (i.e., surgery or radioactive iodine) can be administered after delivery.

Even less common causes of hyperthyroidism in pregnancy are listed in Table 47-3. They include TSH-producing pituitary tumors, metastatic follicular thyroid cancer, viral (de Quervain) thyroiditis, and struma ovarii, which is an ovarian dermoid tumor in which more than 50% of the neoplasm consists of thyroid tissue.

Iodine Defi ciency, Hypothyroidism, and PregnancyA schematic representation of the clinical conditions that can affect thyroid function in the mother, fetus, or fetomaternal unit is provided in Figure 47-6. Although iodine defi ciency is rare in the United States, it is a common cause of maternal, fetal, and neonatal hypothyroidism in the world, where 1 to 1.5 billion are at risk and 500 million live in areas of overt iodine defi ciency. Worldwide, it is the most common cause of mental retardation.

In the past few decades, the physiology of maternal and fetal iodine metabolism, thyroid hormone metabolism, and fetal brain develop-ment and the pathophysiology of iodine defi ciency have been unrav-eled. These fi ndings have revealed a fascinating aspect of pregnancy physiology. Iodine defi ciency and hypothyroidism in pregnancy con-

Clinical Disorders

Fetus

Con

cept

ion

Mid

-ge

stat

ion

Term

Normal NormalIodine

deficiency

Normal Normal Hypothy-roxinemia

Iodinedeficiency

Defectiveontogenesis(congenital

hypothyroidism)

Mother

Thyroxinemiain the fetus

Contribution arisingfrom maternal

hormone transfer

FIGURE 47-6 Thyroid function disorders. Schematic representation of the three sets of clinical conditions that can affect thyroid function in the mother alone, in the fetus alone, or in the fetomaternal unit shows the relative contributions of impaired maternal or fetal thyroid function that may eventually lead to alterations in fetal thyroxinemia. (Reprinted by permission from Glinoer D, Delange F: The potential repercussions of maternal, fetal and neonatal hypothyroxinemia on the progeny. Thyroid 10:871, 2000.)

Ch047-X4224.indd 1005 8/26/2008 4:10:56 PM


tinue to be a worldwide problem worthy of resolution. This topic also has been a subject of numerous reviews.128-131 Even in the United States, iodine intake has declined, and 15% of women of childbearing age and 7% of pregnant women were found to have urinary iodine excretions below 50 μg/L, indicative of moderate iodine defi ciency.132

Pregnancy is an environmental trigger for the thyroid machinery, inducing changes in people who live in geographic areas that have iodine defi ciency. Four biochemical markers are useful for following the changes induced:

1. Relative hypothyroxinemia2. Preferential T3 secretion as refl ected by an elevated T3/T4 molar

ratio3. Increased TSH after the fi rst trimester, progressing until term4. Supranormal thyroglobulin concentrations correlating with gesta-

tional goitrogenesis

Goitrogenesis also occurs in the fetus, indicating the exquisite sen-sitivity of the fetal thyroid gland to the consequences of maternal iodine defi ciency. This process can start during the earliest stages of fetal thyroid development. It occurs against a background of low initial maternal intrathyroidal iodine stores, the increased need for iodine after pregnancy occurs, and the insuffi ciency of iodine intake through-out the gestation.

It appears that maternal thyroxine, traversing the placenta during the fi rst trimester and subsequently, is necessary for fetal brain devel-opment. Even before fetal thyroid hormone synthesis, T3 receptors are found in fetal brain tissues, and local conversion of T4 to T3 can occur. Iodine defi ciency perpetuates the process, because the fetus is less able to synthesize thyroid hormones even when the fetal thyroid has developed.

In severe iodine defi ciency (intake of 20 to 25 μg/day), a condition known as endemic cretinism occurs, with a prevalence up to 15% in severely affected populations. These infants are characterized by severe mental retardation with a neurologic picture including deaf-mutism, squint, and pyramidal and extrapyramidal syndromes. There are few clinical signs of thyroid failure. A remarkable exception to this picture has emerged from Africa, where the cretins have less mental retarda-tion and less in the way of neurologic defi cits. The clinical picture is that of severe thyroid failure with dwarfi sm, delayed sexual maturation, and myxedema. Thyroid function is grossly impaired.

The consensus is that the neurologic picture of endemic cretinism results from insults to the developing brain, occurring perhaps during the fi rst trimester (in the case of deafness) and mostly during the second trimester, with the cerebellar abnormalities resulting from postnatal insult. This is supported by the observation that the full picture can be prevented only when the iodine defi ciency is corrected before the second trimester and, optimally, even before conception.133 In Africa, iodine defi ciency is complicated by selenium defi ciency. The defi ciency of selenium leads to accumulation of peroxide, and excess peroxide leads to destruction of thyroid cells and hypothyroidism.134 Selenium defi ciency also induces monodeiodinase I (a selenoenzyme) defi ciency, resulting in reduced T4 to T3 conversion and increased avail-ability of maternal T4 for the fetal brain. This protective mechanism may prevent the development of neurologic cretinism, and the com-bined iodine-selenium defi ciency prevalent in Africa may help explain the predominance of the myxedematous type observed there.

The neurologic abnormalities and mental retardation depend ulti-mately on the timing and severity of the brain insult. Endemic cretin-ism constitutes only the extreme expression of the spectrum of physical and intellectual abnormalities. In a meta-analysis of 18 studies in areas

of iodine defi ciency, it appeared to be responsible for an IQ loss of 13.5 points.135 Even borderline iodine defi ciency, as seen in Europe, can be accompanied by impaired school achievements by apparently normal children, as reviewed by Glinoer.129

Actions taken to eradicate iodine defi ciency have prevented the occurrence of mental retardation in millions of infants throughout the world. In a study by Xue-Yi and coauthors136 of a severely iodine-defi cient area of the Xinjiang region of China, iodine was administered to pregnant women. The prevalence of moderate or severe neurologic abnormalities among 120 infants whose mothers received iodine in the fi rst or second trimester was 2%, compared with 9% (of 952 infants) when the mothers received iodine in the third trimester (P = .008). Although treatment in the third trimester did not improve neurologic status, head growth and developmental quotients improved slightly.

The importance of thyroid hormone to fetal and neonatal well-being and development was highlighted by a remarkable case of an infant born to a mother with strongly positive TSH receptor-blocking antibodies. The mother was profoundly hypothyroid when tested after delivery. The infant was delivered by cesarean section because of bra-dycardia. She was also profoundly hypothyroid and required intuba-tion. Her brain size was reduced, and her auditory brainstem response was absent at age 2 months. The audiogram at age 4 years revealed sensorineural deafness. At age 6 years, motor development was the same as at age 4 months. She required T4 for 8 months until the anti-body effect had worn off. Her physical growth was normal. The outcome of severe thyroid hormone defi ciency in utero was fetal dis-tress, permanent auditory defi cit, brain atrophy, and severely impaired neuromotor development despite adequate neonatal treatment.137

The Institute of Medicine of the National Academy of Sciences has set the iodine requirement as 110 μg for infants 0 to 6 months, 130 μg for infants 7 to 12 months, 90 μg for children 1 to 8 years, 120 μg for those 9 to 13 years, and 150 μg for those older than 13 years. The rec-ommended intake for pregnancy and lactation is 200 μg/day. Even higher intakes (300 to 400 μg/day) have been suggested.138

HypothyroidismSigns and SymptomsHypothyroidism occurs with a frequency of 1 case in 1600 to 2000 deliveries.67 Population screening studies have revealed a higher inci-dence. In a study in the United States, serum TSH levels were deter-mined in 2000 women between gestational weeks 15 to 18; 49 (2.5%) had TSH levels greater than or equal to 6 mU/L, and positive thyroid antibodies were found in 58% of these 49 women, compared with 11% of control euthyroid pregnant women.139 In a Japanese study, only 0.29% had an elevated TSH level.140 In another U.S. study, 1 infant in 1629 deliveries had hypothyroidism.141

Women with hypothyroidism have higher pregnancy complication rates. As well as miscarriages, complications include preeclampsia, pla-cental abruption, low birth weight, prematurity, and stillbirths.142 These outcomes can be improved with early therapy. Gestational hypertension is also more common.141

The symptoms of hypothyroidism are insidious and can be masked by the hypermetabolic state of pregnancy. Symptoms can include modest weight gain, decrease in exercise capacity, lethargy, and intoler-ance to cold. In moderately symptomatic patients, constipation, hoarseness, hair loss, brittle nails, and dry skin also can occur. Physical signs may include a goiter, a thyroidectomy scar, and delay in the relaxation phase of deep tendon refl exes.

