CR-6 Chapter 47 PDF

/Thyroid Disease and Pregnancy/Maternal-Fetal Thyroid Physiology
Chapter 47 – Thyroid Disease and Pregnancy

Shahla Nader, MD
Thyroid disorders are among the most common endocrinopathies in young women of childbearing age. In large areas of the world, iodine
deficiency is the predominant cause of these disorders. In the Western Hemisphere, these disorders are most often related to altered
immunity. 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 influences 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 afflicting women in the setting of pregnancy, all of which are addressed in this chapter. The combination of
[1,2]
thyroid disease and pregnancy has been the topic of several reviews, and the Endocrine Society's guidelines for management of
[3]
thyroid dysfunction during pregnancy and after delivery have recently been published.
Maternal-Fetal Thyroid Physiology
Normal Thyroid Physiology

The 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 pituitary
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 subunits, and the β subunit confers specificity. Control of TSH secretion occurs by
negative feedback (from circulating thyroid hormone, somatostatin, dopamine) or by stimulation by TRH.
Thyroid gland production of thyroxine (T 4) and triiodothyronine (T 3) 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 organified 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 prevailing iodine availability. Coupling of two diiodotyrosine molecules forms T 4, and one diiodotyrosine and one
monoiodotyrosine form T 3. 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 T 4 and T 3 into
the capillaries. Daily secretion rates approximate 90 μg of T 4 and 30 μg of T 3. Both circulate highly bound to protein (mainly thyroxine-
binding globulin [TBG]), with less than 1% in free form (0.3% of T 3 and 0.03% of T 4). Other binding proteins include thyroxine-binding
prealbumin and albumin. It is the free hormone that enters cells and is active.
Whereas T 4 is completely thyroidal in origin, only approximately 20% of T 3 comes directly from the thyroid. Thyroxine is metabolized in
most tissues (particularly in the liver and kidneys) to T 3 by deiodination. It is also metabolized to reverse T 3, a metabolically inactive
hormone. Removal of an iodine by 5′ monodeiodination from the outer ring of T 4 results in T 3, which is metabolically active. When iodine
is removed from the inner ring, reverse T 3 is produced (Fig. 47-1) Monodeiodinase type I and type II catalyze the formation of T 3, whereas
reverse T 3 is catalyzed by monodeiodinase type III. Normally, approximately 35% of T 4 is converted to T 3, and 40% is converted to
[4,5]
reverse T 3, but this balance is shifted in favor of the metabolically inert reverse T 3 in illness, starvation, or other catabolic states.
About 80% of circulating T 3 is derived from peripheral conversion. The half-life of T 4 is 1 week; 5 to 6 weeks are necessary before a
change in dose of T 4 therapy is reflected in steady-state T 4 values. The half-life of T 3 is 1 day.
/Thyroid Disease and Pregnancy/Maternal-Fetal Thyroid Physiology
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).
Free thyroid hormone enters the cell and binds to nuclear receptors and in this way signals its cellular responses.[6] The affinity of T 3 for
nuclear receptors is tenfold that of T 4, which helps to explain the greater biologic activity of T 3. Thyroid hormone receptors belong to a
large superfamily of nuclear-hormone receptors that include the steroid hormone, vitamin D, and retinoic acid receptors. Thyroid
hormones have diverse effects on cellular growth, development, and metabolism. The major effects of thyroid hormones are genomic,
stimulating transcription and translation of new proteins in a concentration- and time-dependent manner.
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//Maternal Thyroid Physiology
Maternal Thyroid Physiology

Pregnancy alters the thyroidal economy, and the hormonal changes of pregnancy result in profound alterations in the biochemical
parameters of thyroid function. This section reviews maternal thyroid physiology, the role of maternal hormones in fetal growth and
[7]
development, and the development of the fetal hypothalamic-pituitary-thyroid axis. This topic was reviewed by Glinoer.
Three series of events occur at different times during gestation. Starting in the first 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 (T 4 and T 3), which results in stimulation of the
hypothalamicpituitary-thyroid axis. Under conditions of iodine sufficiency, the decrease in free hormone levels is marginal (10% to 15% on
average). When the supply of iodine is insufficient, more pronounced effects occur, and these are addressed in later sections. There is
usually a trend toward a slight increase in TSH between the first trimester and term.
The second event takes place transiently during the first trimester and is a consequence of thyroid stimulation by increasing
concentrations of human chorionic gonadotropin (hCG). As hCG peaks late in the first trimester, there is partial inhibition of the pituitary
and transient lowering of TSH between 8 and 14 weeks' gestation (Fig. 47-2). In about 20% of women, TSH falls below the lower limit of
[8]
normal, and these women often have significantly higher hCG concentrations. The stimulatory action of hCG has been broadly
quantified; 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
[9]
minor consequence.
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.)
In the third series of events, alterations in the peripheral metabolism of thyroid hormone occur throughout pregnancy but are more
prominent in the second half. Three enzymes deiodinate thyroid hormones: deiodinase types I, II, and III. Type I is not significantly
modified. Type II, which is expressed in the placenta, can maintain T 3 production locally, which can be critical when maternal T 4
concentrations are reduced. Type III is also found abundantly in the placenta, and it catalyzes the conversion of T 4 to reverse T 3 and
conversion of T 3 to T 2; this abundance may explain the low T 3 and high reverse T 3 concentrations characteristic of fetal thyroid hormone
[10]
metabolism.
These physiologic adaptations to pregnancy, depicted in Figure 47-3, are attained without difficulty by the normal thyroid gland in a state
of iodine sufficiency. This does not apply when thyroid function is compromised or iodine supply is insufficient.
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.)
//Iodine Deficiency and Goiter
Iodine Deficiency and Goiter

Increased vascularity and some glandular hyperplasia can result in mild thyroid enlargement, but frank goiter occurs because of iodine
deficiency or other thyroidal disease. Although iodine deficiency 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 deficiency. 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 significant 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 sufficiency. Through hypothalamic-pituitary feedback, borderline iodine intake chronically enhances thyroid
stimulation. The iodine deficiency manifests as greater hypothyroxinemia, which increases TSH and thyroglobulin levels and produces
thyroid hypertrophy (Fig. 47-4).
FIGURE 47-4 Iodine deficiency 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 first 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.)
In a study of otherwise healthy pregnant women living under conditions of relative iodine restriction, thyroid volume, as assessed by
[11]
ultrasonography, increased an average of 30% during pregnancy. 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
//Iodine Deficiency and Goiter
delivery, especially in breastfeeding women. Ultrasonography of neonates revealed that thyroid volume was 38% larger in neonates of
[12]
untreated mothers compared with neonates of mothers treated with iodine supplementation.
Other than iodine deficiency, 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 nonpregnant controls have not revealed an increase in goiter during
pregnancy.[13] Ultrasound studies from other areas replete with iodine have confirmed these findings.[14,15]
//Iodine Metabolism in Pregnancy
Iodine Metabolism in Pregnancy
Although radioactive iodine is absolutely contraindicated in pregnancy, 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
[16,17]
uptake during pregnancy compared with the nonpregnant or postpartum state. The mean renal iodine clearance almost doubles
[18]
becauseof increased renal blood flow and an increase in glomerular filtration rate of as much as 50%. If iodine excretion is greater than
[19f]
100 μg in a 24-hour period, the patient's iodine intake is assumed to be sufficient.
//Placental-Fetal Thyroid Physiology
Placental-Fetal Thyroid Physiology

