Chapter 47Thyroid Disease and Pregnancy Shahla Nader, MDThyroid disorders are among the most common endocrinopathies in thyroid growth, differentiation, and all phases of iodine metabolismyoung women of childbearing age. In large areas of the world, iodine from uptake of iodine to secretion of the two thyroid hormones. Indeﬁciency is the predominant cause of these disorders. In the Western the nonpregnant state, 80 to 100 μg of iodine are taken up by the glandHemisphere, these disorders are most often related to altered immu- daily. Dietary iodine is reduced to iodide, which is absorbed and clearednity. The hormonal and immunologic perturbations of pregnancy and by the kidney (80%) and thyroid (20%). Iodide is actively trapped bythe postpartum period and the dependence of the fetus on maternal the thyroid and is the rate-limiting step in hormone biosynthesis. Theiodine and thyroid hormone have profound inﬂuences on maternal iodide is converted back to iodine and organiﬁed by binding to tyrosylthyroid function and consequently on fetal well-being. Appropriate residues, which are part of the glycoprotein thyroglobulin. This processantepartum and postpartum care requires a basic knowledge of thyroid requires the enzyme thyroid peroxidase. Iodination can give rise tofunction, its alteration in pregnancy, and the more common thyroid monoiodotyrosine or diiodotyrosine, with the ratio depending on pre-diseases afﬂicting women in the setting of pregnancy, all of which are vailing iodine availability. Coupling of two diiodotyrosine moleculesaddressed in this chapter. The combination of thyroid disease and forms T4, and one diiodotyrosine and one monoiodotyrosine form T3.pregnancy has been the topic of several reviews,1,2 and the Endocrine Thyroglobulin is extruded into the colloid space at the center of theSociety’s guidelines for management of thyroid dysfunction during follicle, and thyroid hormone is stored as colloid.pregnancy and after delivery have recently been published.3 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-Maternal-Fetal Thyroid binding globulin [TBG]), with less than 1% in free form (0.3% of T3 and 0.03% of T4). Other binding proteins include thyroxine-bindingPhysiology prealbumin and albumin. It is the free hormone that enters cells and is active.Normal Thyroid Physiology Whereas T4 is completely thyroidal in origin, only approximatelyThe thyroid gland is located in the anterior neck below the hyoid bone 20% of T3 comes directly from the thyroid. Thyroxine is metabolizedand above the sternal notch. Consisting of two lobes and connected by in most tissues (particularly in the liver and kidneys) to T3 by deiodin-the isthmus, it weighs approximately 20 to 25 g. Each lobe is divided ation. It is also metabolized to reverse T3, a metabolically inactiveinto lobules, each of which contains 20 to 40 follicles. The follicle hormone. Removal of an iodine by 5′ monodeiodination from theconsists of follicular cells, which surround a glycoprotein material outer ring of T4 results in T3, which is metabolically active. When iodinecalled colloid. is removed from the inner ring, reverse T3 is produced (Fig. 47-1) The hypothalamic-pituitary axis governs the production of thyroid Monodeiodinase type I and type II catalyze the formation of T3, whereashormone by the follicular cells. Tonic stimulation of thyrotropin- reverse T3 is catalyzed by monodeiodinase type III. Normally, approxi-releasing hormone (TRH) is required to maintain normal thyroid mately 35% of T4 is converted to T3, and 40% is converted to reversefunction, and hypothalamic injury or disruption of the stalk results in T3, but this balance is shifted in favor of the metabolically inert reversehypothyroidism. TRH, a tripeptide, is produced in the paraventricular T3 in illness, starvation, or other catabolic states.4,5 About 80% of cir-nucleus of the hypothalamus, and its local production as determined culating T3 is derived from peripheral conversion. The half-life of T4 isby mRNA is inversely related to concentrations of circulating thyroid 1 week; 5 to 6 weeks are necessary before a change in dose of T4 therapyhormones. Traversing the pituitary stalk, TRH is delivered to the pitu- is reﬂected in steady-state T4 values. The half-life of T3 is 1 day.itary thyrotroph by the pituitary portal circulation, and it affects Free thyroid hormone enters the cell and binds to nuclear receptorsthe production and release of thyrotropin (i.e., thyroid-stimulating and in this way signals its cellular responses.6 The afﬁnity of T3 forhormone [TSH]). A glycoprotein, TSH is composed of α and β sub- nuclear receptors is tenfold that of T4, which helps to explain theunits, and the β subunit confers speciﬁcity. Control of TSH secretion greater biologic activity of T3. Thyroid hormone receptors belong to aoccurs by negative feedback (from circulating thyroid hormone, soma- large superfamily of nuclear-hormone receptors that include thetostatin, dopamine) or by stimulation by TRH. steroid hormone, vitamin D, and retinoic acid receptors. Thyroid hor- Thyroid gland production of thyroxine (T4) and triiodothyronine mones have diverse effects on cellular growth, development, and(T3) is regulated by TSH. On binding to its receptor, TSH induces metabolism. The major effects of thyroid hormones are genomic,
996 CHAPTER 47 Thyroid Disease and Pregnancy I I NH2 3′ 3′ T4 HO 5′ O 5′ CH2 CH COOH I I I I NH2 I I NH2 T3 HO O CH2 CH COOH rT3 HO O CH2 CH COOH I I 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).stimulating transcription and translation of new proteins in a concen- state of iodine sufﬁciency. This does not apply when thyroid functiontration- and time-dependent manner. is compromised or iodine supply is insufﬁcient.Maternal Thyroid Physiology Iodine Deﬁciency and GoiterPregnancy alters the thyroidal economy, and the hormonal changes of Increased vascularity and some glandular hyperplasia can result inpregnancy result in profound alterations in the biochemical parame- mild thyroid enlargement, but frank goiter occurs because of iodineters of thyroid function. This section reviews maternal thyroid physiol- deﬁciency or other thyroidal disease. Although iodine deﬁciency isogy, the role of maternal hormones in fetal growth and development, usually not a problem in the United States, Japan, and parts of Europe,and the development of the fetal hypothalamic-pituitary-thyroid axis. 1 to 1.5 billion people in the world are at risk, with 500 million livingThis topic was reviewed by Glinoer.7 in areas of overt iodine deﬁciency. The World Health Organization Three series of events occur at different times during gestation. recommends 150 μg iodine per day for adults and 200 μg for pregnantStarting in the ﬁrst half of gestation and continuing until term, there women. There is increased renal iodine clearance during pregnancy,is an increase in TBG, a direct effect of increasing circulating estrogen and in the latter part of gestation, a signiﬁcant amount of iodine isconcentrations. Basal levels increase twofold to threefold. This increase diverted toward the fetoplacental unit to allow the fetal thyroid tois accompanied by a trend toward lower free hormone concentrations produce its own thyroid hormones. This physiologic adaptation occurs(T4 and T3), which results in stimulation of the hypothalamic- easily with minimal hypothyroxinemia and no goiter formation inpituitary-thyroid axis. Under conditions of iodine sufﬁciency, the areas of iodine sufﬁciency. Through hypothalamic-pituitary feedback,decrease in free hormone levels is marginal (10% to 15% on average). borderline iodine intake chronically enhances thyroid stimulation.When the supply of iodine is insufﬁcient, more pronounced effects The iodine deﬁciency manifests as greater hypothyroxinemia, whichoccur, and these are addressed in later sections. There is usually a trend increases TSH and thyroglobulin levels and produces thyroid hyper-toward a slight increase in TSH between the ﬁrst trimester and term. trophy (Fig. 47-4). The second event takes place transiently during the ﬁrst trimester In a study of otherwise healthy pregnant women living under con-and is a consequence of thyroid stimulation by increasing concentra- ditions of relative iodine restriction, thyroid volume, as assessed bytions of human chorionic gonadotropin (hCG). As hCG peaks late in ultrasonography, increased an average of 30% during pregnancy.11 Inthe ﬁrst trimester, there is partial inhibition of the pituitary and tran- a selected group of these women with goitrogenesis, follow-up a yearsient lowering of TSH between 8 and 14 weeks’ gestation (Fig. 47-2). after delivery did not show a return of thyroid volumes to those foundIn about 20% of women, TSH falls below the lower limit of normal, in early pregnancy. Iodine intake should also be increased after deliv-and these women often have signiﬁcantly higher hCG concentrations.8 ery, especially in breastfeeding women. Ultrasonography of neonatesThe