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Laboratory confi rmation is obtained from an elevated TSH level, with or without suppressed free T4. Test results for thyroid autoanti-bodies (antithyroglobulin and antithyroid peroxidase) may be positive. Other laboratory abnormalities can include elevated levels of creatine phosphokinase, cholesterol, and carotene and liver function abnor-malities. Patients may have macrocytic or normochromic, normocytic anemia. Hypothyroidism may occur more frequently in pregnant women with type 1 diabetes, and T4 replacement therapy can increase insulin requirements.143

Differential DiagnosisHashimoto thyroiditis, also known as chronic lymphocytic thyroiditis, an autoimmune disease, is the most common cause of hypothyroidism and can occur in 8% to 10% of women of reproductive age. It is char-acterized by the presence of antithyroid antibodies, and the patient may have a goiter. Titers of antithyroglobulin are elevated in 50% to 70% of patients, and almost all have antithyroid peroxidase anti-bodies.53 The goiter is fi rm and diffusely enlarged and painless, and the gland is infi ltrated by lymphocytes and plasma cells. Many patients with Hashimoto thyroiditis are actually euthyroid but can subsequently develop hypothyroidism. The thyroid gland can be atrophic and the test result for antibodies negative—so-called idiopathic hypothyroid-ism. Patients with other autoimmune disease also can develop Hashi-moto thyroiditis.

Other important and common causes of hypothyroidism include 131I therapy, ablation for Graves disease, and thyroidectomy (e.g., for thyroid cancer). Of patients who receive 131I therapy, 10% to 20% are hypothyroid within the fi rst 6 months, and 2% to 4% become hypo-thyroid each year thereafter.144 Hypothyroidism can result from sub-acute viral thyroiditis and, much less commonly, from suppurative thyroiditis.

Drugs known to inhibit the synthesis of thyroid hormones include thionamide, iodides, and lithium. Carbamazepine, phenytoin, and rifampin can increase thyroid clearance. Aluminum hydroxide, chole-styramine, and, most important, ferrous sulfate and sucralfate can interfere with the intestinal absorption of thyroxine.

Hypothyroidism resulting from hypothalamic or pituitary disease is rare but can occur in the setting of pituitary tumors, after pituitary surgery or irradiation, and in Sheehan’s syndrome and lymphocytic hypophysitis, an autoimmune disease with a predilection for women, especially in the setting of pregnancy (see Chapter 48). In secondary hypothyroidism, the TSH level may be low or normal, but the free T4 level is low.

TreatmentHypothyroidism must be treated promptly, and a dose of 0.1 to 0.15 mg of T4 per day, should be initiated. The dose is adjusted every 4 weeks until the TSH concentration is in the lower end of the normal range. In women with little or no functioning thyroid tissue, a dose of 2 μg/kg/day may be required. Women who are euthyroid on T4 need to be checked as soon as pregnancy is established; the dose should be adjusted and rechecked in 4 to 8 weeks,145 because the requirements for thyroid hormone increase as early as the fi fth week of gestation. Alternatively, the patient can be instructed to increase her dose by one extra dose per week and be checked a few weeks later. The amount of dose increase may depend on the cause. For example, women who have had total thyroidectomy may need a greater increase than women with mild hypothyroidism. Increased dosage requirements may plateau by the 20th week,145 but the need for increased dosage may be seen as late as

the third trimester in about one third of patients.2 In a study of 12 pregnant women with hypothyroidism, 9 required a higher T4 dose, with a mean dose increase of 45%.146 In a review of 77 pregnancies in 65 hypothyroid women, serum TSH levels became abnormal in 70% of women with prior 131I ablation therapy and in 47% of women with chronic thyroiditis. When data from other studies were pooled, overall, TSH levels increased above normal in 45% with a mean daily thyroxine dose of 146 μg.147,148 It was estimated that the increment in dose could be predicted according to the TSH value at the fi rst evaluation. The TSH concentration should be determined again 4 to 6 weeks after dose adjustment.

The causes of increased T4 requirements include a real increased demand for T4 in pregnancy149 in patients whose thyroid reserve is compromised and, in some cases, iron therapy. Ferrous sulfate inter-feres with T4 absorption and should be taken at a different time of day from thyroxine therapy.150 Patients with thyroid cancer whose target TSH concentration is below the normal range almost uniformly require an increased dose to maintain their suppressed TSH levels, and they should be followed closely.150 After delivery, the dose should be reduced to pre-pregnancy levels in all patients, and the TSH concentration should be measured 6 to 8 weeks later.

The topic of thyroid hormone and intellectual development has received widespread publicity and has been the subject of articles and reviews in the past few years.128,151,152 In 1969, Man and Jones153 studied a cohort of 1349 children and concluded that mild maternal hypothy-roidism alone was associated with lower IQ levels in the offspring. In 1990, Matsuura and Konishi154 documented that fetal brain develop-ment is affected adversely when both mother and fetus have hypothy-roidism caused by chronic autoimmune thyroiditis. With the background of this information and the associations of iodine defi -ciency, its consequent maternal hypothyroxinemia, and abnormal fetal brain development, Haddow and associates151 conducted a study mea-suring TSH levels from stored samples in more than 25,000 pregnant women. They located 62 women with high TSH levels and 124 matched women with normal values. Their 7- to 9-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance. The full-scale IQ in children of hypo-thyroid women was 4 points lower (P = .06); 15% had scores of 85 or less compared with 5% of controls. The IQ of the children of 48 women whose hypothyroidism was not treated averaged 7 points lower than the 124 controls (P = .005), and 19% had scores of 85 or lower. The researchers concluded that undiagnosed hypothyroidism can affect fetuses adversely and recommended screening for hypothyroid-ism in pregnancy. Fukushi and coworkers155 reported on such screen-ing in Japan and found hypothyroidism in 1 of 692 pregnancies.

In a study by Pop and colleagues,156 even the presence of antithyroid peroxidase antibodies in the maternal circulation was shown to have deleterious effects on child development. In two similar studies, thyroid antibody–positive women had lower free T4 levels, and lower scores on psychomotor tests were found in children of mothers whose free T4 value was below the 5th and 10th percentiles as measured at 12 weeks’ gestation.157,158

Subclinical Hypothyroidism and HypothyroxinemiaSubclinical hypothyroidism is defi ned as an elevated TSH level when the free T4 level is in the normal range. More than 90% of hypothyroid-

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ism diagnosed in pregnancy is subclinical. Its estimated prevalence in the general population is between 4% and 8.5%. The prevalence in pregnancy was 2.3% in a study of more than 17,000 women enrolled for prenatal care at 20 weeks’ gestation or less.159 In this study, pregnan-cies in patients with subclinical hypothyroidism were three times more likely to be complicated by placental abruption, and the rate of preterm birth (i.e., delivery at or before 34 weeks) was almost twofold higher.

Hypothyroidism has been associated with impaired neurodevelop-ment of the fetus.151 However, most of the patients in this study had a TSH level of 10 mU/L or greater, and most had a low free T4 level; that is, they had overt rather than subclinical hypothyroidism. Nonetheless, this study has prompted rigorous debate on the merits of universal screening of all pregnant women. The nuances of this debate were carefully addressed by Casey.160 Although a panel from the American Thyroid Association, the Endocrine Society, and the American Associa-tion of Clinical Endocrinologists did not fi nd suffi cient evidence to recommend routine screening in pregnancy in 2003, leaders of the same societies later published a consensus statement, recommending screening and treatment.161 The American College of Obstetricians and Gynecologists (ACOG) suggests it is premature to recommend univer-sal screening for hypothyroidism, because effi cacy of treatment has not been demonstrated. The ACOG and the various endocrine associations recommend TSH measurements in women with a family history of thyroid disease, prior thyroid dysfunction, symptoms of hypothyroid-ism, an abnormal thyroid gland, type 1 diabetes, or personal history of autoimmune disease. However, targeting high-risk cases may miss signifi cant numbers with hypothyroidism, as was shown by Vaidya and coworkers.162 The investigators evaluated more than 1500 consecutive pregnancies and found increased TSH levels in 40 women (2.6%). Although the prevalence of high TSH levels was higher in the high-risk group (6.8% versus 1% in low-risk patients), 30% of women with high TSH levels were in the low-risk group.