The thyroid gland forms as a midline outpouching of the anterior pharyngeal floor, migrates caudally, and reaches its final position by 7
weeks' gestation. Lateral contributions from the fourth and fifth pharyngeal pouches give it its bilateral shape by 8 to 9 weeks' gestation.
Active trapping of iodide is detectable by week 12, and the first indication of T 4 production is detectable by week 14. Hypothalamic TRH is
detectable at weeks 8 to 9, and the pituitary portal circulation is functional by weeks 10 to 12. Until mid-gestation, fetal TSH and T 4
concentrations remain low. At 18 to 20 weeks' gestation, the fetal thyroid gland's iodine uptake and serum T 4 concentrations begin to
[20]
increase. Concentrations of T 4 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 T 4 concentrations increase from 0.1 ng/dL at 12 weeks' gestation to 1.5 ng/dL near term. Increases in T 3
and free T 3 are smaller, presumably because of the availability of placental type III deiodinase, which converts T 4 rapidly to reverse T 3.
Fetal serum T 3 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
[21,22]
between weeks 12 and term. In summary, most fetal T 4 is inactivated to reverse T 3. The T 3 (from T 4 conversion or direct fetal
thyroid secretion) has limited availability. Fetal tissues that depend on T 3 for development (e.g., brain structures) are supplied by local T 4
to T 3 conversion by means of deiodinase type II.[22]
Placental Transfer of Thyroid Hormones

Although earlier studies suggested only limited T 4 and T 3 transfer through the placenta, later studies have shown that T 4 can be found in
first-trimester celomic fluid by 6 weeks' gestation. Nuclear T 3 receptors can be identified in the brain of 10-week-old fetuses, and they
[24]
increase tenfold by 16 weeks' gestation before the fetal thyroid becomes fully functional. These studies suggest that maternal T 4
transfer occurs early in gestation and that low levels of T 4 are sustained in the fetus at this time.[25] Vulsma and colleagues[26] reported
that cord serum T 4 levels in hypothyroid neonates with glandular agenesis represented as much as 30% of normal circulating values, a
[27]
strong indication of maternal T 4 transfer, although this has not been a uniform finding.
It appears that the first phase of maximum growth velocity of developing brain structures—neuronal multiplication and organization
occurring during the second trimester—corresponds to a phase during which the supply of thyroid hormones to the fetus is almost
[20]
exclusively of maternal origin. 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 deficit in offspring. When it occurs later, the damage to the fetal brain is less and is partially
reversible. The need for T 3 by mid-gestation for development of the human cerebral cortex was also demonstrated by Kester and
[28]
associates. Concentrations of TSH, T 4, T 3, and reverse T 3 are measurable in the amniotic fluid and correlate with the fetal rather than
maternal serum.
//Neonatal Thyroid Function
Neonatal Thyroid Function

Immediately after birth, there is a surge of TRH and TSH that is followed by an increase in T 3 (from increased T 4 to T 3 conversion) and a
[10]
moderate increase in T 4. Within a few days, the increased TSH falls to adult levels through T 4 and T 3 negative-feedback inhibition.
[29]
Neonatal T 4 and T 3 concentrations return to normal adult levels within 4 to 6 weeks. The transient hyperthyroxinemia can be triggered
[30,31]
by neonatal cooling and may represent an adaptation of thermogenesis to extrauterine life.
In premature neonates, free T 4 levels are low, TSH levels are normal (adult), and T 4 levels are related to gestational age. The clinical
consequence of this transient hypothalamic hypothyroidism is unknown, but it has been associated with impaired neurologic and mental
[32–34]
development.
//Placental Transfer of Drugs Affecting Thyroid Function
Placental Transfer of Drugs Affecting Thyroid Function

The potential influence of the placenta on fetal thyroid and neurologic development is evident by the ready transfer of several agents that
[35,36]
affect thyroid function. 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 administered antenatally before 32 weeks' gestation stimulates T 4 release and
[37]
decreases the frequency of chronic lung disease among neonates. Intra-amniotic administration of T 4 in the preterm setting increases
fetal maturation, as reflected by an increase in the lecithin-tosphingomyelin ratio and decrease in respiratory distress syndrome of the
[38]
newborn.
//Pregnancy, the Immune System, and Thyroid Disease
Pregnancy, the Immune System, and Thyroid Disease

Chapter 6 offers a detailed review of pregnancy immunology. The fetus, with its complete set of paternal antigens, survives because of
adjustments in the maternal-placental-fetal immune systems. This immunologic compromise of pregnancy is orchestrated primarily by the
[39,40]
placental tissues and passaged fetal cells that are able to modulate the local and systemic maternal immune responses.
Autoimmune responses are usually reduced in pregnancy, as evidenced by amelioration of Graves disease, rheumatoid arthritis, and
[41–43]
multiple sclerosis. Although there is a shift from proinflammatory T H1 cytokines to T H2 cytokines, driven perhaps by
[44]
progesterone, 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
[39]
levels during the first 6 months after delivery, suggesting continuing nonspecific immune stimulation.
//Laboratory Evaluation of Thyroid Function during Pregnancy
Laboratory Evaluation of Thyroid Function during Pregnancy
Thyrotropin and Thyroid Hormones