stimulatory action of hCG has been broadly quantiﬁed; an revealed that thyroid volume was 38% larger in neonates of untreatedincrement of 10,000 IU/L is associated with a lowering of basal mothers compared with neonates of mothers treated with iodineTSH of 0.1 mU/L. In most normal pregnancies, this is of minor supplementation.12consequence.9 Other than iodine deﬁciency, goiter in pregnancy can be related to In the third series of events, alterations in the peripheral metabo- the following:lism of thyroid hormone occur throughout pregnancy but are moreprominent in the second half. Three enzymes deiodinate thyroid hor- Graves diseasemones: deiodinase types I, II, and III. Type I is not signiﬁcantly modi- Hashimoto thyroiditisﬁed. Type II, which is expressed in the placenta, can maintain T3 Excessive iodine intakeproduction locally, which can be critical when maternal T4 concentra- Lymphocytic thyroiditistions are reduced. Type III is also found abundantly in the placenta, Thyroid cancerand it catalyzes the conversion of T4 to reverse T3 and conversion of T3 Lymphomato T2; this abundance may explain the low T3 and high reverse T3 con- Therapy with lithium or thionamidescentrations characteristic of fetal thyroid hormone metabolism.10 These physiologic adaptations to pregnancy, depicted in Figure In the United States, clinical studies of pregnant women and non-47-3, are attained without difﬁculty by the normal thyroid gland in a pregnant controls have not revealed an increase in goiter during preg-
CHAPTER 47 Thyroid Disease and Pregnancy 997 Mother Hypothalamus TBG TRH Total T4 Pituitary TSH hCG Free T4 hCG Thyroid Thyrotropin T4, T3 Liver Fetus TBG Free hormones TBG Estrogen Total T4 Placenta Placental Deiodinases Type II - T4 to T3 Thyrotropin Type III - T4 to reverse T3 Free T4 Total T3 Free T3 FIGURE 47-3 Physiologic adaptation to pregnancy. Schematic representation of the physiologic adaptation to pregnancy shows 10 20 30 40 increased thyroxine-binding globulin (TBG) concentrations, increased Week of pregnancy levels of human chorionic gonadotropin (hCG) with its thyrotropin-like activity, and alterations in the peripheral metabolism of thyroidFIGURE 47-2 Relative changes in maternal and fetal thyroid hormones in the placenta. TRH, thyrotropin-releasing hormone; TSH,function during pregnancy. The effects of pregnancy on the thyroid-stimulating hormone, T4, thyroxine, T3, triiodothyronine.mother include a marked and early increase in hepatic production of (Adapted from Glinoer D: What happens to the normal thyroid duringthyroxine-binding globulin (TBG) and placental production of human pregnancy? Thyroid 9:631, 1999.)chorionic gonadotropin (hCG). The increased level of serum TBGincreases total serum thyroxine (T4) concentrations; hCG hasthyrotropin-like activity and stimulates maternal T4 secretion. Thetransient hCG-induced increase in the serum level of free T4 inhibits of increased renal blood ﬂow and an increase in glomerular ﬁltrationmaternal secretion of thyrotropin. (Reprinted by permission from rate of as much as 50%.18 If iodine excretion is greater than 100 μgBurrow GN, Fisher DA, Larsen PR: Maternal and fetal thyroid in a 24-hour period, the patient’s iodine intake is assumed to befunction. N Engl J Med 331:1072, 1994.) sufﬁcient.19fnancy.13 Ultrasound studies from other areas replete with iodine haveconﬁrmed these ﬁndings.14,15 Placental-Fetal Thyroid PhysiologyIodine Metabolism in Pregnancy The thyroid gland forms as a midline outpouching of the anteriorAlthough radioactive iodine is absolutely contraindicated in preg- pharyngeal ﬂoor, migrates caudally, and reaches its ﬁnal position by 7nancy, early studies using 132I showed a threefold increase in thyroidal weeks’ gestation. Lateral contributions from the fourth and ﬁfth pha-iodine clearance in pregnant women. Another set of studies enrolling ryngeal pouches give it its bilateral shape by 8 to 9 weeks’ gestation.25 pregnant women also revealed increased radioactive iodine uptake Active trapping of iodide is detectable by week 12, and the ﬁrst indica-during pregnancy compared with the nonpregnant or postpartum tion of T4 production is detectable by week 14. Hypothalamic TRH isstate.16,17 The mean renal iodine clearance almost doubles because detectable at weeks 8 to 9, and the pituitary portal circulation is func-
998 CHAPTER 47 Thyroid Disease and Pregnancy It appears that the ﬁrst phase of maximum growth velocity of 20 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 15 brain growth velocity, occurring from the third trimester to 2 to 3 years Thyroid hypertrophy (%) 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 deﬁcit in offspring. When it occurs 10 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 5 ﬂuid and correlate with the fetal rather than maternal serum. Neonatal Thyroid Function Immediately after birth, there is a surge of TRH and TSH that is fol- 0 5 5 10 10 lowed by an increase in T3 (from increased T4 to T3 conversion) and a Urinary iodide (μg/dL) moderate increase in T4.10 Within a few days, the increased TSH falls to adult levels through T4 and T3 negative-feedback inhibition. Neona-FIGURE 47-4 Iodine deﬁciency can manifest as thyroid tal T4 and T3 concentrations return to normal adult levels within 4 tohypertrophy. The percentage of maternal thyroid hypertrophy 6 weeks.29 The transient hyperthyroxinemia can be triggered by neo-(thyroid volume > 18 mL) is plotted against the urinary iodine natal cooling and may represent an adaptation of thermogenesis toconcentration measured during the ﬁrst trimester of pregnancy. extrauterine life.30,31(Reprinted by permission from Caron P, Hoff M, Bassi S, et al: Urinary In premature neonates, free T4 levels are low, TSH levels are normaliodine excretion during normal pregnancy in healthy women living in (adult), and T4 levels are related to gestational age. The clinical conse-the southwest of France: Correlation with maternal thyroid quence of this transient hypothalamic hypothyroidism is unknown,parameters. Thyroid 7:749, 1997.) but it has been associated with impaired neurologic and mental development.32-34tional by weeks 10 to 12. Until mid-gestation, fetal TSH and T4 con-centrations remain low. At 18 to 20 weeks’ gestation, the fetal thyroidgland’s iodine uptake and serum T4 concentrations begin to increase.20 Placental Transfer of Drugs AffectingConcentrations of T4 increase from 2 μg /dL at 20 weeks to 10 μg/dL Thyroid Functionat term, with increasing TBG concentrations contributing to this rise. The potential inﬂuence of the placenta on fetal thyroid and neurologicSimilarly, free fetal T4 concentrations increase from 0.1 ng/dL at 12 development is evident by the ready transfer of several agents thatweeks’ gestation to 1.5 ng/dL near term. Increases in T3 and free T3 are affect thyroid function.35,36 These agents include the following:smaller, presumably because of the availability of placental type IIIdeiodinase, which converts T4 rapidly to reverse T3. Fetal serum T3 Iodineincreases from 6 ng/dL at 12 weeks’ gestation to 45 ng/dL near term. ThionamidesFetal serum TSH increases from 4 to 8 mU/L between weeks 12 and β-Adrenergic receptor blockersterm.21,22 In summary, most fetal T4 is inactivated to reverse T3. The T3 Somatostatin(from T4 conversion or direct fetal thyroid secretion) has limited avail- Exogenous TRHability. Fetal tissues that depend on T3 for development (e.g., brain Dopamine agonists and antagonistsstructures) are supplied by local T4 to T3 conversion by means of deio- Thyroid-stimulating immunoglobulins and other antibodiesdinase type II.22 TSH does not cross the placenta. TRH and corticosteroid adminis- tered antenatally before 32 weeks’ gestation stimulates T4 release andPlacental Transfer of decreases the frequency of chronic lung disease among neonates.37Thyroid Hormones Intra-amniotic administration of T4 in the preterm setting increasesAlthough earlier studies suggested only limited T4 and T3 transfer fetal maturation, as reﬂected by an increase in the lecithin-to-through the placenta, later studies have shown that T4 can be found in sphingomyelin ratio and decrease in respiratory distress syndromeﬁrst-trimester celomic ﬂuid by 6 weeks’ gestation. Nuclear T3 receptors of the newborn.38can be identiﬁed in the brain of 10-week-old fetuses, and they increasetenfold by 16 weeks’ gestation before the fetal thyroid becomes fullyfunctional.24 These studies suggest that maternal T4 transfer occursearly in gestation and that low levels of T4 are sustained in the fetus at Pregnancy, the Immunethis time.25 Vulsma and colleagues26 reported that cord serum T4 levelsin hypothyroid neonates with glandular agenesis represented as much System, and Thyroid Diseaseas 30% of normal circulating values, a strong indication of maternal Chapter 6 offers a detailed review of pregnancy immunology. TheT4 transfer, although this has not been a uniform ﬁnding.27 fetus, with its complete set of paternal antigens, survives because of