Isolated maternal hypothyroxinemia (i.e., low free T4 and normal TSH levels) during early pregnancy has been associated with impaired neurodevelopment of the fetus.158,163 The issue of detecting and treating isolated maternal hypothyroxinemia is an area of equal uncertainty. Unfortunately, assays of true free T4 (e.g., equilibrium dialysis, ultra-fi ltration, gel fi ltration) are expensive and labor intensive. Clinical laboratories use a variety of tests that estimate the free hormone con-centrations in the presence of protein-bound hormone, and they are binding protein dependent to some extent. This negatively affects the accuracy of free hormone assays.164 Free T4 assays usually result in lower values in late pregnancy.165,166 Nonetheless, in a “Clinical Perspec-tives” article in the Journal of Clinical Endocrinology and Metabolism, Morreale de Escobar and colleagues167 made a compelling case for screening pregnant women for hypothyroxinemia, pointing out that maternal T4 (as opposed to T3) is the required substrate for the onto-genetically regulated production of T3 in the amounts needed for optimal temporal and spatial development in different brain struc-tures. This issue is important for women with relative iodine defi ciency, because T3 is preferentially synthesized.

To address these dilemmas, the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network initiated a randomized trial of T4 treatment for subclinical hypothy-roidism or hypothyroxinemia diagnosed during pregnancy. The primary end point is the intellectual function of the children and sec-ondary end points include determination of the frequency of preg-nancy complications, including preterm delivery, preeclampsia, abruption, and stillbirth.

What do we do in the meantime? In an editorial by Brent67 accom-panying the paper on low-risk versus high-risk case fi nding, it was felt

that until the results of large, randomized trials become available, the extant evidence supports the benefi ts of T4 therapy, at least to reduce pregnancy loss and preterm delivery.69 This view was also held and previously stated by Larsen.168 I recommend screening at least high-risk women (as defi ned by ACOG and others) for TSH and free T4 levels. Subclinical hypothyroidism should be treated with thyroxine. Adequate iodine intake should be ensured in those with isolated hypothyroxinemia and treatment with thyroxine initiated if the hypothyroxinemia does not resolve. I also recommend screening patients who have delivered or had a miscarriage within 1 year of the index pregnancy, because postpartum or postmiscarriage thyroid disease is commonly found in the general population.

Fetal and Neonatal HypothyroidismThe relationship between iodine defi ciency and fetal development was previously discussed. Severe neurologic defi cits also occur in children with congenital defi ciency of thyroid hormone unrelated to iodine defi ciency. Neurologic development is impaired if infants are untreated before they are 3 months old. Screening of neonates for thyroid hormone defi ciency is mandatory in some states, and with early therapy, their development is reasonably normal.29 Causes include thyroid agenesis and inborn errors of metabolism, such as peroxidase defi ciency. Congenital pituitary and hypothalamic hypothyroidism also occur but are rare. Thyroid hormone defi ciency can result from maternal blocking antibodies that are transferred to the fetus and that block TSH action or thyroid growth and development.169,170

Gruner and associates171 reported a case of fetal goitrous hypothy-roidism in which fetal TSH levels were determined on three occasions by cordocentesis to monitor weekly intra-amniotic administration of T4. This therapy was initiated to reduce the fetal goiter and polyhy-dramnios (which it did) and to aid in fetal neurologic development. They also reviewed other reported cases of such therapy and concluded that the optimal dose of T4 necessary to correct hypothyroidism could more accurately be determined by cordocentesis than by measurement of amniotic fl uid hormone concentrations.

Thyroid Nodules, Malignant Tumors, and Nontoxic Goiter in PregnancyThyroid tumors are the most common endocrine neoplasms. Most nodules are benign hyperplastic (or colloid) nodules, but between 5% and 20% are true neoplasms, which are benign follicular adenomas or carcinomas of follicular or parafollicular (C) cell origin. Nodular thyroid disease is common, especially in women. A prospective study found that the incidence of incipient thyroid nodules increased from 15% in the fi rst trimester to 24% after delivery, with an increase in the growth of existing nodules.172 There is no evidence that thyroid cancer arises more frequently in pregnancy.

When a solitary or a dominant nodule is found within the thyroid, biopsy is recommended. Cytopathologic diagnosis of fi ne-needle aspi-ration biopsy (FNAB) in women between the ages of 15 and 40 years seen at the Mayo Clinic revealed benign fi ndings in 64% and suspicious fi ndings in 12%; FNAB was positive for cancer in 7% and nondiagnos-

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tic in 17%.173 The topic of nodular thyroid disease in pregnancy was also reviewed. During a 10-year period, 40 pregnant women were evaluated at the Mayo Clinic, and 39 had FNAB, 95% of which were diagnostic.174 Most (64%) were benign. Three (8%) were positive for papillary thyroid cancer, and nine (23%) were suspicious for papillary cancer or a follicular (Hurthle cell) neoplasm. Comparable fi ndings were reported by others.175

The principles of nodular thyroid disease diagnosis in pregnancy resemble those for nonpregnant women. Serum TSH and free T4 levels should be obtained, and an FNAB should be performed on dominant nodules. Radionucleotide scanning is contraindicated, but ultrasound is often performed and can demonstrate other nodules, lymphade-nopathy, or abnormal calcifi cation. FNAB is safe in pregnancy and can be performed at any stage. If a nodule is benign, ultrasound can monitor growth of the nodule during pregnancy. If the nodule is suspi-cious for a follicular or Hurthle cell neoplasm, it usually represents a 10% to 15% risk of malignancy. It is generally recommended that surgery be performed after delivery, but if a malignancy is diagnosed in early pregnancy, surgery may be performed in the second trimester for the patient needing reassurance. If the FNAB result is positive or suspicious for papillary thyroid cancer, the risk is high (50% for suspi-cious and 100% for positive), and neck exploration should be per-formed at the soonest safe date. Figure 47-7 outlines the decision-making process.

The impact of pregnancy on papillary thyroid cancer was evaluated by Moosa and Mazzaferri.176 They compared outcomes in pregnant and nonpregnant women and found no difference in the rates of recur-rence, distant spread, or cause-specifi c mortality. Outcomes were similar when neck surgery was performed during or after pregnancy. A similar conclusion was reached in a study of thyroid cancer cases from the New Mexico Tumor Registry.177 If medullary thyroid cancer is suspected, early surgery is advised.

Postpartum Thyroid DiseaseAutoimmune thyroid disease, which is suppressed during pregnancy, is exacerbated in the postpartum period. New-onset autoimmune thyroid disease occurs in up to 10% of all postpartum women.39 Up to 60% of Graves patients in the reproductive years give a history of postpartum onset.178 Most of the immune changes of pregnancy grad-ually return to normal in the 12-month postpartum period. Unlike pregnancy, the major immune changes in T and B cells in the postpar-tum period are overall T-cell deactivation, enhanced TH1-type T-cell function, loss of tolerance for fetal alloantigens, enhanced IgG secre-tion, and autoantibody secretion. Possible mechanisms explaining postpartum autoimmune exacerbation suggested by Davies39 include a reduced number of fetal cells, leading to loss of maternal tolerance to remaining microchimeric cells, and a loss of placental major histo-compatibility complex-peptide complexes, which were inducing T-cell anergy during pregnancy.

Postpartum Graves DiseaseThe onset of Graves disease after delivery correlates with the develop-ment of TSIs. Peak antibody production is observed 3 to 6 months after delivery. Almost all patients with persisting TSIs at the end of preg-nancy have a recurrence of Graves if antithyroid drugs are withdrawn. The prevalence of postpartum Graves disease, which can be transient or persistent, is estimated at 11% of those with postpartum thyroid dysfunction.179

Postpartum ThyroiditisThe topic of postpartum thyroiditis (PPT) has been the focus of numerous reviews.39,179-183 For the diagnosis of PPT, there must be a documented abnormal TSH level (suppressed or elevated) during the fi rst postpartum year in the absence of a positive result for TSIs (excluding Graves) or a toxic nodule.