Total T 4 and total T 3 are elevated because of increased TBG production and reduced clearance induced by the hyperestrogenic state of
[45]
pregnancy. The normal reference range for total T 4 should be adjusted by a factor of 1.5 for pregnant patients.[2] The T 3 resin uptake
(i.e., indirect laboratory measure of available TBG binding sites) is reduced in pregnancy because increased TBG binding sites take up
more of the added T 3, leaving less to bind to resin. The free thyroxine index, which is a product of the total T 4 and T 3 resin uptake,
usually falls to within the normal range in pregnancy. Because free T 4 can be determined, however, third-generation TSH and free T 4
assessments are the best ways to evaluate thyroid function in pregnancy. However, automated free T 4 assays are sensitive to
alternations in binding proteins as occurs in pregnancy. Because these proteins change, they can falsely elevate or lower the free T 4
assay result. The free T 4, as measured by equilibrium dialysis, is not affected by these protein changes. Trimester-specific normative data
for iodine-sufficient women using specific commercially 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 T 3 can be determined. The third-generation TSH assays
[46]
can differentiate profound from marginal suppression. Trimesterspecific TSH concentrations were obtained by Dashe and colleagues,
who determined these concentrations at each point during gestation in singleton and twin pregnancies. They constructed nomograms for
both using regression analysis and showed significantly lower TSH concentrations in the first 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
pregnancies 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 nonsymptomatic first-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
[8]
below the detection limit. Free T 3 and T 4 concentrations can be in the high-normal rangeearly in pregnancy because of the stimulatory
[2]
effects of hCG. Free T 4 levels tend to fall through the rest of pregnancy and occasionally to levels below those of nonpregnant women.
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 and therefore total hormone concentrations.
TABLE 47-1 -- FACTORS INFLUENCING THYROXINE-BINDING GLOBULIN

Factors Increasing TBG Levels Factors Decreasing TBG Levels
Oral contraceptives Testosterone
Pregnancy Nephrotic syndrome
Estrogen Cirrhosis
Hepatitis Glucocorticoids
Acute intermittent porphyria Severe illness
Inherited defect Inherited defect
TBG, thyroxine-binding globulin.
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 T 4 concentration along with an inappropriately elevated or
nonsuppressed 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
[48]
α-subunit levels. In a case reported by Anselmo and colleagues,[49] transient thyrotoxicosis 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 pregnancy 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 unaffected
[50]
infants born to affected mothers had lower birth weights, demonstrating a direct toxic effect of thyroid hormone excess on the fetus.
//Thyrotropin Receptor Antibodies
Thyrotropin Receptor Antibodies

Several 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 Antibodies
Antithyroid Antibodies
Patients with autoimmune thyroid disease commonly develop antibodies to thyroid antigens. The two most commonly determined
[51]
antibodies are those to thyroglobulin and to thyroid peroxidase (anti-TPO). Among nonpregnant women, the incidence of anti-TPO
antibodies is about 3%, with the incidence ranging from 5% to 15% among pregnant women. A substantial proportion of women with
[52,53]
positive anti-TPO antibodies in early pregnancy develop postpartum thyroiditis.
//Drugs and Thyroid Function
Drugs and Thyroid Function

Table 47-2 outlines drug effects on thyroid function and metabolism, absorption of thyroid hormones, and interpretation of thyroid function
tests. Iodine and lithium inhibit thyroid function. Propranolol and ipodate block T 4 to T 3 conversion, as do glucocorticoids; however,
glucocorticoids also reduce release of TSH from the pituitary, as do dopamine, dopamine agonists, and somatostatin. The antiseizure
medication phenytoin reduces total T 4 levels (up to 30%) by inhibiting the binding of thyroid hormones to binding proteins and increasing
T 4 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.
TABLE 47-2 -- EFFECTS OF DRUGS ON THYROID HORMONES AND FUNCTION TEST RESULTS
Inhibition of thyroid function
Iodine
Lithium
Inhibition of T 4 to T 3 conversion
Glucocorticoid
Ipodate
Propranolol
Amiodarone
Propylthiouracil
Increased level of TSH

Iodine
Lithium
Dopamine antagonists
Decreased level of TSH

Glucocorticoids
Dopamine agonists
Somatostatin
Inhibition of T 4 and T 3 binding to binding proteins

Phenytoin
Salicylates
Sulfonylureas
Inhibition of gastrointestinal absorption of thyroid

hormone
Ferrous sulfate
Sucralfate
Cholestyramine
Aluminum hydroxide
TSH, thyroid-stimulating hormone; T 3, l-triiodothyronine; T 4, l-thyroxine.
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
hypothyroidism and goiter, because the fetus acquires the capacity to escape from the acute Wolff-Chaikoff effect (i.e., decrease in
//Drugs and Thyroid Function
peroxidase activity and organification 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). Hypothyroidism 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
[54]
continue to use the medication.
//Nonthyroidal Illness and Thyroid Function
Nonthyroidal Illness and Thyroid Function
Nonthyroidal illness has been the topic of various reviews and commentaries.[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 T 4 to T 3 conversion (a
constant accompaniment of nonthyroidal illness), and abnormalities in binding and clearance of thyroid hormone. Reverse T 3 levels are
substantially elevated because of increased T 4 to reverse T 3 conversion and impaired metabolic clearance of reverse T 3. TSH
[55]
concentrations can be low, normal, or elevated, although seldom higher than 20 mU/L. The more severe the illness, the lower the T 4
values, and this relationship has been used as a prognostic indicator, because a high correlation has been found between a low T 4 value
[56]
and a fatal outcome. The best test for assessing thyroid function in severely or chronically ill patients is the free T 4 concentration.
Despite the low T 3 and total T 4 state, this situation does not represent true hypothyroidism, but rather an adaptation to stress, and it
should not be treated.
//Thyroid Dysfunction and Reproductive Disorders
Thyroid Dysfunction and Reproductive Disorders

Thyroid hormones are important for normal reproductive function. Deficiency of thyroid hormone can result in delayed sexual
[57]
development. As reviewed by Winters and Berga and Krassas,[58] all women with infertility and menstrual disturbances should have
thyroid function tests, usually T 4, T 3, and TSH. Women with type 1 diabetes, who have a relatively high incidence of hypothyroidism,
[59]
should probably undergo screening before conception. This topic has been reviewed by Trokoudes and coworkers.
Hyperthyroidism
Hyperthyroidism has been linked to oligomenorrhea, hypomenorrhea, amenorrhea, and infertility, although many thyrotoxic women remain
[60]
ovulatory. In one survey, only 21.5% of 214 thyrotoxic patients had menstrual disturbances, compared with 50% to 60% in older series.
Thyroxine upregulates the production of sex hormone–binding globulin. Elevated levels of circulating testosterone and estrogen may be
[61,62]
observed, and the clearance of testosterone is reduced. Gonadotropin concentrations can be tonically elevated. The substantial
weight loss seen in some hyperthyroid patients can affect the hypothalamicpituitary-gonadal axis and can contribute to the infertility of
severe hyperthyroidism.
//Hypothyroidism
Hypothyroidism
Hypothyroidism in fetal life does not affect the development of the reproductive tract, but during childhood, it leads to sexual immaturity
and usually a delay in puberty, followed by anovulatory cycles. Almost 25% of women with untreated hypothyroidism have menstrual
irregularities. Menorrhagia occurs frequently and can reflect interference with the endometrial maturational process and response to
[63]
ovarian steroids; it usually responds to thyroxine treatment. The increased miscarriage rate seen in hypothyroid patients may reflect
disrupted endometrial maturation. Hypothyroidism, through increased TRH, can be associated with hyperprolactinemia, which itself can
[64]
disrupt reproductive function and menstrual cyclicity, leading to oligomenorrhea or amenorrhea. Galactorrhea can sometimes be seen
[65]
in this setting, as can elevated levels of luteinizing hormone, possibly through diminished dopamine secretion.
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 suggested increased risk of miscarriage in the presence of thyroid
antibodies, even in the face of a euthyroid status. Although previous studies did not demonstrate benefit in using T 4 to treat euthyroid
[66–68]
women with recurrent spontaneous abortions, benefit was shown by Negro and colleagues[69] in a group of 115 antibody-positive
women, one half of whom received thyroxine. Treatment decreased miscarriages and prematurity by 75% and 69%, respectively. In a
[70]
thoughtful accompanying editorial, Glinoer stated that the statistical strength of the association between miscarriages and autoimmune
thyroid disease has been largely confirmed, 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 deficiency in thyroid hormone concentration or
reduced ability of maternal thyroid function to adapt adequately in women with autoimmune thyroid disease was the main reason for the
beneficial effects of thyroid hormone administration.
//Radioiodine and Gonadal Function
Radioiodine and Gonadal Function