CHAPTER 47 Thyroid Disease and Pregnancy 999adjustments in the maternal-placental-fetal immune systems. This TABLE 47-1 FACTORS INFLUENCINGimmunologic compromise of pregnancy is orchestrated primarily by THYROXINE-BINDING GLOBULINthe placental tissues and passaged fetal cells that are able to modulatethe local and systemic maternal immune responses.39,40 Autoimmune Factors Increasing TBG Levels Factors Decreasing TBG Levelsresponses are usually reduced in pregnancy, as evidenced by ameliora- Oral contraceptives Testosteronetion of Graves disease, rheumatoid arthritis, and multiple sclerosis.41-43 Pregnancy Nephrotic syndromeAlthough there is a shift from proinﬂammatory TH1 cytokines to TH2 Estrogen Cirrhosiscytokines, driven perhaps by progesterone,44 it is occurring against a Hepatitis Glucocorticoidsbackground of reduced B-cell reactivity. The reduced B-cell responses Acute intermittent porphyria Severe illnessare likely orchestrated by placental sex steroids, which are powerful Inherited defect Inherited defectnegative regulators of B-cell activity. Whereas most of the immunechanges in pregnancy return to normal by 12 months after delivery, TBG, thyroxine-binding globulin.there is a marked increase after most pregnancies in many differenttypes of autoantibody secretion and an exacerbation of autoimmunedisease. In most studies, total immunoglobulin G and autoantibody early in pregnancy because of the stimulatory effects of hCG. Free T4levels rise above pre-pregnancy levels during the ﬁrst 6 months after levels tend to fall through the rest of pregnancy and occasionally todelivery, suggesting continuing nonspeciﬁc immune stimulation.39 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 inﬂuence TBG andLaboratory Evaluation therefore total hormone concentrations. Resistance to thyroid hormone is a rare condition encompassing aof Thyroid Function number of different defects. The pituitary and other peripheral tissues can manifest this resistance. These patients present with an increasedduring Pregnancy free T4 concentration along with an inappropriately elevated or non- suppressed TSH, and they may have goiters. Whereas patients withThyrotropin and Thyroid Hormones thyroid hormone resistance have normal α-subunit concentrations,Total T4 and total T3 are elevated because of increased TBG production patients with TSH-secreting tumors (i.e., differential diagnosis ofand reduced clearance induced by the hyperestrogenic state of preg- thyroid hormone resistance) often have elevated serum α-subunitnancy.45 The normal reference range for total T4 should be adjusted by levels.48 In a case reported by Anselmo and colleagues,49 transient thy-a factor of 1.5 for pregnant patients.2 The T3 resin uptake (i.e., indirect rotoxicosis occurred during pregnancy in a woman with resistance tolaboratory measure of available TBG binding sites) is reduced in preg- thyroid hormone caused by a mutation in the thyroid receptor β gene.nancy because increased TBG binding sites take up more of the added This thyrotoxicosis manifested clinically by hypermetabolic featuresT3, leaving less to bind to resin. The free thyroxine index, which is and paralleled the rise and peak of hCG concentrations. Symptomsa product of the total T4 and T3 resin uptake, usually falls to within ameliorated and thyroid hormone concentrations declined as preg-the normal range in pregnancy. Because free T4 can be determined, nancy progressed and hCG concentrations fell.however, third-generation TSH and free T4 assessments are the best Concern has been raised regarding unaffected fetuses of mothersways to evaluate thyroid function in pregnancy. However, automated with thyroid hormone resistance. Outcomes of pregnancies in anfree T4 assays are sensitive to alternations in binding proteins as occurs extended Azorean family with resistance to thyroid hormone werein pregnancy. Because these proteins change, they can falsely elevate or analyzed; miscarriages were found to be more common, and unaf-lower the free T4 assay result. The free T4, as measured by equilibrium fected infants born to affected mothers had lower birth weights, dem-dialysis, is not affected by these protein changes. Trimester-speciﬁc onstrating a direct toxic effect of thyroid hormone excess on thenormative data for iodine-sufﬁcient women using speciﬁc commer- fetus.50cially available assays is not available. This topic is discussed further inthe section on Subclinical Hypothyroidism and Hypothyroxinemia. If the TSH is suppressed, suggesting overproduction of thyroid Thyrotropin Receptor Antibodieshormones, free T3 can be determined. The third-generation TSH assays Several functional types of TSH receptor antibodies are recognized.can differentiate profound from marginal suppression. Trimester- Some antibodies promote gland function (i.e., thyroid-stimulatingspeciﬁc TSH concentrations were obtained by Dashe and colleagues,46 immunoglobulins [TSIs]), some inhibit binding of TSH to its receptorwho determined these concentrations at each point during gestation (i.e., thyroid-binding inhibitory immunoglobulins [TBIIs]), and somein singleton and twin pregnancies. They constructed nomograms for enhance or inhibit thyroid growth. These antibodies can be measuredboth using regression analysis and showed signiﬁcantly lower TSH by a variety of bioassays and receptor assays. For example, maternalconcentrations in the ﬁrst trimester. These levels were lower in twin production of TSIs causes maternal Graves disease, is transferredpregnancies, as would be expected from the known effects of hCG. across the placenta, and can lead to neonatal Graves disease. ExcessValues were converted to multiples of the median for singleton preg- TBIIs can cause maternal and neonatal hypothyroidism.nancies at each week of gestation, and they suggested that valuesexpressed this way might facilitate comparison across laboratories andpopulations. In another study, using sensitive TSH assays, 9% of non- Antithyroid Antibodiessymptomatic ﬁrst-trimester women were found to have TSH values Patients with autoimmune thyroid disease commonly develop anti-higher than 0.05 mU/L (i.e., lower limit of assay detection) but less bodies to thyroid antigens. The two most commonly determinedthan 0.4 mU/L, and another 9% had TSH values below the detection antibodies are those to thyroglobulin and to thyroid peroxidaselimit.8 Free T3 and T4 concentrations can be in the high-normal range (anti-TPO).51 Among nonpregnant women, the incidence of anti-TPO
1000 CHAPTER 47 Thyroid Disease and Pregnancy TABLE 47-2 EFFECTS OF DRUGS ON THYROID short term with thyroid hormones. Only two newborns had transient HORMONES AND FUNCTION hyperthyroxinemia. Although breastfeeding resulted in substantial infant amiodarone ingestion, it did not cause major changes in neonatal TEST RESULTS thyroid function. The study authors concluded that amiodarone should Inhibition of thyroid function be used only when tachyarrhythmias are unresponsive to other drugs Iodine and are life threatening and that hypothyroid neonates (and perhaps Lithium the fetus in utero) should be treated. It is prudent to monitor the infants Inhibition of T4 to T3 conversion of breastfeeding mothers who continue to use the medication.54 Glucocorticoid Ipodate Propranolol Nonthyroidal Illness and Amiodarone Propylthiouracil Thyroid Function Increased level of TSH Nonthyroidal illness has been the topic of various reviews and com- Iodine mentaries.4,5,55 Severely ill patients can manifest thyroid function test Lithium abnormalities that may correlate with functional inhibition of the Dopamine antagonists hypothalamic-pituitary-thyroid axis, impaired T4 to T3 conversion (a Decreased level of TSH constant accompaniment of nonthyroidal illness), and abnormalities Glucocorticoids in binding and clearance of thyroid hormone. Reverse T3 levels are Dopamine agonists substantially elevated because of increased T4 to reverse T3 conversion Somatostatin and impaired metabolic clearance of reverse T3. TSH concentrations Inhibition of T4 and T3 binding to binding proteins Phenytoin can be low, normal, or elevated, although seldom higher than 20 mU/ Salicylates L.55 The more severe the illness, the lower the T4 values, and this rela- Sulfonylureas tionship has been used as a prognostic indicator, because a high cor- Inhibition of gastrointestinal absorption of thyroid hormone relation has been found between a low T4 value and a fatal outcome.56 Ferrous sulfate The best test for assessing thyroid function in severely or chronically Sucralfate ill patients is the free T4 concentration. Despite the low T3 and total T4 Cholestyramine state, this situation does not represent true hypothyroidism, but rather Aluminum hydroxide an adaptation to stress, and it should not be treated. TSH, thyroid-stimulating hormone; T3, l-triiodothyronine; T4, l-thyroxine. Thyroid Dysfunction andantibodies is about 3%, with the incidence ranging from 5% to 15%among