Classically, PPT manifests with a transient hyperthyroid phase of 6 weeks to 6 months after delivery. A hypothyroid phase follows and can last up to 1 year after delivery. Figure 47-8 schematically demonstrates this and the accompanying changes in serum thyroid antibody con-centrations. A review of 11 studies of PPT184 revealed that only 26% of patients presented in this classic manner. Most patients present with hyperthyroidism alone (38%) or hypothyroidism alone (36%). The incidence of PPT is 6% to 9%. It is an autoimmune disorder, and patients with type 1 diabetes have an increased incidence, which was found to be approximately 25% in two North American studies.185,186 Women with a history of PPT in a prior pregnancy had a 69% recur-rence rate in the subsequent pregnancy.

Symptoms of the hyperthyroid phase of PPT include fatigue, pal-pitations, heat intolerance, and nervousness. This destructive hyper-thyroid phase always has a limited duration (a few weeks to a few months). Although β-blockers may reduce symptoms, antithyroid medications have no role to play.

The hypothyroid phase can be marked by fatigue, hair loss, depres-sion, impairment of concentration, and dry skin. The hypothyroid phase frequently requires treatment, but it is reasonable to wean the patient off therapy 6 months after initiation. Some authorities recom-mend maintaining T4 therapy in these patients until the childbearing years are over and then attempting to wean them off the therapy a year after the last delivery.

Solitary thyroid nodulenormal TSH

ultrasound: solid or semi-cystic

FNAB of palpable nodule

Frankly malignantor suspicious forpapillary cancer

Suspicious forfollicular

neoplasm

Benign

Observe Operatepostpartum

Reaspirateif enlarges

1st or 2nd TM

Operate in2nd TM

Operatepostpartum

3rd TM

FIGURE 47-7 Evaluation of thyroid nodules. The decision-making process is outlined for management of a solitary thyroid nodule in pregnancy. (Adapted from Tan GH, Gharib H, Goellner JR, et al: Management of thyroid nodules in pregnancy. Arch Intern Med 156:2317, 1996. Copyright © 1996, American Medical Association. All rights reserved.)

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The thyroid gland is enlarged in PPT, and thyroid hypoechogenicity appears to be the characteristic ultrasonographic fi nding.187 PPT is an autoimmune disorder, and there is an association between it and HLA-DR3, HLA-DR4, and HLA-DR5 status. The lymphocytic infi ltration is similar to that seen in Hashimoto thyroiditis. Stagnaro-Green182 reported that 33% of women who were antithyroid antibody positive in the fi rst trimester of pregnancy had PPT, compared with 3% of women who were antibody negative.

The laboratory hallmarks of PPT, which is a destructive process, are positive test results for antithyroid antibodies (i.e., antithyroglobulin and antithyroid peroxidase), suppressed TSH levels, and high T4 levels (released from destroyed thyroid cells) in the hyperthyroid phase, along with a profoundly suppressed radioactive iodine uptake (contra-indicated in a breastfeeding woman). The absence of TSIs usually rules out Graves disease, which can also be distinguished by high radioactive iodine uptake.

Depression and Postpartum ThyroiditisDepression and PPT are common postpartum events.188 Four large-scale studies have been performed to evaluate their association. Harris and colleagues189 evaluated 147 women (65 were thyroid antibody positive, and 82 were negative) at 6 to 8 weeks after delivery for thyroid status and depression. Although there was a positive correlation between PPT and postpartum depression, there was no association between antibody positivity and depression.

Pop and associates190 evaluated 293 women during the third trimes-ter and then every 6 weeks up to 34 weeks after delivery. They found that 38% of women with PPT experienced depression compared with 9.5% of women in a matched control group, and the difference was highly signifi cant. Status of antibodies was not reported.

Harris and coauthors191 investigated the association between depression and PPT in 232 women (110 were thyroid antibody posi-tive). The women had psychiatric assessment fi ve times during the fi rst 28 weeks after delivery. No association was found between PPT and depression, but an association was found between depression and anti-body positivity. They concluded that 4% of women experience post-partum depression that has an autoimmune origin.

Pop and colleagues192 performed a further analysis of the same 293 women in their earlier study; antibody status was determined during the pregnancy, but only a slightly increased association between the

presence of antibody and depression was found, and they concluded that antibody status during pregnancy was an important predictor of PPT but not of depression. In a subsequent study, Pop and associates193 reported an association between thyroid antibodies and depression in postmenopausal women.

In summary, the data suggest some association for PPT, thyroid antibodies, and depression. Of the four clinical trials, two demon-strated an association between PPT and depression, whereas two dem-onstrated an association between thyroid antibodies and depression. The role of potential interventions such as T4 therapy has not been evaluated systematically.

Hypothyroidism and Postpartum ThyroiditisRecovery of thyroid function in women with PPT is not universal, and some women remain permanently hypothyroid. In a study of 44 women with PPT with a mean follow-up of 8.7 years after delivery, Tachi and associates194 reported that 77% of the women recovered during the fi rst postpartum year and remained euthyroid. Permanent hypothyroidism developed in the other 23%; one half of these never recovered euthyroid function after the initial postpartum insult, and the other half developed hypothyroidism during the years of follow-up. A 23% incidence of permanent hypothyroidism at long-term follow-up (mean, 3.5 years) was also reported by Othman and cowork-ers.195 It is recommended that women with a history of PPT be evalu-ated annually for the possible development of hypothyroidism.

Thyroiditis after AbortionSeveral studies have described cases of thyroiditis occurring after an abortion.196,197 Neither the incidence nor clinical sequelae are known. In the case of Stagnaro-Green,196 the patient developed transient hypo-thyroidism after a spontaneous miscarriage. After a subsequent term delivery, the patient became severely hypothyroid, and this condition remained permanent.

Prevention and Screening of

Postpartum ThyroiditisLevothyroxine (0.1 mg daily) or iodide (0.15 mg daily) was adminis-tered for 40 weeks after delivery to women who were thyroid antibody positive during pregnancy. A control group of antibody-negative women received no treatment. The incidence of PPT was similar in all

FIGURE 47-8 Postpartum thyroiditis and changes in thyroid antibody concentrations. A, Postpartum thyroiditis manifests with a transient hyperthyroid phase, during which serum levels of thyroxine (T4) are elevated. A hypothyroid phase follows. B, Serum thyroid antibody levels fl uctuate during and after pregnancy. (From Smallridge RC, Fein HC, Hayship CC: Postpartum thyroiditis. Bridge Newslett Thyroid Found Am 3:3, 1988.)

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three groups, and the degree of postpartum elevation of thyroid per-oxidase antibodies was indistinguishable in the three groups.198

Whether screening for PPT is worthwhile is a contentious issue. A “Therapeutic Controversy” article in the Journal of Clinical Endocrinol-ogy and Metabolism addressed this topic.179 Arguments for and against screening were presented. It was suggested that screening and treat-ment of symptomatic hypothyroidism would improve the quality of life of the mother, and the importance of recognizing postpartum depression was stressed. Contradicting arguments posited that the optimal screening strategy was undefi ned and that no cost-benefi t analysis has been performed. It is agreed that women who present with symptoms should have a TSH assay performed. High-risk women (i.e., women with a history of PPT and women with type 1 diabetes) should be screened.186,199

References 1. Casey BM, Leveno KJ: Thyroid disease in pregnancy. Obstet Gynecol

108:1283, 2006. 2. LeBeau SO, Mandel SJ: Thyroid disorders during pregnancy. Endocrinol

Metab Clin North Am 35:117, 2006. 3. Abalovich M, Amino N, Barbour LA, et al: Management of thyroid

dysfunction during pregnancy and postpartum: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 92(suppl):S1, 2007.