The prevalence of infertility, premature births, miscarriage, and genetic damage in the offspring of women treated with radioactive iodine
[71,72]
for thyrotoxicosis does not seem to be increased. Although thyroid cancer doses of 131I may be associated with subsequent
[73]
menstrual irregularities, exposure to radioiodine does not appear to reduce fecundity. In a study of 32 women who conceived after 131I
131
treatment for thyroid cancer (resulting in 60 term deliveries), two children conceived within a year of I therapy had birth defects, but no
[74] 131
anomalies were seen in the remaining 58. Contraception has been recommended for 1 year after I treatment. In a large study,
[75]
Schlumberger and associates 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 first year of life
were not significantly different between pregnancies conceived before or after radioiodine therapy. Miscarriages were more common for
131
the women treated with I in the year preceding conception (40%).
131
All women need pregnancy tests before I treatment. Treatment late in the first trimester and in the second trimester may result in
131
irreversible hypothyroidism in the fetus. Lactating mothers who have received diagnostic or therapeutic doses of I should not
[76] [77]
breastfeed their infants. These topics are reviewed by Gorman and Berlin.
//Hyperthyroidism and Pregnancy
Hyperthyroidism and Pregnancy
Signs and Symptoms
The prevalence of hyperthyroidism in pregnant women ranges from 0.05% to 0.2%.[78] The signs and symptoms of mild to moderate
hyperthyroidism—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
[79]
thyrotoxicosis. Gastrointestinal symptoms such as severe nausea and excessive vomiting can accompany thyrotoxicosis in pregnancy,
as can diarrhea, myopathy, lymphadenopathy, and congestive heart failure.
//Diagnosis
Diagnosis
Biochemical confirmation of the hyperthyroid state can be obtained through laboratory measurement of free T 4, free T 3, and TSH.
Typically, elevated values of free T 4 and T 3 and greatly suppressed TSH values are found, but a normal free T 4 level can be seen in
cases of T 3 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 antithyroid antibodies (i.e., antithyroglobulin
and antithyroid peroxidase), but they are not specific to Graves disease. TSIs are considered to be the antibodies specific to Graves
[80]
disease and can be measured by bioassays or receptor assays.
//Differential Diagnosis
Differential Diagnosis
Causes 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 reflect
infiltrative ophthalmopathy of Graves disease. Graves disease is an autoimmune disease mediated by antibodies (i.e., TSIs) that activate
[81]
the TSH receptor and stimulate the thyroid follicular cell. It affects 3% of women of reproductive age.
TABLE 47-3 -- CAUSES OF HYPERTHYROIDISM IN PREGNANCY