pregnant women. A substantial proportion of women with Reproductive Disorderspositive anti-TPO antibodies in early pregnancy develop postpartum Thyroid hormones are important for normal reproductive function.thyroiditis.52,53 Deﬁciency 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-Drugs and Thyroid Function tion tests, usually T4, T3, and TSH. Women with type 1 diabetes, whoTable 47-2 outlines drug effects on thyroid function and metabolism, have a relatively high incidence of hypothyroidism, should probablyabsorption of thyroid hormones, and interpretation of thyroid func- undergo screening before conception. This topic has been reviewed bytion tests. Iodine and lithium inhibit thyroid function. Propranolol and Trokoudes and coworkers.59ipodate block T4 to T3 conversion, as do glucocorticoids; however,glucocorticoids also reduce release of TSH from the pituitary, as dodopamine, dopamine agonists, and somatostatin. The antiseizure med- Hyperthyroidismication phenytoin reduces total T4 levels (up to 30%) by inhibiting the Hyperthyroidism has been linked to oligomenorrhea, hypomenorrhea,binding of thyroid hormones to binding proteins and increasing T4 amenorrhea, and infertility, although many thyrotoxic women remainclearance. Ferrous sulfate, aluminum hydroxide, and sucralfate may ovulatory. In one survey, only 21.5% of 214 thyrotoxic patients hadinhibit thyroid hormone absorption substantially—an important menstrual disturbances, compared with 50% to 60% in older series.60interaction in pregnant women who are taking both iron and thyroid Thyroxine upregulates the production of sex hormone–binding globu-hormones. lin. Elevated levels of circulating testosterone and estrogen may be Amiodarone, an iodine-rich drug, has been used in pregnancy for observed, and the clearance of testosterone is reduced. Gonadotropinmaternal or fetal tachyarrhythmias. Amiodarone and the iodine are concentrations can be tonically elevated.61,62 The substantial weight losstransferred across the placenta, exposing the fetus to the drug and iodine seen in some hyperthyroid patients can affect the hypothalamic-overload. This iodine overload can cause fetal or neonatal hypothyroid- pituitary-gonadal axis and can contribute to the infertility of severeism and goiter, because the fetus acquires the capacity to escape from hyperthyroidism.the acute Wolff-Chaikoff effect (i.e., decrease in peroxidase activity andorganiﬁcation that follow iodine excess) only late in gestation. Among64 pregnancies in which amiodarone was given to the mother, 17% of Hypothyroidismprogeny developed hypothyroidism (goitrous and nongoitrous). Hypo- Hypothyroidism in fetal life does not affect the development of thethyroidism was transient, although a few of the infants were treated reproductive tract, but during childhood, it leads to sexual immaturity
CHAPTER 47 Thyroid Disease and Pregnancy 1001and usually a delay in puberty, followed by anovulatory cycles. Almost25% of women with untreated hypothyroidism have menstrual irregu-larities. Menorrhagia occurs frequently and can reﬂect interference Hyperthyroidism andwith the endometrial maturational process and response to ovariansteroids; it usually responds to thyroxine treatment.63 The increased Pregnancymiscarriage rate seen in hypothyroid patients may reﬂect disruptedendometrial maturation. Hypothyroidism, through increased TRH, Signs and Symptomscan be associated with hyperprolactinemia, which itself can disrupt The prevalence of hyperthyroidism in pregnant women ranges fromreproductive function and menstrual cyclicity,64 leading to oligomen- 0.05% to 0.2%.78 The signs and symptoms of mild to moderate hyper-orrhea or amenorrhea. Galactorrhea can sometimes be seen in this thyroidism—heat intolerance, diaphoresis, fatigue, anxiety, emotionalsetting, as can elevated levels of luteinizing hormone, possibly through lability, tachycardia, and a wide pulse pressure—can be mimicked bydiminished dopamine secretion.65 the hypermetabolic state of normal pregnancy. However, weight loss, Women with hypothyroidism have diminished rates of metabolic tachycardia greater than 100 beats/min, and diffuse goiter are featuresclearance of androstenedione and estrone and an increase in peripheral that may suggest hyperthyroidism. Graves ophthalmopathy can bearomatization. Whereas plasma concentrations of testosterone and helpful but does not necessarily indicate active thyrotoxicosis.79 Gas-estradiol are decreased because of diminished binding activity, their trointestinal symptoms such as severe nausea and excessive vomitingunbound fractions are actually increased. Several studies have sug- can accompany thyrotoxicosis in pregnancy, as can diarrhea, myopathy,gested increased risk of miscarriage in the presence of thyroid anti- lymphadenopathy, and congestive heart failure.bodies, even in the face of a euthyroid status. Although previous studiesdid not demonstrate beneﬁt in using T4 to treat euthyroid women withrecurrent spontaneous abortions,66-68 beneﬁt was shown by Negro and Diagnosiscolleagues69 in a group of 115 antibody-positive women, one half of Biochemical conﬁrmation of the hyperthyroid state can be obtainedwhom received thyroxine. Treatment decreased miscarriages and pre- through laboratory measurement of free T4, free T3, and TSH. Typi-maturity by 75% and 69%, respectively. In a thoughtful accompanying cally, elevated values of free T4 and T3 and greatly suppressed TSHeditorial, Glinoer70 stated that the statistical strength of the association values are found, but a normal free T4 level can be seen in cases of T3between miscarriages and autoimmune thyroid disease has been largely toxicosis. Other laboratory features include normochromic, normocyticconﬁrmed, with a threefold increase in the overall miscarriage rate. anemia; mild neutropenia; elevated levels of liver enzymes and alkalineBecause there is no reason to believe that thyroxine treatment altered phosphatase; and mild hypercalcemia. Patients may test positive for anti-autoimmunity, it was thought that the subtle deﬁciency in thyroid thyroid antibodies (i.e., antithyroglobulin and antithyroid peroxidase),hormone concentration or reduced ability of maternal thyroid func- but they are not speciﬁc to Graves disease. TSIs are considered to betion to adapt adequately in women with autoimmune thyroid disease the antibodies speciﬁc to Graves disease and can be measured by bioas-was the main reason for the beneﬁcial effects of thyroid hormone says or receptor assays.80administration. Differential Diagnosis Causes of hyperthyroidism are outlined in Table 47-3. ApproximatelyRadioiodine and Gonadal Function 90% to 95% of hyperthyroid pregnant women have Graves disease, andThe prevalence of infertility, premature births, miscarriage, and genetic this can be diagnosed with certainty in a thyrotoxic pregnant womandamage in the offspring of women treated with radioactive iodine who has diffuse thyromegaly with a bruit and ophthalmopathy.for thyrotoxicosis does not seem to be increased.71,72 Although thyroid Whereas excess circulating thyroid hormones cause lid retraction andcancer doses of 131I may be associated with subsequent menstrual lid lag, proptosis and external ocular muscle palsies reﬂect inﬁltrativeirregularities, exposure to radioiodine does not appear to reduce ophthalmopathy of Graves disease. Graves disease is an autoimmunefecundity.73 In a study of 32 women who conceived after 131I treatment disease mediated by antibodies (i.e., TSIs) that activate the TSH recep-for thyroid cancer (resulting in 60 term deliveries), two childrenconceived within a year of 131I therapy had birth defects, but noanomalies were seen in the remaining 58.74 Contraception has beenrecommended for 1 year after 131I treatment. In a large study, TABLE 47-3 CAUSES OF HYPERTHYROIDISMSchlumberger and associates75 obtained data on 2113 pregnancies IN PREGNANCYconceived after exposure to 30 to 100 mCi of radioiodine given for Graves diseasethyroid cancer. The incidences of stillbirths, preterm labor, low birth Toxic adenomaweight, congenital malformations, and death during the ﬁrst year of Toxic multinodular goiterlife were not signiﬁcantly different between pregnancies conceived Hyperemesis gravidarumbefore or after radioiodine therapy. Miscarriages were more common Gestational trophoblastic diseasefor the women treated with 131I in the year preceding conception TSH-producing pituitary tumor(40%). Metastatic follicular cell carcinoma All women need pregnancy tests before 131I treatment. Treatment Exogenous T4 and T3late in the ﬁrst trimester and in the second trimester may result De Quervain (subacute) thyroiditisin irreversible hypothyroidism in the fetus. Lactating mothers Painless lymphocytic thyroiditis Struma ovariiwho have received diagnostic or therapeutic doses of 131I should notbreastfeed their infants. These topics are reviewed by Gorman76 and TSH, thyroid-stimulating hormone; T3, l-triiodothyronine; T4,Berlin.77 l-thyroxine.