4. Brennan MD, Bahn RS: Thyroid hormones and illness. Endocr Pract 4:396, 1998.

5. DeGroot LJ: Dangerous dogmas in medicine: The non-thyroidal illness syndrome. J Clin Endocrinol Metab 84:151, 1999.

6. Brent GA: The molecular basis of thyroid hormone action. N Engl J Med 331:847, 1994.

7. Glinoer D: What happens to the normal thyroid during pregnancy? Thyroid 9:631, 1999.

8. Glinoer D, De Nayer P, Robyn C, et al: Serum levels of intact human cho-rionic gonadotropin (hCG) and its free α and β subunits, in relation to maternal thyroid stimulation during normal pregnancy. J Endocrinol Invest 16:881, 1993.

9. Grün JP, Meuris S, DeNayer P, et al: The thyrotropic role of human cho-rionic gonadotropin (hCG) in the early stages of twin (versus single) pregnancy. Clin Endocrinol 46:719, 1997.

10. Burrow GN, Fisher DA, Larsen PR: Maternal and fetal thyroid function. N Engl J Med 331:1072, 1994.

11. Glinoer D, De Nayer P, Delange F, et al: A randomized trial for the treat-ment of mild iodine defi ciency during pregnancy: Maternal and neonatal effects. J Clin Endocrinol Metab 80:258, 1995.

12. Glinoer D: The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocr Rev 18:404, 1997.

13. Levy RP, Newman M, Rejah LS, et al: The myth of goiter in pregnancy. Am J Obstet Gynecol 137:701, 1980.

14. Nelson M, Wickos GG, Caplan RH, et al: Thyroid gland size in pregnancy. J Reprod Med 32:888, 1987.

15. Brander A, Kivsaari L: Ultrasonography of the thyroid during pregnancy. J Clin Ultrasound 17:403, 1989.

16. Halnan KE: The radioiodine uptake of the human thyroid in pregnancy. Clin Sci 17:281, 1958.

17. Abdoul-Khair SA, Crooks J, Turnbull AC, et al: The physiological changes in thyroid function during pregnancy. Clin Sci 27:195, 1964.

18. Ferris TF: Renal disease. In Burrow GN, Ferris TF (eds): Medical Compli-cations During Pregnancy. Philadelphia, WB Saunders, 1988, p 277.

19. Beckers C: Iodine economy in and around pregnancy. In Beckers C, Rein-wein D (eds): The Thyroid and Pregnancy. New York, John Wiley and Sons, 1992.

20. Glinoer D, Delange F: The potential repercussions of maternal, fetal and neonatal hypothyroxinemia on the progeny. Thyroid 10:871, 2000.

21. Radunovic N, Domez Y, Mandelbrot L, et al: Thyroid function in fetus and mother during the second half of normal pregnancy. Biol Neonate 59:139, 1991.

22. LaFranchi S: Thyroid function in the preterm infant. Thyroid 9:71, 1999. 23. Fisher DA: Hypothyroxinemia in premature infants: Is thyroxine treat-

ment necessary? Thyroid 9:715, 1999. 24. Bernal J, Perkonen F: Ontogenesis of the nuclear 3,5,3′-triiodothyronine

receptor in the human fetal brain. Endocrinology 114:677, 1984. 25. Santini F, Chiovato L, Ghirri P, et al: Serum iodothyronine in the human

fetus and the newborn: Evidence for an important role of placenta in fetal thyroid hormone homeostasis. J Clin Endocrinol Metab 84:493, 1999.

26. Vulsma T, Gons MH, de Vijlder JJ: Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organifi cation defect or thyroid agenesis. N Engl J Med 321:13, 1989.

27. Delange F, de Vilder JJ, Morreale de Escobar G, et al: Signifi cance of early diagnostic data in congenital hypothyroidism: Report of the Subcommit-tee on Neonatal Hypothyroidism of the European Thyroid Association. In Delange F, Fisher DA, Glinoer D (eds): Research in Congenital Hypothy-roidism. New York, Plenum Press, 1989, pp 225-234.

28. Kester MHA, Martinez de Mena R, Obregon MJ, et al: Iodothyronine levels in the human developing brain: Major regulatory roles of iodothyronine deiodinases in different areas. J Clin Endocrinol Metab 9:3117, 2004.

29. Fisher DA, Polk DH: Development of the thyroid. Baillieres Clin Endocri-nol Metab 3:627,1989.

30. Fisher DA, Dussault JH, Sack J, et al: Ontogenesis of hypothalamic-pituitary-thyroid function and metabolism in man, sheep and rat. Recent Prog Horm Res 3:59, 1977.

31. Polk DH: Thyroid hormone effects on neonatal thermogenesis. Semin Perinatol 12:151, 1988.

32. Reuss ML, Paneth N, Pinto-Martin JA, et al: The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age. N Engl J Med 443:821, 1996.

33. Vulsma Y, Kok JK: Prematurity-associated neurological and development abnormalities and neonatal thyroid function. N Engl J Med 3343:857, 1996.

34. Williams FLR, Mires GJ, Barnett C, et al: Transient hypothyroxinemia in preterm infants: The role of cord sera thyroid hormone levels adjusted for prenatal and antepartum factors. J Clin Endocrinol Metab 90:4599, 2005.

35. Burrow GN, May PB, Spaulding SW, et al: TRH and dopamine interac-tions affecting pituitary hormone secretion. J Clin Endocrinol Metab 45:65, 1977.

36. Roti E, Gnudi A, Braverman LE: The placental transport, synthesis and metabolism of hormones and drugs, which affect thyroid function. Endocr Rev 4:131, 1983.

37. Ballard RA, Ballard PL, Creasy RK, et al: Respiratory disease in very-low-birthweight infants after prenatal thyrotropin-releasing hormone and glucocorticoid. Lancet 339:510, 1992.

38. Romaguera J, Ramirez M, Adamsons K: Intra-amniotic thyroxine to accel-erate fetal maturation. Semin Perinatol 17:260, 1993.

39. Davies TF: The thyroid immunology of the postpartum period. Thyroid 9:675, 1999.

40. Weetman AP: The immunology of pregnancy. Thyroid 9:643, 1999. 41. Nelson JL, Hughes KA, Smith AG, et al: Maternal fetal disparity in HLA

class II alloantigens and the pregnancy induced amelioration of rheuma-toid arthritis. N Engl J Med 329:466, 1993.

42. Buyon JP, Nelson JL, Lockshine MD: The effects of pregnancy on autoim-mune thyroid diseases. Clin Immunol Immunopathol 79:99, 1996.

43. Confavreuz C, Hutchinson M, Hours MH, et al: Rate of pregnancy related relapse in multiple sclerosis. New Engl J Med 339:285, 1998.

44. Piccinini MP, Giudizi MG, Biagiotti R, et al: Progesterone favors the devel-opment of human T helper cells producing Th2-type cytokines and pro-motes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol 155:128, 1995.

45. Ain KB, Mori Y, Refetoff F: Reduced clearance rate of thyroxine-binding globulin (TBG) with increased sialylation: A mechanism for estrogen induced elevation of serum TBG concentration. J Clin Endocrinol Metab 65:689, 1987.

Ch047-X4224.indd 1011 8/26/2008 4:10:58 PM


46. Dashe JS, Casey BM, Wells CE, et al: Thyroid stimulating hormone in singleton and twin pregnancy: Importance of gestational age-specifi c ref-erence ranges. Obstet Gynecol 106:753, 2005

47. Glinoer D, Soto MF, Bouroux P, et al: Pregnancy in patients with mild thyroid abnormalities: Maternal and neonatal repercussions. J Clin Endo-crinol Metab 73:421, 1991.

48. Weintraub BD: Inappropriate secretion of thyroid-stimulating hormone. Ann Intern Med 95:339, 1981.

49. Anselmo J, Kay T, Dennis K, et al: Resistance to thyroid hormone does not abrogate the transient thyrotoxicosis associated with gestation: Report of a case. J Clin Endocrinol Metab 86:4273, 2001.

50. Anselmo J, Cao D, Karrison T, et al: Fetal loss associated with excess thyroid hormone exposure. JAMA 292:691, 2004.

51. Mariotti S, Chiovato L, Vitti P, et al: Recent advances in the understanding of humoral and cellular mechanisms implicated in thyroid autoimmune disorders. Clin Immunol Immunopathol 50:573, 1989.