Graves disease
Toxic adenoma
Toxic multinodular goiter
Hyperemesis gravidarum
Gestational trophoblastic
disease
TSH-producing pituitary tumor
Metastatic follicular cell
carcinoma
Exogenous T 4 and T 3
De Quervain (subacute)
thyroiditis
Painless lymphocytic thyroiditis
Struma ovarii
TSH, thyroid-stimulating hormone; T 3, l-triiodothyronine; T 4, l-thyroxine.
//Treatment
Treatment
The 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 pregnant women, preterm delivery, perinatal mortality, and
maternal heart failure were significantly increased among women who remained thyrotoxic. Thyroid hormone status at delivery correlated
[82]
directly with pregnancy outcome. In another study by Momotani and Ito,[83] hyperthyroidism 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
[84]
also been associated with uncontrolled hyperthyroidism.
Thionamide Therapy
Thionamide therapy has been reviewed by Cooper[85] 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 T 4 to T 3. The goal of therapy is to control the hyperthyroidism without causing fetal or
[87]
neonatal hypothyroidism. Maternal free T 4 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.,
[82]
600 mg or more) because the risk of uncontrolled maternal hyperthyroidism is greater than that of high-dose PTU. It can take 6 to 8
weeks for major clinical effects to manifest. After the patient is euthyroid (reflected by monthly free T 4 and free T 3 values), the dose of
PTU should be tapered (e.g., halved), with further reduction as the pregnancy 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
[88]
delivery. It has been suggested that a change from stimulatory to blocking antibody activity may contribute to this remission.
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
[89]
most serious side effect, develops in only 0.1%, occurring especially in older women and those receiving higher doses. All patients
experiencing 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.
[90]
Methimazole is not used in the United States. Although the transplacental passage is similar, methimazole may cause cutis aplasia, a
[91–93]
scalp deformity. Although rare, there are reports of methimazole and carbimazole embryopathy, with choanal atresia,
[94–97]
tracheoesophageal fistula, and facial anomalies.
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 uncontrolled 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
[84]
16.5 for the uncontrolled group. Similar findings related to preeclampsia, with an odds ratio of 4.7 for the controlled group. This was
[98]
confirmed by a later study. In other reports, higher frequencies of small-for-gestational-age births, congestive heart failure, and
[82,99]
stillbirths have been found. It is uncertain whether untreated Graves disease is associated with a higher frequency of congenital
[87,100]
malformation.
Infants of mothers receiving thionamides should be evaluated ultrasonographically for signs of hypothyroidism, such as goiter,
bradycardia, and intrauterine growth restriction. If needed, cordocentesis may be performed and fetal thyroid function determined;
[101]
reference ranges have been reported. Doses of PTU should be adjusted to keep free T 4 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 significantly 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
[87,102,103]
lactation. Antithyroid medication should be taken just after breastfeeding, allowing a 3- to 4-hour interval before the woman
lactates again.
β-Blockers
//Treatment
β-Blockers are useful for the control of adrenergic symptoms, particularly maternal heart rate. Propranolol is commonly used in doses of
20 to 40 mg two or three times daily, and it inhibits T 4 to T 3 conversion. Alternatively, atenolol (50 to 100 mg daily) may be used, and in an
[104]
emergency, esmolol, an ultra-short-acting cardioselective intravenous β-blocker, has been used successfully. Prolonged therapy with
β-blockers can be associated with intrauterine growth restriction, fetal bradycardia, and hypoglycemia.
Iodides
Iodides decrease circulating T 4 and T 3 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 benefit of inhibiting conversion of T 4 to T 3. 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-containing bronchodilators, and the drug amiodarone.
131
I thyroid ablation is contraindicated in pregnancy because the radioactive iodine is concentrated in the fetal thyroid after 10 to 12
131
weeks' gestation. If a woman inadvertently receives I during pregnancy, SSKI should be given immediately, along with PTU, to block
organification 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
[76]
benefit, SSKI and PTU treatment must be given within 7 to 10 days of exposure.
Surgery
In select cases of thyrotoxicosis with severe complications or noncompliance, 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
[105]
performed in the second trimester, although it can be done in the first or third trimester. The risks are those of anesthesia,
hypoparathyroidism, and recurrent laryngeal nerve paralysis.
Thyroid Storm
Thyroid storm is a life-threatening exacerbation of thyrotoxicosis. Criteria for its diagnosis have been introduced,[106] and the classic
findings are various degrees of thermoregulatory dysfunction, central nervous system effects (e.g., agitation, delirium, coma),
gastrointestinal dysfunction, 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
[107]
preeclampsia. Thyrotoxic cardiomyopathy may also lead to heart failure in pregnancy.[108] Intensive care treatment with fluid 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 five 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 T 4 to T 3
conversion. For tachycardia exceeding 120 beats/min, βblockers such as propranolol, labetalol, or esmolol may be used.[1] Table 47-4
summarizes the management of thyroid storm.
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 5 drops of supersaturated solution of potassium iodide every 8 hr or
PTU 500-1000 mg of intravenous sodium iodide infusion every 12 hr
Lithium Used if patient is allergic to iodine 300 mg every 6 hr
carbonate
Dexamethasone Given to block T 4 to T 3 conversion 2 mg every 6 hr for four doses
β -Blockers Given to control tachycardia ≥ 120 IV propranolol at 1 mg/min up to several doses until blockade is
beats/min (use cautiously if patient in heart achieved and concurrent 60 mg of propranolol (PO or NG tube)
failure) every 6 hours or
IV loading dose of 250-500 μ/kg of esmolol, followed by infusion at
50-100 μg/kg/min
//Treatment
IV, intravenous; NG, nasogastric; PO, orally; PTU, propylthiouracil.
//Subclinical Hyperthyroidism
Subclinical Hyperthyroidism
Subclinical hyperthyroidism, as defined by suppressed TSH and normal free T 4 and free T 3 levels, is also seen in pregnancy. In a study by Casey and associates,[109] 1.7% of women
screened had subclinical hyperthyroidism, which they defined as TSH values at or below the 2.5th percentile for gestational age and a free T 4 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 pregnancy was unwarranted.
//Fetal and Neonatal Hyperthyroidism
//Fetal and Neonatal Hyperthyroidism
Fetal and Neonatal Hyperthyroidism
The 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 continue 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.
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.
Maternal TSI levels in excess of 300% of control values are predictive of fetal hyperthyroidism[99] and should be measured at 28 to 30 weeks. The assay used should be a functional
[99,111]
one, because TSH-receptor antibodies are heterogeneous and can stimulate or block the TSH receptor. Neonatal syndromes have been caused by transplacental passage of
[112]
stimulating and blocking antibodies.
Fetal Thyrotoxicosis
Features of fetal thyrotoxicosis include a heart rate greater than 160 beats/min, growth retardation, advanced bone age, and craniosynostosis, all of which can be detected by
[113]
ultrasound examination. Occasionally, nonimmune fetal hydrops and fetal death occur with associated diminished subcutaneous fat and thyroid enlargement. In utero, most cases
[114]
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. Cordocentesis can be used for diagnosis and
for monitoring therapy. A combination of PTU and T 4 treats the fetal hyperthyroidism while keeping the mother euthyroid.
//Neonatal Thyrotoxicosis
Neonatal Thyrotoxicosis
Features of thyrotoxicosis in the neonate include hyperkinesis, diarrhea, poor weight gain, vomiting, exophthalmos, arrhythmias, cardiac failure, hypertension (systemic and
pulmonary), hepatosplenomegaly, thrombocytopenia, and craniosynostosis. The infant should be examined immediately after birth. Cord blood reflects the in utero environment, 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 T 4 to T 3 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
[115,116]
receptor.
//Hyperthyroidism Related to Human Chorionic Gonadotropin
Hyperthyroidism Related to Human Chorionic Gonadotropin

When hyperthyroidism is diagnosed during the first 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
[117]
tail, or molecules in which the 47-48 peptide bond in the β-subunit loop is nicked. This relationship is further complicated by differences in clearance rates of different hCG
[118]
glycoforms. 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
[9]
suppressed values in up to 20% of normal pregnancies. Twin pregnancies can be associated with biochemical hyperthyroidism, as may pregnancies complicated by trophoblastic
disease. Several clinical scenarios can arise and are described in the following sections.
Gestational Transient Thyrotoxicosis

Gestational transient thyrotoxicosis (GTT) occurs in the first trimester in women without a personal or family history of autoimmune disease. It results directly from hCG stimulation of
[8]
the thyroid. Glinoer and colleagues found an overall prevalence of GTT in 2.4% in a prospective cohort study between 8 and 14 weeks' gestation. Symptoms compatible with
thyrotoxicosis were often present, and elevated free T 4 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 Gravidarum
Hyperemesis Gravidarum
Hyperemesis gravidarum is a serious pregnancy complication associated with weight loss and severe dehydration, often necessitating hospitalization.[119] Biochemical hyperthyroidism
[120,121]
is found in most women with this condition. Whereas Goodwin and colleagues[120,121] found that the severity of disease varied directly with the hCG concentration, Wilson and
[122]
associates did not find 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 T 4 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
thyroid hormones. In patients who require treatment, PTU therapy can be attempted if tolerated; methimazole suppositories can also be used.
//Gestational Trophoblastic Disease
Gestational Trophoblastic Disease