1002 CHAPTER 47 Thyroid Disease and Pregnancytor and stimulate the thyroid follicular cell. It affects 3% of women of directly to the control and severity of the hyperthyroidism. In a studyreproductive age.81 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 euthyroidTreatment and remained so. Similarly, prematurity was more common in theThe outcome of treatment before pregnancy is better than that of hyperthyroid group; the odds ratio was 2.8 for the controlled grouptreatment in pregnancy,82 and hyperthyroidism is therefore best treated and 16.5 for the uncontrolled group. Similar ﬁndings related to pre-before conception. If untreated or treated inadequately, women may eclampsia, with an odds ratio of 4.7 for the controlled group.84 Thishave more complications during pregnancy and delivery. Very mild was conﬁrmed by a later study.98 In other reports, higher frequenciescases of hyperthyroidism, with adequate weight gain and appropriate of small-for-gestational-age births, congestive heart failure, andobstetric progress, may be followed carefully, but moderate or severe stillbirths have been found.82,99 It is uncertain whether untreatedcases must be treated. In a retrospective study of 60 thyrotoxic preg- Graves disease is associated with a higher frequency of congenitalnant women, preterm delivery, perinatal mortality, and maternal heart malformation.87,100failure were signiﬁcantly increased among women who remained thy- Infants of mothers receiving thionamides should be evaluatedrotoxic. Thyroid hormone status at delivery correlated directly with ultrasonographically for signs of hypothyroidism, such as goiter, bra-pregnancy outcome.82 In another study by Momotani and Ito,83 hyper- dycardia, and intrauterine growth restriction. If needed, cordocentesisthyroidism at conception was associated with a 25% rate of abortion may be performed and fetal thyroid function determined; referenceand 15% rate of premature delivery, compared with 14% and 10%, ranges have been reported.101 Doses of PTU should be adjusted to keeprespectively, for euthyroid patients. Preeclampsia has also been associ- free T4 level in the upper normal range and TSH level less than 0.5 mU/ated with uncontrolled hyperthyroidism.84 L during pregnancy to avoid hypothyroidism in the fetus. PTU often can be stopped in late gestation.Thionamide Therapy PTU is not signiﬁcantly concentrated in breast milk (10% of serum)Thionamide therapy has been reviewed by Cooper85 and Clark and and does not appear to affect the infant’s thyroid hormone levels inassociates.86 The thionamides inhibit the iodination of thyroglobulin any major way. Methimazole also does not appear to affect subsequentand thyroglobulin synthesis by competing with iodine for the enzyme somatic or intellectual growth in children exposed to it during lacta-peroxidase. Propylthiouracil (PTU) is more frequently prescribed in tion.87,102,103 Antithyroid medication should be taken just after breast-the United States. Carbimazole (a drug metabolized to methimazole) feeding, allowing a 3- to 4-hour interval before the woman lactatesand methimazole itself are used often in Europe and Canada. PTU (but again.not methimazole) also inhibits the conversion of T4 to T3. The goal oftherapy is to control the hyperthyroidism without causing fetal or b-Blockersneonatal hypothyroidism.87 Maternal free T4 should be maintained in β-Blockers are useful for the control of adrenergic symptoms, particu-the high-normal range. PTU is given every 8 hours at doses of 100 to larly maternal heart rate. Propranolol is commonly used in doses of 20150 mg (300 to 450 mg total daily dosage) according to thyrotoxicosis to 40 mg two or three times daily, and it inhibits T4 to T3 conversion.severity. The occasional patient may require higher doses (e.g., 600 mg Alternatively, atenolol (50 to 100 mg daily) may be used, and in anor more) because the risk of uncontrolled maternal hyperthyroidism emergency, esmolol, an ultra-short-acting cardioselective intravenousis greater than that of high-dose PTU.82 It can take 6 to 8 weeks for β-blocker, has been used successfully.104 Prolonged therapy with β-major clinical effects to manifest. After the patient is euthyroid blockers can be associated with intrauterine growth restriction, fetal(reﬂected by monthly free T4 and free T3 values), the dose of PTU bradycardia, and hypoglycemia.should be tapered (e.g., halved), with further reduction as the preg-nancy progresses. For many patients, PTU can be discontinued by 32 Iodidesto 36 weeks’ gestation, because remission of Graves disease during Iodides decrease circulating T4 and T3 levels by up to 50% within 10pregnancy is commonly observed, often with relapse after delivery. It days by acutely inhibiting the release of stored hormone. Their usehas been suggested that a change from stimulatory to blocking anti- is appropriate in combination with thionamides (which shouldbody activity may contribute to this remission.88 be started before the iodide) and β-blockers in patients with Maternal side effects of PTU treatment can include rash (≈5%), severe thyrotoxicosis or thyroid storm. Potassium iodide (SSKI, 5pruritus, drug-related fever, hepatitis, a lupus-like syndrome, and drops every 8 hours) is given. Sodium ipodate, a radiographicbronchospasm. An alternative thionamide can be used, although cross- contrast agent, is an alternative and has the added beneﬁt of inhibitingsensitivity occurs in 50% of patients. Agranulocytosis, which is the conversion of T4 to T3. Its safety in pregnancy has not beenmost serious side effect, develops in only 0.1%, occurring especially in documented.older women and those receiving higher doses.89 All patients experi- Because iodides cross the placenta readily, they should be used forencing fever or unexpected sore throat on therapy should discontinue no longer than 2 weeks, or fetal goiter can result. Inadvertent use ofthe drug and have white blood cell count monitoring. Agranulocytosis iodides also follows use of Betadine cleansing solutions, iodine-con-is a contraindication to further thionamide therapy; the blood count taining bronchodilators, and the drug amiodarone. 131gradually improves over days or weeks. I thyroid ablation is contraindicated in pregnancy because the Methimazole is not used in the United States. Although the trans- radioactive iodine is concentrated in the fetal thyroid after 10 to 12placental passage is similar,90 methimazole may cause cutis aplasia, a weeks’ gestation. If a woman inadvertently receives 131I during preg-scalp deformity.91-93 Although rare, there are reports of methimazole nancy, SSKI should be given immediately, along with PTU, to blockand carbimazole embryopathy, with choanal atresia, tracheoesopha- organiﬁcation and reduce radiation exposure to the fetal thyroid by ageal ﬁstula, and facial anomalies.94-97 factor of 100 and to the fetal whole body by a factor of 10. To be of The risks of untreated hyperthyroidism need to be considered in beneﬁt, SSKI and PTU treatment must be given within 7 to 10 days ofrelation to the risk of antithyroid medications. They appear to relate exposure.76
CHAPTER 47 Thyroid Disease and Pregnancy 1003Surgery among these women, and it was recommended that treatment in preg-In select cases of thyrotoxicosis with severe complications or noncom- nancy was unwarranted.pliance, surgery can be performed in the pregnant patient. Two weeksof low-dose iodine therapy, such as one or two drops of SSKI daily, canreduce gland vascularity preoperatively. Surgery is best performed inthe second trimester, although it can be done in the ﬁrst or third tri- Fetal and Neonatalmester.105 The risks are those of anesthesia, hypoparathyroidism, andrecurrent laryngeal nerve paralysis. Hyperthyroidism The topic of fetal and neonatal hyperthyroidism has been reviewedThyroid Storm by Zimmerman.110 Hyperthyroidism in fetuses and neonates is usuallyThyroid storm is a life-threatening exacerbation of thyrotoxicosis. Cri- produced by transplacental passage of TSIs. Although they are ateria for its diagnosis have been introduced,106 and the classic ﬁndings common component of active Graves disease, the antibodies can con-are various degrees of thermoregulatory dysfunction, central nervous tinue to be present in the maternal circulation after surgical (Fig. 47-5)system effects (e.g., agitation, delirium, coma), gastrointestinal dys- or radioactive iodine ablation or even in patients with Hashimotofunction, and cardiovascular problems manifesting as tachycardia or thyroiditis. Fetal hyperthyroidism occurs when TSIs cross the placentaheart failure. For example, a patient with a