52. Learoyd DL, Fund HYM, McGregor AM: Postpartum thyroid dysfunction. Thyroid 2:73, 1992.

53. Weetman AP, McGregor AM: Autoimmune thyroid disease: Further devel-opments in our understanding. Endocr Rev 15:788, 1994.

54. Bartalena L, Bogazzi F, Braverman LE, et al: Effect of amiodarone admin-istration during pregnancy on neonatal thyroid function and subsequent neurodevelopment. J Endocrinol Invest 24:116, 2001.

55. Wartofsky L, Burman KD: Alterations in thyroid function in patients with systemic illness: The “euthyroid sick syndrome.” Endocr Rev 3:164, 1982.

56. Brent GA, Hershman JM: Thyroxine therapy in patients with severe non-thyroidal illnesses and low serum thyroxine concentration. J Clin Endo-crinol Metab 63:1, 1986.

57. Winters SJ, Berga SL: Gonadal dysfunction in patients with thyroid disease. Endocrinologist 7:167, 1997.

58. Krassas GE: Thyroid disease and female reproduction. Fertil Steril 74:1063, 2000.

59. Trokoudes KM, Skordis N, Picolos MK: Infertility and thyroid disorders. Curr Opin Obstet Gynecol 18:446, 2006.

60. Krassas GE, Pontikides N, Kaltsas TH, et al: Menstrual disturbances in thyroidism. Clin Endocrinol 40:641, 1994.

61. Akande EO, Hockaday TD: Plasma estrogen and luteinizing hormone concentrations in thyrotoxic menstrual disturbances. Proc R Soc Med 65:789, 1972.

62. Tanaka T, Tamin H, Kuma K, et al: Gonadotropin response to luteinizing hormone releasing hormone in hyperthyroid patients with menstrual dis-turbances. Metabolism 30:323, 1981.

63. Wilansky DL, Greisman B: Early hypothyroidism in patients with menor-rhagia. Am J Obstet Gynecol 160:673, 1989.

64. Del Pozo E, Wyss H, Tolis G, et al: Prolactin and defi cient luteal function. Obstet Gynecol 53:282, 1979.

65. Thomas R, Reid RL: Thyroid disease and reproductive dysfunction. Obstet Gynecol 70:789, 1987.

66. Wasserstrum N, Anania CA: Perinatal consequences of maternal hypothy-roidism in early pregnancy and inadequate replacement. Clin Endocrinol 42:343, 1997.

67. Brent GA: Diagnosing thyroid dysfunction in pregnant women: Is case fi nding enough? J Clin Endocrinol Metab 92:39, 2007.

68. Montoro MN: Management of hypothyroidism during pregnancy. Clin Obstet Gynecol 40:65, 1997.

69. Negro R, Fomoso G, Manieri T, et al: Levothyroxine treatment in euthy-roid pregnant women with autoimmune thyroid disease: Effects on obstetrical complications. J Clin Endocrinol Metab 91:2587, 2006.

70. Glinoer D: Miscarriage in women with positive anti-TPO antibodies: Is thyroxine the answer [editorial]? J Clin Endocrinol Metab 91:2500, 2006.

71. Greig WR: Radioactive iodine therapy for thyrotoxicosis. Br J Surg 758:765, 1973.

72. Safa AM, Schumacher OP, Rodriguez-Antunez A: Long-term follow-up results in children and adolescents treated with radioactive iodine (131I) for hyperthyroidism. N Engl J Med 292:167, 1975.

73. Sioka C, Kouaklis G, Zafi rakis, et al: Menstrual cycle disorders after therapy with iodine-131. Fertil Steril 86:625, 2006.

74. Smith MB, Xue H, Takahashi H, et al: Iodine 131I thyroid ablation in female children and adolescents: Long term risk of infertility and birth defects. Ann Surg Oncol 1:128, 1994.

75. Schlumberger M, deVathaire F, Ceccarelli C, et al: Exposure to radioactive iodine 131I for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients. J Nucl Med 37:606, 1996.

76. Gorman CA: Radio iodine and pregnancy. Thyroid 9:721, 1999. 77. Berlin L: Malpractice issues in radiology. Iodine 131I and the pregnant

patient. Am J Radiol 176:869, 2001. 78. Fernandez-Soto ML, Jovanovic LG, Gonzalez-Jimenez A, et al: Thyroid

function during pregnancy and the postpartum period iodine metabolism and disease status. Endocr Pract 4:97, 1998.

79. Seely BL, Burrow GN: Thyrotoxicosis in pregnancy. Endocrinologist 7:409, 1991.

80. Costagliola S, Morgenthaler NG, Hoermann R, et al: Second generation assay for thyrotoxicosis receptor and bodies has superior diagnostic sen-sitivity for Graves disease. J Clin Endocrinol Metab 84:90, 1999.

81. Varner MW: Autoimmune disorders and pregnancy. Semin Perinatol 15:238, 1991.

82. Davis LE, Lucas MJ, Hankins GDV, et al: Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 160:63, 1989.

83. Momotani N, Ito K: Treatment of pregnant patients with Basedow’s disease. Exp Clin Endocrinol 97:268, 1991.

84. Millar LK, Wing DA, Leung AS, et al: Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 84:946, 1994.

85. Cooper DS: Antithyroid drugs. N Engl J Med 352:905, 2005. 86. Clark SM, Saade GR, Sodgrass WR, et al: Pharmacokinetics and pharma-

cotherapy of thionamides in pregnancy. Ther Drug Monit 28:477, 2006. 87. Momotani N, Noh J, Oyanagi H, et al: Antithyroid drug therapy for

Graves’ disease during pregnancy. N Engl J Med 315:24, 1986. 88. Kung AWC, Jones BM: A change from stimulatory to blocking antibody

activity in Graves’ disease during pregnancy. J Clin Endocrinol Metab 8:514, 1998.

89. Cooper DS, Goldminz D, Levin AA, et al: Agranulocytosis associated with antithyroid drugs. Ann Intern Med 98:26, 1983.

90. Mortimer RH, Cannell GR, Addison RS, et al: Methimazole and propyl-thiouracil equally cover the perfused human term placental lobule. J Clin Endocrinol Metab 82:3099, 1997.

91. Milham S, Elledge W: Maternal methimazole and congenital defects in children. Teratology 5:525, 1972.

92. Van Djihe UP, Heydendael RJ, De Kleine MR: Methimazole, carbimazole and congenital skin defects. Ann Intern Med 106:60, 1987.

93. Martinez-Frias ML, Cereijo A, Rodriguez-Pinella E, et al: Methimazole in animal feed and congenital aplasia cutis. Lancet 399:742, 1992.

94. Johnsson E, Larsson G, Ljunggren M: Severe malformations in infants born to hyperthyroid women on methimazole. Lancet 350:1520, 1997.

95. Clementi M, DiGianantonio E, Pelo E, et al: Methimazole embryopathy: Delineation of the phenotype. Am J Med Genet 83:43, 1999.

96. Di Gianantonio E, Schaefer C, Mastroiacovo PP, et al: Adverse effects of prenatal methimazole exposure. Teratology 64:262, 2001.

97. Wolf D, Foulds N, Daya H: Antenatal carbimazole and choanal atresia: A new embryopathy Arch Otolaryngol Head Neck Surg 132:1009, 2006.

98. Phoojaroenchanachai M, Sriussadaporn S, Peerapatdir T, et al: Effect of maternal hyperthyroidism during late pregnancy on the risk of neonatal low birth weight. Clin Endocrinol 54:365, 2001.

99. Mitsuda N, Tamaki H, Amino N, et al: Risk factors for development dis-orders in infants born to women with Graves’ disease. Obstet Gynecol 80:359, 1992.

100. Wing DA, Millar LK, Kooings PP, et al: A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 170:90, 1994.

101. Thorpe-Beeston JG, Nicolaides KH, Felton CV, et al: Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N Engl J Med 324:532, 1991.

Ch047-X4224.indd 1012 8/26/2008 4:10:58 PM


102. Kampmann JP, Johansen K, Hansen JM, et al: Propylthiouracil in human milk: Revision of a dogma. Lancet 1:736, 1980.

103. Azzizi F: Effect of methimazole treatment of maternal thyrotoxicosis on thyroid function in breast-feeding infants. J Pediatr 128:855, 1996.