Both 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 hydatidiform mole or choriocarcinoma restores thyroid function to normal. Treatment with
[124]
antithyroid drugs and β-blockers is frequently necessary, however, before surgical treatment of the mole.
//Recurrent Gestational Hyperthyroidism
Recurrent Gestational Hyperthyroidism
Cases 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 Hyperthyroidism
Other Causes of Hyperthyroidism

Much less common causes of hyperthyroidism include thyrotoxicosis factitia (i.e., ingestion of exogenous hormone surreptitiously); in such cases, serum thyroglobulin, which is
[127]
produced by the thyroid, is suppressed. Women with large nodular goiters may have hyperthyroidism 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 definitive 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 Deficiency, Hypothyroidism, and Pregnancy
Iodine Deficiency, Hypothyroidism, and Pregnancy

A 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 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 in areas of overt iodine
deficiency. Worldwide, it is the most common cause of mental retardation.
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.)
In the past few decades, the physiology of maternal and fetal iodine metabolism, thyroid hormone metabolism, and fetal brain development and the pathophysiology of iodine deficiency
have been unraveled. These findings have revealed a fascinating aspect of pregnancy physiology. Iodine deficiency and hypothyroidism in pregnancy continue to be a worldwide
[128–131]
problem worthy of resolution. This topic also has been a subject of numerous reviews. Even in the United States, iodine intake has declined, and 15% of women of
[132]
childbearing age and 7% of pregnant women were found to have urinary iodine excretions below 50 μg/L, indicative of moderate iodine deficiency.
Pregnancy is an environmental trigger for the thyroid machinery, inducing changes in people who live in geographic areas that have iodine deficiency. Four biochemical markers are
useful for following the changes induced:
1. Relative hypothyroxinemia
2. Preferential T 3 secretion as reflected by an elevated T 3/T 4 molar ratio
3. Increased TSH after the first trimester, progressing until term
4. Supranormal thyroglobulin concentrations correlating with gestational goitrogenesis
Goitrogenesis also occurs in the fetus, indicating the exquisite sensitivity of the fetal thyroid gland to the consequences of maternal iodine deficiency. 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 insufficiency of iodine intake throughout the gestation.
It appears that maternal thyroxine, traversing the placenta during the first trimester and subsequently, is necessary for fetal brain development. Even before fetal thyroid hormone
synthesis, T 3 receptors are found in fetal brain tissues, and local conversion of T 4 to T 3 can occur. Iodine deficiency perpetuates the process, because the fetus is less able to
synthesize thyroid hormones even when the fetal thyroid has developed.
In severe iodine deficiency (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 retardation and less in the way of neurologic deficits. The clinical picture is
that of severe thyroid failure with dwarfism, 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 first 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
[133]
when the iodine deficiency is corrected before the second trimester and, optimally, even before conception. In Africa, iodine deficiency is complicated by selenium deficiency. The
[134]
deficiency of selenium leads to accumulation of peroxide, and excess peroxide leads to destruction of thyroid cells and hypothyroidism. Selenium deficiency also induces
monodeiodinase I (a selenoenzyme) deficiency, resulting in reduced T 4 to T 3 conversion and increased availability of maternal T 4 for the fetal brain. This protective mechanism may
prevent the development of neurologic cretinism, and the combined iodine-selenium deficiency prevalent in Africa may help explain the predominance of the myxedematous type
observed there.
The neurologic abnormalities and mental retardation depend ultimately on the timing and severity of the brain insult. Endemic cretinism constitutes only the extreme expression of the
[135]
spectrum of physical and intellectual abnormalities. In a meta-analysis of 18 studies in areas of iodine deficiency, it appeared to be responsible for an IQ loss of 13.5 points. Even
[129]
borderline iodine deficiency, as seen in Europe, can be accompanied by impaired school achievements by apparently normal children, as reviewed by Glinoer.
Actions taken to eradicate iodine deficiency have prevented the occurrence of mental retardation in millions of infants throughout the world. In a study by Xue-Yi and coauthors[136] of a
severely iodine-deficient 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 first 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 bradycardia. She was also
profoundly hypothyroid and required intubation. 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 T 4 for 8 months until the antibody effect had worn off. Her physical growth
was normal. The outcome of severe thyroid hormone deficiency in utero was fetal distress, permanent auditory deficit, brain atrophy, and severely impaired neuromotor development
[137]
despite adequate neonatal treatment.
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 recommended intake for pregnancy and lactation is 200 μg/day. Even higher intakes (300 to
[138]
400 μg/day) have been suggested.
//Hypothyroidism
Hypothyroidism
Signs and Symptoms
Hypothyroidism occurs with a frequency of 1 case in 1600 to 2000 deliveries.[67] Population screening studies have revealed a higher incidence. In a study in the United States, serum
TSH levels were determined 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
[139]
found in 58% of these 49 women, compared with 11% of control euthyroid pregnant women. In a Japanese study, only 0.29% had an elevated TSH level.[140] In another U.S.
[141]
study, 1 infant in 1629 deliveries had hypothyroidism.
Women with hypothyroidism have higher pregnancy complication rates. As well as miscarriages, complications include preeclampsia, placental abruption, low birth weight, prematurity,
[142]
and stillbirths. 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 intolerance 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 reflexes.
Laboratory confirmation is obtained from an elevated TSH level, with or without suppressed free T 4. Test results for thyroid autoantibodies (antithyroglobulin and antithyroid
peroxidase) may be positive. Other laboratory abnormalities can include elevated levels of creatine phosphokinase, cholesterol, and carotene and liver function abnormalities. Patients
may have macrocytic or normochromic, normocytic anemia. Hypothyroidism may occur more frequently in pregnant women with type 1 diabetes, and T 4 replacement therapy can
[143]
increase insulin requirements.
//Differential Diagnosis
Differential Diagnosis
Hashimoto 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 characterized 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
[53]
almost all have antithyroid peroxidase antibodies. The goiter is firm and diffusely enlarged and painless, and the gland is infiltrated 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 hypothyroidism. Patients with other autoimmune disease also can develop Hashimoto thyroiditis.
131
Other important and common causes of hypothyroidism include I therapy, ablation for Graves disease, and thyroidectomy (e.g., for thyroid cancer). Of patients who receive 131I
[144]
therapy, 10% to 20% are hypothyroid within the first 6 months, and 2% to 4% become hypothyroid each year thereafter. Hypothyroidism can result from subacute 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, cholestyramine, 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 T 4 level is low.
//Treatment
Treatment
Hypothyroidism must be treated promptly, and a dose of 0.1 to 0.15 mg of T 4 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 T 4 need to be checked as
[145]
soon as pregnancy is established; the dose should be adjusted and rechecked in 4 to 8 weeks, because the requirements for thyroid hormone increase as early as the fifth 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
[145]
by the 20th week, 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
[146]
hypothyroidism, 9 required a higher T 4 dose, with a mean dose increase of 45%. In a review of 77 pregnancies in 65 hypothyroid women, serum TSH levels became abnormal in
131
70% of women with prior I ablation therapy and in 47% of women with chronic thyroiditis. When data from other studies were pooled, overall, TSH levels increased above normal in
[147,148]
45% with a mean daily thyroxine dose of 146 μg. It was estimated that the increment in dose could 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.
[149]
The causes of increased T 4 requirements include a real increased demand for T 4 in pregnancy in patients whose thyroid reserve is compromised and, in some cases, iron therapy.
[150]
Ferrous sulfate interferes with T 4 absorption and should be taken at a different time of day from thyroxine therapy. Patients with thyroid cancer whose target TSH concentration is
[150]
below the normal range almost uniformly require an increased dose to maintain their suppressed TSH levels, and they should be followed closely. 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.
[128,151,152]
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. In
[153]
1969, Man and Jones studied a cohort of 1349 children and concluded that mild maternal hypothyroidism alone was associated with lower IQ levels in the offspring. In 1990,
[154]
Matsuura and Konishi documented that fetal brain development is affected adversely when both mother and fetus have hypothyroidism caused by chronic autoimmune thyroiditis.
With the background of this information and the associations of iodine deficiency, its consequent maternal hypothyroxinemia, and abnormal fetal brain development, Haddow and
[151]
associates conducted a study measuring 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 hypothyroid 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 hypothyroidism in pregnancy. Fukushi and
[155]
coworkers reported on such screening in Japan and found hypothyroidism in 1 of 692 pregnancies.
[156]
In a study by Pop and colleagues, 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 T 4 levels, and lower scores on psychomotor tests were found in children of mothers whose free T 4 value was
[157,158]
below the 5th and 10th percentiles as measured at 12 weeks' gestation.
//Subclinical Hypothyroidism and Hypothyroxinemia
Subclinical Hypothyroidism and Hypothyroxinemia