temperature of 102°F who and activate the fetal thyroid; this occurs in 1% of infants born to theseis agitated and tachycardic with a pulse rate exceeding 130 beats/min women.would be diagnosed with thyroid storm. Although rare in pregnancy, Maternal TSI levels in excess of 300% of control values areit may be seen and can be precipitated by labor and delivery, cesarean predictive of fetal hyperthyroidism99 and should be measured at 28 tosection, infection, or preeclampsia.107 Thyrotoxic cardiomyopathy may 30 weeks. The assay used should be a functional one, because TSH-also lead to heart failure in pregnancy.108 Intensive care treatment with receptor antibodies are heterogeneous and can stimulate or block theﬂuid and nutritional support is necessary for thyroid storm and heart TSH receptor.99,111 Neonatal syndromes have been caused by transpla-failure. A loading dose of PTU of 600 mg may be given orally or cental passage of stimulating and blocking antibodies.112through a nasogastric tube, and 200 to 300 mg of PTU is continuedevery 6 hours. An hour after the initial dose of PTU, iodine is given asﬁve drops of SSKI every 8 hours (or 500 to 1000 mg of intravenous Fetal Thyrotoxicosissodium iodide every 8 hours) to inhibit thyroid hormone release. If Features of fetal thyrotoxicosis include a heart rate greater than 160the patient is iodine allergic, lithium (300 mg every 6 hours) is an beats/min, growth retardation, advanced bone age, and craniosynos-alternative. Dexamethasone (2 mg every 6 hours) is also given to block tosis, all of which can be detected by ultrasound examination.113 Occa-T4 to T3 conversion. For tachycardia exceeding 120 beats/min, β- sionally, nonimmune fetal hydrops and fetal death occur with associatedblockers such as propranolol, labetalol, or esmolol may be used.1 diminished subcutaneous fat and thyroid enlargement. In utero, mostTable 47-4 summarizes the management of thyroid storm. 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.Subclinical Hyperthyroidism A combination of PTU and T4 treats the fetal hyperthyroidism while keeping the mother euthyroid.Subclinical hyperthyroidism, as deﬁned by suppressed TSH and normalfree T4 and free T3 levels, is also seen in pregnancy. In a study by Caseyand associates,109 1.7% of women screened had subclinical hyperthy- Neonatal Thyrotoxicosisroidism, which they deﬁned as TSH values at or below the 2.5th per- Features of thyrotoxicosis in the neonate include hyperkinesis, diar-centile for gestational age and a free T4 level of 1.75 ng/dL or less. rhea, poor weight gain, vomiting, exophthalmos, arrhythmias, cardiacPregnancy complications, morbidity, and mortality were not increased 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 ﬂuid hydration and nutritional support Propylthiouracil Initial: 600 mg orally or crushed and given by NG tube Maintenance: 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 or 500-1000 mg of intravenous sodium iodide infusion every 12 hr Lithium carbonate Used if patient is allergic to iodine 300 mg every 6 hr Dexamethasone Given to block T4 to T3 conversion 2 mg every 6 hr for four doses β-Blockers Given to control tachycardia ≥ 120 beats/min IV propranolol at 1 mg/min up to several doses until blockade is (use cautiously if patient in heart failure) 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.
1004 CHAPTER 47 Thyroid Disease and PregnancyFIGURE 47-5 Graves disease. A, Hypothyroid 21-year-old woman who developed Graves disease at age 7 was treated by subtotalthyroidectomy. She was given maintenance therapy with thyroid hormone (0.15 mg of Synthroid) throughout pregnancy. B, Her daughter wasborn at term with severe Graves disease, goiter, and exophthalmos that persisted for 6 months. C, The child was normal at 20 months old.thrombocytopenia, and craniosynostosis. The infant should be exam- production can suppress the TSH to low or suppressed values in up toined immediately after birth. Cord blood reﬂects the in utero environ- 20% of normal pregnancies. Twin pregnancies can be associated withment, and by day 2 of life, the maternal antithyroid drug effects have biochemical hyperthyroidism,9 as may pregnancies complicated byreceded. Affected neonates are treated with PTU, β-blockers, iodine, trophoblastic disease. Several clinical scenarios can arise and areand glucocorticoids and digoxin, as needed. Ipodate may be preferable described in the following sections.because it blocks T4 to T3 conversion. Remission by 20 weeks iscommon, and it usually occurs by 48 weeks; occasionally, there ispersistent disease when there is a strong family history of Graves Gestational Transient Thyrotoxicosisdisease. Gestational transient thyrotoxicosis (GTT) occurs in the ﬁrst trimester Other mechanisms of fetal and neonatal hyperthyroidism include in women without a personal or family history of autoimmune disease.activating mutations of the stimulatory G protein in McCune-Albright It results directly from hCG stimulation of the thyroid. Glinoer andsyndrome and activating mutations of the TSH receptor.115,116 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 theHyperthyroidism Related decline in hCG, and usually did not require treatment. The thyroid gland was not enlarged. Occasionally, β-blockers were used. GTT wasto Human Chorionic not associated with a less favorable outcome of pregnancy.GonadotropinWhen hyperthyroidism is diagnosed during the ﬁrst trimester, the Hyperemesis Gravidarumphysician has a challenging differential diagnosis, usually that of Graves Hyperemesis gravidarum is a serious pregnancy complication associ-disease versus hCG-mediated hyperthyroidism. The hCG has TSH-like ated with weight loss and severe dehydration, often necessitating hos-stimulatory activity, which can result in overproduction of thyroid pitalization.119 Biochemical hyperthyroidism is found in most womenhormone when the concentrations are high or when there is a change with this condition.120,121 Whereas Goodwin and colleagues120,121 foundin its molecular structure. Molecular variants of hCG with increased that the severity of disease varied directly with the hCG concentration,thyrotropic potency include basic molecules with reduced sialic acid Wilson and associates122 did not ﬁnd such a correlation. As in thecontent, truncated molecules lacking the C-terminal tail, or molecules case of GTT, certain hCG fractions may be more important than totalin which the 47-48 peptide bond in the β-subunit loop is nicked.117 hCG as thyroid stimulators.123 The duration of the hyperthyroidismThis relationship is further complicated by differences in clearance varies widely from 1 to 10 weeks but is usually self-limited. Vomitingrates of different hCG glycoforms.118 In vivo thyrotropic activity is and normalization of T4 levels occur by 20 weeks, though TSH mayregulated by the glycoforms and the plasma half-life. remain suppressed a little longer. Treatment is usually supportive, with The hCG concentrations peak at 6 to 12 weeks and then decline to correction of dehydration, antiemetics, and occasionally, parenterala plateau after 18 to 20 weeks. The stimulation of thyroid hormone nutrition. The vomiting may not be controlled by normalization of
CHAPTER 47 Thyroid Disease and Pregnancy 1005 Clinical Disorders Defective ontogenesis Iodine Fetus Normal Normal (congenital deficiency hypothyroidism) Iodine Hypothy- Mother Normal Normal deficiency roxinemia Thyroxinemia in the fetus Contribution arising from maternal hormone transfer Conception Mid- gestation Term 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.)thyroid hormones. In patients who require treatment, PTU therapy adenoma. If either of these entities is diagnosed during pregnancy, thecan be attempted if tolerated; methimazole suppositories can also be correct treatment is control of hyperthyroidism with antithyroid drugsused. until deﬁnitive treatment (i.e., surgery or radioactive iodine) can be administered after delivery. Even less common causes of hyperthyroidism in pregnancy areGestational Trophoblastic Disease listed in Table 47-3. They include TSH-producing pituitary tumors,Both hydatidiform mole and choriocarcinoma can be associated with metastatic follicular thyroid cancer, viral (de Quervain) thyroiditis, andhCG levels that are greater than 1000 times normal and thus can cause struma ovarii, which is an ovarian dermoid tumor in which more thanhyperthyroidism (biochemically seen in approximately 50% of such 50% of the neoplasm consists of thyroid tissue.