104. Isley WL, Dahl S, Gibbs H: Use of esmolol in managing a thyrotoxic patient needing emergency surgery. Am J Med 89:122, 1990.

105. Burrow GN: The management of thyrotoxicosis in pregnancy. N Engl J Med 313:562,1985.

106. Burch HB, Wartofsky L: Life threatening thyrotoxicosis: Thyroid storm. Endocrinol Metab Clin North Am 22:263, 1993.

107. Waltman PA, Brewer JM, Lobert S: Thyroid storm during pregnancy. A medical emergency. Crit Care Nurse 24:74, 2004.

108. Sheffi eld JS, Cunningham FG: Thyrotoxicosis and heart failure that com-plicate pregnancy. Am J Obstet Gynecol 190:211, 2004.

109. Casey BM, Dashe JS, Wells CE, et al: Clinical hyperthyroidism and preg-nancy outcomes. Obstet Gynecol 107:337, 2006.

110. Zimmerman D: Fetal and neonatal hyperthyroidism. Thyroid 9:727, 1999.

111. Clavel S, Madec A, Bornet H, et al: Anti TSH-receptor antibodies in preg-nant patients with autoimmune thyroid disorder. BJOG 97:1003, 1990.

112. Zakarija M, McKenzie JM: Pregnancy-associated changes in thyroid-stimulating antibody of Graves’ disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab 57:1036, 1983.

113. Becks GP, Burrow G: Thyroid disease and pregnancy. Med Clin North Am 75:121, 1991.

114. Houck JA, Davis RE, Sharma HM: Thyroid-stimulating immunoglobulin as a cause of recurrent intrauterine fetal death. Obstet Gynecol 71:1018, 1988.

115. Yoshimoto M, Nakayama Itoi, Baba P, et al: A case of neonatal McCune-Albright syndrome with Cushing syndrome and hyperthyroidism. Acta Pediatr Scand 89:984, 1991.

116. Kopp P, Van Sande J, Parmer J, et al: Brief report: Congenital hyperthyroid-ism caused by a mutation in the thyrotropin receptor gene. N Engl J Med 322:150, 1995.

117. Hershman JM: Human chorionic gonadotropin and the thyroid: Hyperemesis gravidarum and trophoblastic tumors. Thyroid 9:653, 1999.

118. Talbot JA, Lambert A, Anobile LJ, et al: The nature of human chorionic gonadotropin glycoforms in gestational thyrotoxicosis. Clin Endocrinol 55:33, 2001.

119. Bashiri A, Neumann L, Maymon E, et al: Hyperemesis gravidarum: Epi-demiologic features, complications and outcome. Eur J Obstet Gynecol Reprod Biol 63:135, 1995.

120. Goodwin TM, Montoro M, Mestman JH: The role of chorionic gonado-tropin in transient hyperthyroidism of hyperemesis gravidarum. J Clin Endocrinol Metab 75:1333, 1992.

121. Goodwin TM, Montoro M, Mestman JH: Transient hyperthyroidism and hyperemesis gravidarum: Clinical aspects. Am J Obstet Gynecol 167:648, 1992.

122. Wilson R, McKillop JH, MacLean M, et al: Thyroid function tests are rarely abnormal in patients with severe hyperemesis gravidarum. Clin Endocri-nol (Oxf) 37:331, 1992.

123. Pekary AE, Jackson IM, Goodwin TM, et al: Increased in vitro thyrotropic activity of partially sialated human chorionic gonadotropin extracted from hydatidiform moles of patients with hyperthyroidism. J Clin Endo-crinol Metab 76:70, 1993.

124. Morgan LS: Hormonally active gynecologic tumors. Semin Surg Oncol 6:83, 1990.

125. Nader S, Mastrobattista J: Recurrent hyperthyroidism in consecutive preg-nancies characterized by hyperemesis. Thyroid 6:465, 1996.

126. Rodien P, Bremont C, Sanson M-LR, et al: Familial gestational hyperthy-roidism caused by a mutant thyrotropic receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 339:1823, 1998.

127. Mariotti S, Martino E, Cupini C: Low serum thyroglobulin as a clue to the diagnosis of thyrotoxicosis factitia. N Engl J Med 307:410, 1982.

128. Lazarus JH: Thyroid hormone and intellectual development: A clinician’s view. Thyroid 9:659, 1999.

129. Glinoer D: Pregnancy and iodine. Thyroid 11:471, 2001.130. Dunn JT, Delange F: Damaged reproduction: The most important

consequence of iodine defi ciency. J Clin Endocrinol Metab 86:2360, 2001.

131. Delange F, de Benoist B, Pretell E, et al: Iodine defi ciency in the world: Where do we stand at the turn of the century? Thyroid 11:437, 2001.

132. Hollowell JG, Staehling NW, Hannon WH, et al: Iodine nutrition in the United States. Trends from public health implications: Iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971-1974 and 1988-1994). J Clin Endocrinol Metab 83:3401, 1998.

133. Pharoah PQ, Butterfi eld IH, Hetzel BS: Neurological damage to the fetus resulting from severe iodine defi ciency during pregnancy. Lancet 1:308, 1971.

134. Vanderpas JB, Contempré B, Dvale NL, et al: Iodine and selenium defi -ciency associated with cretinism in Northern Zaire. Am J Clinic Nutr 52:1087, 1990.

135. Bleichrodt N, Born MP: A meta-analysis of research on iodine and its relationship to cognitive development. In Stanbury JB (ed): The Damaged Brain of Iodine Defi ciency. New York, Cognizant Communication, 1994, p 195.

136. Xue-Yi C, Xin-Min J, Zhi-Hong D, et al: Time of vulnerability of the brain to iodine defi ciency in endemic cretinism. N Engl J Med 331:1739, 1994.

137. Yasuda T, Ohnishi H, Wataki K, et al: Outcome of a baby born from a mother with acquired juvenile hypothyroidism having undetectable thyroid hormone concentrations. J Clin Endocrinol Metab 84:2630, 1999.

138. Utiger RD: Iodine nutrition: More is better. N Engl J Med 354:26, 2006.139. Klein RZ, Haddow JE, Faix JD, et al: Prevalence of thyroid defi ciency in

pregnant women. Clin Endocrinol 35:41, 1991.140. Kamijo K, Saito T, Saito M, et al: Transient subclinical hypothyroidism in

early pregnancy. Endocrinol Jpn 37:387, 1990.141. Leung AS, Millar LK, Koonings PP, et al: Perinatal outcome in hypothyroid

patients. Obstet Gynecol 81:349, 1993.142. Davis LE, Leveno KJ, Cunningham FG: Hypothyroidism complicating

pregnancy. Obstet Gynecol 72:108, 1988.143. Jovanovic-Peterson L, Peterson CM: De novo clinical hypothyroidism in

pregnancies complicated by type I diabetes, subclinical hypothyroidism and proteinuria. Am J Obstet Gynecol 159:442, 1988.

144. Werner S: Modifi cation of the classifi cation of eye changes of Graves’ disease: Recommendation of the Ad Hoc Committee of the American Thyroid Association. J Clin Endocrinol Metab 44:203, 1977.

145. Alexander EK, Marqusee E, Lawrence J, et al: Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 351:241, 2004.

146. Mandel SJ, Larsen PR, Seely EW, et al: Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 323:91, 1990.

147. Kaplan MM: Monitoring thyroxine treatment during pregnancy. Thyroid 2:147, 1992.

148. Kaplan MM: Management of thyroxine therapy during pregnancy. Endocr Pract 2:281, 1996.

149. Mestman JH: Thyroid disease in pregnancy other than Graves’ and post partum thyroid dysfunction. Endocrinologist 9:294, 1999.

150. Brent GA: Maternal hypothyroidism recognition and management. Thyroid 9:661, 1999.

151. Haddow JE, Palomaki GE, Alan WC, et al: Maternal thyroid defi ciency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341:549, 1999.

152. Klein RZ, Mitchell ML: Maternal hypothyroidism and child development. Horm Res 52:55, 1999.

153. Man EB, Jones WS: Thyroid function in human pregnancy. V. Incidence of maternal serum low butanol-extractable iodines and of normal gesta-tional TBG and TBPA capacities: Retardation of 8-month old infants. Am J Obstet Gynecol 104:898, 1969.