Subclinical hypothyroidism is defined as an elevated TSH level when the free T 4 level is in the normal range. More than 90% of hypothyroidism 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
[159]
at 20 weeks' gestation or less. In this study, pregnancies 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.
[151]
Hypothyroidism has been associated with impaired neurodevelopment of the fetus. However, most of the patients in this study had a TSH level of 10 mU/L or greater, and most
had a low free T 4 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
[160]
pregnant women. The nuances of this debate were carefully addressed by Casey. Although a panel from the American Thyroid Association, the Endocrine Society, and the
American Association of Clinical Endocrinologists did not find sufficient evidence to recommend routine screening in pregnancy in 2003, leaders of the same societies later published a
[161]
consensus statement, recommending screening and treatment. The American College of Obstetricians and Gynecologists (ACOG) suggests it is premature to recommend universal
screening for hypothyroidism, because efficacy 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 hypothyroidism, an abnormal thyroid gland, type 1 diabetes, or personal history of autoimmune disease.
[162]
However, targeting high-risk cases may miss significant numbers with hypothyroidism, as was shown by Vaidya and coworkers. 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.
[158,163]
Isolated maternal hypothyroxinemia (i.e., low free T 4 and normal TSH levels) during early pregnancy has been associated with impaired neurodevelopment of the fetus. The
issue of detecting and treating isolated maternal hypothyroxinemia is an area of equal uncertainty. Unfortunately, assays of true free T 4 (e.g., equilibrium dialysis, ultrafiltration, gel
filtration) are expensive and labor intensive. Clinical laboratories use a variety of tests that estimate the free hormone concentrations in the presence of protein-bound hormone, and
[164]
they are binding protein dependent to some extent. This negatively affects the accuracy of free hormone assays. Free T 4 assays usually result in lower values in late pregnancy.
[165,166]
Nonetheless, in a “Clinical Perspectives” article in the Journal of Clinical Endocrinology and Metabolism, Morreale de Escobar and colleagues[167] made a compelling case
for screening pregnant women for hypothyroxinemia, pointing out that maternal T 4 (as opposed to T 3) is the required substrate for the ontogenetically regulated production of T 3 in the
amounts needed for optimal temporal and spatial development in different brain structures. This issue is important for women with relative iodine deficiency, because T 3 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 T 4 treatment for
subclinical hypothyroidism or hypothyroxinemia diagnosed during pregnancy. The primary end point is the intellectual function of the children and secondary end points include
determination of the frequency of pregnancy complications, including preterm delivery, preeclampsia, abruption, and stillbirth.
[67]
What do we do in the meantime? In an editorial by Brent accompanying the paper on low-risk versus high-risk case finding, it was felt that until the results of large, randomized trials
[69]
become available, the extant evidence supports the benefits of T 4 therapy, at least to reduce pregnancy loss and preterm delivery. This view was also held and previously stated by
[168]
Larsen. I recommend screening at least high-risk women (as defined by ACOG and others) for TSH and free T 4 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 Hypothyroidism
Fetal and Neonatal Hypothyroidism

The relationship between iodine deficiency and fetal development was previously discussed. Severe neurologic deficits also occur in children with congenital deficiency of thyroid
hormone unrelated to iodine deficiency. Neurologic development is impaired if infants are untreated before they are 3 months old. Screening of neonates for thyroid hormone deficiency
[29]
is mandatory in some states, and with early therapy, their development is reasonably normal. Causes include thyroid agenesis and inborn errors of metabolism, such as peroxidase
deficiency. Congenital pituitary and hypothalamic hypothyroidism also occur but are rare. Thyroid hormone deficiency can result from maternal blocking antibodies that are transferred
[169,170]
to the fetus and that block TSH action or thyroid growth and development.
Gruner and associates[171] reported a case of fetal goitrous hypothyroidism in which fetal TSH levels were determined on three occasions by cordocentesis to monitor weekly intra-
amniotic administration of T 4. This therapy was initiated to reduce the fetal goiter and polyhydramnios (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 T 4 necessary to correct hypothyroidism could more accurately be determined by cordocentesis than by
measurement of amniotic fluid hormone concentrations.
//Thyroid Nodules, Malignant Tumors, and Nontoxic Goiter in Pregnancy
Thyroid Nodules, Malignant Tumors, and Nontoxic Goiter in Pregnancy