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 Iodine Deﬁciency, Hypothyroidism,Recurrent Gestational Hyperthyroidism and PregnancyCases of recurrent gestational hyperthyroidism have been described.125,126In the case described by Rodien and colleages,126 the hyperthyroidism A schematic representation of the clinical conditions that can affectwas caused by a mutant TSH receptor that was hypersensitive to thyroid function in the mother, fetus, or fetomaternal unit is providedhCG. in Figure 47-6. Although iodine deﬁciency 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 inOther Causes of Hyperthyroidism areas of overt iodine deﬁciency. Worldwide, it is the most commonMuch less common causes of hyperthyroidism include thyrotoxicosis cause of mental retardation.factitia (i.e., ingestion of exogenous hormone surreptitiously); in such In the past few decades, the physiology of maternal and fetal iodinecases, serum thyroglobulin, which is produced by the thyroid, is sup- metabolism, thyroid hormone metabolism, and fetal brain develop-pressed.127 Women with large nodular goiters may have hyperthyroid- ment and the pathophysiology of iodine deﬁciency have been unrav-ism from autonomously functioning nodules within such goiters. eled. These ﬁndings have revealed a fascinating aspect of pregnancyAlternatively, women can have hyperthyroidism from a single toxic physiology. Iodine deﬁciency and hypothyroidism in pregnancy con-
1006 CHAPTER 47 Thyroid Disease and Pregnancytinue to be a worldwide problem worthy of resolution. This topic also of iodine deﬁciency, it appeared to be responsible for an IQ loss of 13.5has been a subject of numerous reviews.128-131 Even in the United States, points.135 Even borderline iodine deﬁciency, as seen in Europe, can beiodine intake has declined, and 15% of women of childbearing age and accompanied by impaired school achievements by apparently normal7% of pregnant women were found to have urinary iodine excretions children, as reviewed by Glinoer.129below 50 μg/L, indicative of moderate iodine deﬁciency.132 Actions taken to eradicate iodine deﬁciency have prevented the Pregnancy is an environmental trigger for the thyroid machinery, occurrence of mental retardation in millions of infants throughoutinducing changes in people who live in geographic areas that have the world. In a study by Xue-Yi and coauthors136 of a severely iodine-iodine deﬁciency. Four biochemical markers are useful for following deﬁcient area of the Xinjiang region of China, iodine was administeredthe changes induced: to pregnant women. The prevalence of moderate or severe neurologic abnormalities among 120 infants whose mothers received iodine in the1. Relative hypothyroxinemia ﬁrst or second trimester was 2%, compared with 9% (of 952 infants)2. Preferential T3 secretion as reﬂected by an elevated T3/T4 molar when the mothers received iodine in the third trimester (P = .008). ratio Although treatment in the third trimester did not improve neurologic3. Increased TSH after the ﬁrst trimester, progressing until term status, head growth and developmental quotients improved slightly.4. Supranormal thyroglobulin concentrations correlating with gesta- The importance of thyroid hormone to fetal and neonatal well- tional goitrogenesis being and development was highlighted by a remarkable case of an infant born to a mother with strongly positive TSH receptor-blocking Goitrogenesis also occurs in the fetus, indicating the exquisite sen- antibodies. The mother was profoundly hypothyroid when tested aftersitivity of the fetal thyroid gland to the consequences of maternal delivery. The infant was delivered by cesarean section because of bra-iodine deﬁciency. This process can start during the earliest stages of dycardia. She was also profoundly hypothyroid and required intuba-fetal thyroid development. It occurs against a background of low initial tion. Her brain size was reduced, and her auditory brainstem responsematernal intrathyroidal iodine stores, the increased need for iodine was absent at age 2 months. The audiogram at age 4 years revealedafter pregnancy occurs, and the insufﬁciency of iodine intake through- sensorineural deafness. At age 6 years, motor development was theout the gestation. same as at age 4 months. She required T4 for 8 months until the anti- It appears that maternal thyroxine, traversing the placenta during body effect had worn off. Her physical growth was normal. Thethe ﬁrst trimester and subsequently, is necessary for fetal brain devel- outcome of severe thyroid hormone deﬁciency in utero was fetal dis-opment. Even before fetal thyroid hormone synthesis, T3 receptors are tress, permanent auditory deﬁcit, brain atrophy, and severely impairedfound in fetal brain tissues, and local conversion of T4 to T3 can occur. neuromotor development despite adequate neonatal treatment.137Iodine deﬁciency perpetuates the process, because the fetus is less The Institute of Medicine of the National Academy of Sciences hasable to synthesize thyroid hormones even when the fetal thyroid has set the iodine requirement as 110 μg for infants 0 to 6 months, 130 μgdeveloped. for infants 7 to 12 months, 90 μg for children 1 to 8 years, 120 μg for In severe iodine deﬁciency (intake of 20 to 25 μg/day), a condition those 9 to 13 years, and 150 μg for those older than 13 years. The rec-known as endemic cretinism occurs, with a prevalence up to 15% in ommended intake for pregnancy and lactation is 200 μg/day. Evenseverely affected populations. These infants are characterized by severe higher intakes (300 to 400 μg/day) have been suggested.138mental retardation with a neurologic picture including deaf-mutism,squint, and pyramidal and extrapyramidal syndromes. There are fewclinical signs of thyroid failure. A remarkable exception to this picturehas emerged from Africa, where the cretins have less mental retarda- Hypothyroidismtion and less in the way of neurologic deﬁcits. The clinical picture isthat of severe thyroid failure with dwarﬁsm, delayed sexual maturation, Signs and Symptomsand myxedema. Thyroid function is grossly impaired. Hypothyroidism occurs with a frequency of 1 case in 1600 to 2000 The consensus is that the neurologic picture of endemic cretinism deliveries.67 Population screening studies have revealed a higher inci-results from insults to the developing brain, occurring perhaps during dence. In a study in the United States, serum TSH levels were deter-the ﬁrst trimester (in the case of deafness) and mostly during the mined in 2000 women between gestational weeks 15 to 18; 49 (2.5%)second trimester, with the cerebellar abnormalities resulting from had TSH levels greater than or equal to 6 mU/L, and positive thyroidpostnatal insult. This is supported by the observation that the full antibodies were found in 58% of these 49 women, compared with 11%picture can be prevented only when the iodine deﬁciency is corrected of control euthyroid pregnant women.139 In a Japanese study, onlybefore the second trimester and, optimally, even before conception.133 0.29% had an elevated TSH level.140 In another U.S. study, 1 infant inIn Africa, iodine deﬁciency is complicated by selenium deﬁciency. The 1629 deliveries had hypothyroidism.141deﬁciency of selenium leads to accumulation of peroxide, and excess Women with hypothyroidism have higher pregnancy complicationperoxide leads to destruction of thyroid cells and hypothyroidism.134 rates. As well as miscarriages, complications include preeclampsia, pla-Selenium deﬁciency also induces monodeiodinase I (a selenoenzyme) cental abruption, low birth weight, prematurity, and stillbirths.142deﬁciency, resulting in reduced T4 to T3 conversion and increased avail- These outcomes can be improved with early therapy. Gestationalability of maternal T4 for the fetal brain. This protective mechanism hypertension is also more common.141may prevent the development of neurologic cretinism, and the com- The symptoms of hypothyroidism are insidious and can be maskedbined iodine-selenium deﬁciency prevalent in Africa may help explain by the hypermetabolic state of pregnancy. Symptoms can includethe predominance of the myxedematous type observed there. modest weight gain, decrease in exercise capacity, lethargy, and intoler- The neurologic abnormalities and mental retardation depend ulti- ance to cold. In moderately symptomatic patients, constipation,mately on the timing and severity of the brain insult. Endemic cretin- hoarseness, hair loss, brittle nails, and dry skin also can occur. Physicalism constitutes only the extreme expression of the spectrum of physical signs may include a goiter, a thyroidectomy scar, and delay in theand intellectual abnormalities. In a meta-analysis of 18 studies in areas relaxation phase of deep tendon reﬂexes.