154. Matsuura N, Konishi J: Transient hypothyroidism in infants born to mothers with chronic thyroiditis—a nationwide study of 23 cases. Endo-crinol Jpn 37:767, 1990.

Ch047-X4224.indd 1013 8/26/2008 4:10:58 PM


155. Fukushi M, Honma IC, Fujita K: Maternal thyroid defi ciency during preg-nancy and subsequent neuropsychological development of the child [letter]. N Engl J Med 341:556, 1999.

156. Pop VJM, deVries E, van Baar AL, et al: Maternal thyroid peroxidase anti-bodies during pregnancy: A marker of impaired child development? J Clin Endocrinol Metab 80:3561, 1995.

157. Lazarus JH, Aloa A, Parkes AB, et al: The effect of anti-TPO antibodies on thyroid function in early gestation: Implications for screening. Presented at the American Thyroid Association meeting, Portland, Oregon, 1998.

158. Pop VJM, Kuijpens JV, van Baar AL, et al: Low maternal FT4 concentra-tions during early pregnancy associated with impaired psychomotor development in infancy. Clin Endocrinol 50:149, 1999.

159. Casey BM, Dashe JS, Wells CE, et al: Clinical hypothyroidism and preg-nancy outcomes. Obstet Gynecol 105:239, 2005.

160. Casey BM: Subclinical hypothyroidism and pregnancy. Obstet Gynecol Surv 61:415, 2006.

161. Gharib H, Cobin RH, Dickey RA: Subclinical hypothyroidism during pregnancy: Position statement from the American Association of Clinical Endocrinologists. Endocr Pract 5:367, 1999.

162. Vaidya B, Anthony S, Bilous M, et al: Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high risk case fi nding. J Clin Endocrinol Metab 92:203, 2007.

163. Pop VJ, Brouwers EP, Vader HL, et al: Maternal hypothyroxinemia during early pregnancy and subsequent child development: A 3-year follow-up study. Clin Endocrinol 59:282, 2003.

164. Demers L, Spencer CA: Laboratory medicine practice guidelines: Labora-tory support for the diagnosis and monitoring of thyroid disease. Thyroid 13:6,2003.

165. Glinoer D, De Nayer P, Bourdoux P, et al: Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 71:276, 1990.

166. Mandel SJ, Spencer CA, Hollowell JG: Are detection and treatment of thyroid insuffi ciency in pregnancy feasible? Thyroid 15:44, 2005.

167. Morreale de Escobar G, Obregon MJ, Escobar del Rey F: Is neuropsycho-logical development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 85:3975, 2000.

168. Larsen PR: Detecting and treating hypothyroidism during pregnancy. Nat Clin Pract Endocrinol Metab 2:59, 2006.

169. Dussault JH, Rousseau F: Immunologically mediated hypothyroidism. Endocrinol Metab Clin North Am 16:417, 1987.

170. Bogner U, Gruters A, Sigle B, et al: Cytotoxic antibodies in congenital hypothyroidism. J Clin Endocrinol Metab 68:671, 1989.

171. Gruner C, Kollert A, Wildt L, et al: Intrauterine treatment of fetal goitrous hypothyroidism controlled by determination of thyroid-stimulating hormone in fetal serum. A case report and review of the literature. Fetal Diagn Ther 16:47, 2001.

172. Kung A, Chau M, Lao T, et al: The effect of pregnancy on thyroid nodule formation. J Clin Endocrinol Metab 87:1010, 2002.

173. Hay ID: Nodular thyroid disease diagnosed during pregnancy: How and when to treat. Thyroid 9:667, 1999.

174. Tan GH, Gharib H, Goellner JR, et al: Management of thyroid nodules in pregnancy. Arch Intern Med 156:2317, 1996.

175. Marley EF, Oertil YC: Fine needle aspiration of thyroid lesions in 57 pregnant and postpartum women. Diagn Cytopathol 16:122, 1997.

176. Moosa M, Mazzaferri EL: Outcome of differentiated thyroid cancer diag-nosed in pregnant women. J Clin Endocrinol Metab 82:2862, 1997.

177. Herzon FS, Morris DM, Segal MN, et al: Coexistent thyroid cancer and pregnancy. Arch Otolaryngol Head Neck Surg 120:1191, 1994.

178. Janssen R, Dahlberg PA, Winsa B, et al: The postpartum period constitutes an important risk for the development of clinical Graves’ disease in young women. Acta Endocrinol 116:321, 1987.

179. Amino N, Tada H, Hidaka Y, et al: Therapeutic controversy. Screening for postpartum thyroiditis. J Clin Endocrinal Metab 84:1813, 1999.

180. Lazarus JH: Clinical manifestations of postpartum thyroid disease. Thyroid 9:685, 1999.

181. Lucas A, Pizarro E, Granada ML, et al: Postpartum thyroiditis: Epidemiol-ogy and clinical evolution in a non-selected population. Thyroid 10:71, 2000.

182. Stagnaro-Green AS: Recognizing, understanding and treating postpartum thyroiditis. Endocrinol Metab Clinics NA 29:417, 2000.

183. Pearce EN, Farwell AP, Braverman LE: Thyroiditis [published erratum appears in N Engl J Med 349:62, 2003]. N Engl J Med 348:2646, 2003.

184. Stagnaro-Green AS: Postpartum thyroiditis: Prevalence, etiology, and clinical implications. Thyroid Today 16:1, 1993.

185. Gerstein HC: Incidence of postpartum thyroid dysfunction in patients with type I diabetes mellitus. Ann Intern Med 188:419, 1993.

186. Alvarez-Marfany M, Roman SH, Drexler AJ, et al: Long-term prospective study of postpartum thyroid dysfunction in women with insulin depen-dent diabetes mellitus. J Clin Endocrinol 79:10, 1994.

187. Adams H, Jones MC, Othman S, et al: The sonographic appearances in postpartum thyroiditis. Clin Radiol l45:311, 1992.

188. Pedersen CA: Postpartum mood and anxiety disorders: A guide for the non-psychiatric clinician with an aside on thyroid associations with post-partum mood. Thyroid 9:691, 1999.

189. Harris B, Fung H, Johns S, et al: Transient postpartum thyroid dysfunction and postnatal depression. J Affect Disord 17:243, 1989.

190. Pop VJM, de Rooy HAM, Vader HL, et al: Postpartum thyroid dysfunction and depression in an unselected population. N Engl J Med 324:1815, 1991.

191. Harris B, Othman S, Davies JA, et al: Association between postpartum thyroid dysfunction and thyroid antibodies and depression. BMJ 305:152, 1992.

192. Pop VJM, de Rooy HAM, Vader VL, et al: Microsomal antibodies during gestation in relation to postpartum thyroid dysfunction and depression. Acta Endocrinol 129:26, 1993.

193. Pop VJM, Maarteens LH, Levsink G, et al: Are autoimmune thyroid dys-function and depression related? J Clin Endocrinol Metab 83:3194, 1998.

194. Tachi J, Amino N, Tamaski H, et al: Long-term follow-up and HLA asso-ciation in patients with postpartum hypothyroidism. J Clin Endocrinol Metab 66:480, 1988.

195. Othman S, Phillips DL, Parkes AB, et al: Long-term follow-up of postpar-tum thyroiditis. Clin Endocrinol 32:559, 1990.

196. Stagnaro-Green AS: Post-miscarriage thyroid dysfunction. Obstet Gynecol 803:490, 1992.

197. Marqusee E, Hill JA, Mandel SJ: Thyroiditis after pregnancy loss. J Clin Endocrinol Metab 82:2455, 1997.

198. Kampe O, Jansson R, Karlsson FA: Effects of L-thyroxine and iodide on the development of autoimmune postpartum thyroiditis. J Clin Endocri-nol Metab 70:1014, 1990.

199. Weetman AP: Editorial: Insulin-dependent diabetes mellitus and postpar-tum thyroiditis: An important association. J Clin Endocrinol Metab 79:7, 1994.

Ch047-X4224.indd 1014 8/26/2008 4:10:58 PM

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