CHAPTER 47 Thyroid Disease and Pregnancy 1007 Laboratory conﬁrmation is obtained from an elevated TSH level, the third trimester in about one third of patients.2 In a study of 12with or without suppressed free T4. Test results for thyroid autoanti- pregnant women with hypothyroidism, 9 required a higher T4 dose,bodies (antithyroglobulin and antithyroid peroxidase) may be positive. with a mean dose increase of 45%.146 In a review of 77 pregnancies inOther laboratory abnormalities can include elevated levels of creatine 65 hypothyroid women, serum TSH levels became abnormal in 70%phosphokinase, cholesterol, and carotene and liver function abnor- of women with prior 131I ablation therapy and in 47% of women withmalities. Patients may have macrocytic or normochromic, normocytic chronic thyroiditis. When data from other studies were pooled, overall,anemia. Hypothyroidism may occur more frequently in pregnant TSH levels increased above normal in 45% with a mean daily thyroxinewomen with type 1 diabetes, and T4 replacement therapy can increase dose of 146 μg.147,148 It was estimated that the increment in dose couldinsulin requirements.143 be predicted according to the TSH value at the ﬁrst evaluation. The TSH concentration should be determined again 4 to 6 weeks after dose adjustment.Differential Diagnosis The causes of increased T4 requirements include a real increasedHashimoto thyroiditis, also known as chronic lymphocytic thyroiditis, demand for T4 in pregnancy149 in patients whose thyroid reserve isan autoimmune disease, is the most common cause of hypothyroidism compromised and, in some cases, iron therapy. Ferrous sulfate inter-and can occur in 8% to 10% of women of reproductive age. It is char- feres with T4 absorption and should be taken at a different time of dayacterized by the presence of antithyroid antibodies, and the patient from thyroxine therapy.150 Patients with thyroid cancer whose targetmay have a goiter. Titers of antithyroglobulin are elevated in 50% to TSH concentration is below the normal range almost uniformly require70% of patients, and almost all have antithyroid peroxidase anti- an increased dose to maintain their suppressed TSH levels, and theybodies.53 The goiter is ﬁrm and diffusely enlarged and painless, and the should be followed closely.150 After delivery, the dose should be reducedgland is inﬁltrated by lymphocytes and plasma cells. Many patients to pre-pregnancy levels in all patients, and the TSH concentrationwith Hashimoto thyroiditis are actually euthyroid but can subsequently should be measured 6 to 8 weeks later.develop hypothyroidism. The thyroid gland can be atrophic and the The topic of thyroid hormone and intellectual development hastest result for antibodies negative—so-called idiopathic hypothyroid- received widespread publicity and has been the subject of articles andism. Patients with other autoimmune disease also can develop Hashi- reviews in the past few years.128,151,152 In 1969, Man and Jones153 studiedmoto thyroiditis. a cohort of 1349 children and concluded that mild maternal hypothy- Other important and common causes of hypothyroidism include roidism alone was associated with lower IQ levels in the offspring. In131 I therapy, ablation for Graves disease, and thyroidectomy (e.g., for 1990, Matsuura and Konishi154 documented that fetal brain develop-thyroid cancer). Of patients who receive 131I therapy, 10% to 20% are ment is affected adversely when both mother and fetus have hypothy-hypothyroid within the ﬁrst 6 months, and 2% to 4% become hypo- roidism caused by chronic autoimmune thyroiditis. With thethyroid each year thereafter.144 Hypothyroidism can result from sub- background of this information and the associations of iodine deﬁ-acute viral thyroiditis and, much less commonly, from suppurative ciency, its consequent maternal hypothyroxinemia, and abnormal fetalthyroiditis. brain development, Haddow and associates151 conducted a study mea- Drugs known to inhibit the synthesis of thyroid hormones include suring TSH levels from stored samples in more than 25,000 pregnantthionamide, iodides, and lithium. Carbamazepine, phenytoin, and women. They located 62 women with high TSH levels and 124 matchedrifampin can increase thyroid clearance. Aluminum hydroxide, chole- women with normal values. Their 7- to 9-year-old children, none ofstyramine, and, most important, ferrous sulfate and sucralfate can whom had hypothyroidism as newborns, underwent 15 tests relatinginterfere with the intestinal absorption of thyroxine. to intelligence, attention, language, reading ability, school performance, Hypothyroidism resulting from hypothalamic or pituitary disease and visual-motor performance. The full-scale IQ in children of hypo-is rare but can occur in the setting of pituitary tumors, after pituitary thyroid women was 4 points lower (P = .06); 15% had scores of 85 orsurgery or irradiation, and in Sheehan’s syndrome and lymphocytic less compared with 5% of controls. The IQ of the children of 48hypophysitis, an autoimmune disease with a predilection for women, women whose hypothyroidism was not treated averaged 7 points lowerespecially in the setting of pregnancy (see Chapter 48). In secondary than the 124 controls (P = .005), and 19% had scores of 85 or lower.hypothyroidism, the TSH level may be low or normal, but the free T4 The researchers concluded that undiagnosed hypothyroidism canlevel is low. 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.Treatment In a study by Pop and colleagues,156 even the presence of antithyroidHypothyroidism must be treated promptly, and a dose of 0.1 to 0.15 mg peroxidase antibodies in the maternal circulation was shown to haveof T4 per day, should be initiated. The dose is adjusted every 4 weeks deleterious effects on child development. In two similar studies, thyroiduntil the TSH concentration is in the lower end of the normal range. antibody–positive women had lower free T4 levels, and lower scores onIn women with little or no functioning thyroid tissue, a dose of 2 μg/ psychomotor tests were found in children of mothers whose free T4kg/day may be required. Women who are euthyroid on T4 need to be value was below the 5th and 10th percentiles as measured at 12 weeks’checked as soon as pregnancy is established; the dose should be adjusted gestation.157,158and rechecked in 4 to 8 weeks,145 because the requirements for thyroidhormone increase as early as the ﬁfth week of gestation. Alternatively,the patient can be instructed to increase her dose by one extra doseper week and be checked a few weeks later. The amount of dose increase Subclinical Hypothyroidismmay depend on the cause. For example, women who have had totalthyroidectomy may need a greater increase than women with mild and Hypothyroxinemiahypothyroidism. Increased dosage requirements may plateau by the Subclinical hypothyroidism is deﬁned as an elevated TSH level when20th week,145 but the need for increased dosage may be seen as late as the free T4 level is in the normal range. More than 90% of hypothyroid-