Thyroid 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
[172]
incipient thyroid nodules increased from 15% in the first trimester to 24% after delivery, with an increase in the growth of existing nodules. 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 fine-needle aspiration biopsy (FNAB) in women between the
[173]
ages of 15 and 40 years seen at the Mayo Clinic revealed benign findings in 64% and suspicious findings in 12%; FNAB was positive for cancer in 7% and nondiagnostic in 17%.
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
[174]
which were diagnostic. Most (64%) were benign. Three (8%) were positive for papillary thyroid cancer, and nine (23%) were suspicious for papillary cancer or a follicular (Hurthle
[175]
cell) neoplasm. Comparable findings were reported by others.
The principles of nodular thyroid disease diagnosis in pregnancy resemble those for nonpregnant women. Serum TSH and free T 4 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, lymphadenopathy, or abnormal
calcification. 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
suspicious 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 suspicious and 100% for positive), and neck exploration should be performed at the soonest safe date. Figure 47-7 outlines the
decision-making process.
//Thyroid Nodules, Malignant Tumors, and Nontoxic Goiter in Pregnancy
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.)
[176]
The impact of pregnancy on papillary thyroid cancer was evaluated by Moosa and Mazzaferri. They compared outcomes in pregnant and nonpregnant women and found no
difference in the rates of recurrence, distant spread, or cause-specific mortality. Outcomes were similar when neck surgery was performed during or after pregnancy. A similar
[177]
conclusion was reached in a study of thyroid cancer cases from the New Mexico Tumor Registry. If medullary thyroid cancer is suspected, early surgery is advised.
//Postpartum Thyroid Disease
Postpartum Thyroid Disease

Autoimmune 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
[39]
postpartum women. Up to 60% of Graves patients in the reproductive years give a history of postpartum onset.[178] Most of the immune changes of pregnancy gradually return to
normal in the 12-month postpartum period. Unlike pregnancy, the major immune changes in T and B cells in the postpartum period are overall T-cell deactivation, enhanced T H1-type
T-cell function, loss of tolerance for fetal alloantigens, enhanced IgG secretion, and autoantibody secretion. Possible mechanisms explaining postpartum autoimmune exacerbation
[39]
suggested by Davies include a reduced number of fetal cells, leading to loss of maternal tolerance to remaining microchimeric cells, and a loss of placental major histocompatibility
complex-peptide complexes, which were inducing T-cell anergy during pregnancy.
Postpartum Graves Disease

The onset of Graves disease after delivery correlates with the development of TSIs. Peak antibody production is observed 3 to 6 months after delivery. Almost all patients with
persisting TSIs at the end of pregnancy have a recurrence of Graves if antithyroid drugs are withdrawn. The prevalence of postpartum Graves disease, which can be transient or
[179]
persistent, is estimated at 11% of those with postpartum thyroid dysfunction.
//Postpartum Thyroiditis
Postpartum Thyroiditis
The 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 first 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
[184]
schematically demonstrates this and the accompanying changes in serum thyroid antibody concentrations. A review of 11 studies of PPT 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
[185,186]
disorder, and patients with type 1 diabetes have an increased incidence, which was found to be approximately 25% in two North American studies. Women with a history of
PPT in a prior pregnancy had a 69% recurrence rate in the subsequent pregnancy.
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 fluctuate during and after pregnancy.
(From Smallridge RC, Fein HC, Hayship CC: Postpartum thyroiditis. Bridge Newslett Thyroid Found Am 3:3, 1988.)
Symptoms of the hyperthyroid phase of PPT include fatigue, palpitations, heat intolerance, and nervousness. This destructive hyperthyroid 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, depression, 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 recommend maintaining T 4 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.
[187]
The thyroid gland is enlarged in PPT, and thyroid hypoechogenicity appears to be the characteristic ultrasonographic finding. PPT is an autoimmune disorder, and there is an
[182]
association between it and HLA-DR3, HLA-DR4, and HLA-DR5 status. The lymphocytic infiltration is similar to that seen in Hashimoto thyroiditis. Stagnaro-Green reported that
33% of women who were antithyroid antibody positive in the first 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
//Postpartum Thyroiditis
levels, and high T 4 levels (released from destroyed thyroid cells) in the hyperthyroid phase, along with a profoundly suppressed radioactive iodine uptake (contraindicated 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 Thyroiditis
Depression and PPT are common postpartum events.[188] Four large-scale studies have been performed to evaluate their association. Harris and colleagues[189] 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.
[190]
Pop and associates evaluated 293 women during the third trimester 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 significant. Status of antibodies was not reported.
[191]
Harris and coauthors investigated the association between depression and PPT in 232 women (110 were thyroid antibody positive). The women had psychiatric assessment five
times during the first 28 weeks after delivery. No association was found between PPT and depression, but an association was found between depression and antibody positivity. They
concluded that 4% of women experience postpartum depression that has an autoimmune origin.
[192]
Pop and colleagues 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
[193]
depression. In a subsequent study, Pop and associates 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 demonstrated an association between PPT and depression,
whereas two demonstrated an association between thyroid antibodies and depression. The role of potential interventions such as T 4 therapy has not been evaluated systematically.
Hypothyroidism and Postpartum Thyroiditis

Recovery 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
[194]
years after delivery, Tachi and associates reported that 77% of the women recovered during the first 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
[195]
follow-up. A 23% incidence of permanent hypothyroidism at long-term follow-up (mean, 3.5 years) was also reported by Othman and coworkers. It is recommended that women with
a history of PPT be evaluated annually for the possible development of hypothyroidism.
Thyroiditis after Abortion
Several 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 hypothyroidism after a spontaneous miscarriage. After a subsequent term delivery, the patient became severely hypothyroid, and this condition remained
permanent.
Prevention and Screening of Postpartum Thyroiditis

Levothyroxine (0.1 mg daily) or iodide (0.15 mg daily) was administered 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 three groups, and the degree of postpartum elevation of thyroid peroxidase antibodies was
[198]
indistinguishable in the three groups.
Whether screening for PPT is worthwhile is a contentious issue. A “Therapeutic Controversy” article in the Journal of Clinical Endocrinology and Metabolism addressed this topic.[179]
Arguments for and against screening were presented. It was suggested that screening and treatment 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 undefined and that no cost-benefit
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
[186,199]
women with type 1 diabetes) should be screened.
//References
References
1. Casey BM, Leveno KJ: Thyroid disease in pregnancy. Obstet Gynecol 2006; 108:1283.
2. LeBeau SO, Mandel SJ: Thyroid disorders during pregnancy. Endocrinol Metab Clin North Am 2006; 35:117.
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 2007; 92(suppl):S1.
4. Brennan MD, Bahn RS: Thyroid hormones and illness. Endocr Pract 1998; 4:396.
5. DeGroot LJ: Dangerous dogmas in medicine: The non-thyroidal illness syndrome. J Clin Endocrinol Metab 1999; 84:151.
6. Brent GA: The molecular basis of thyroid hormone action. N Engl J Med 1994; 331:847.
7. Glinoer D: What happens to the normal thyroid during pregnancy?. Thyroid 1999; 9:631.
8. Glinoer D, De Nayer P, Robyn C, et al: Serum levels of intact human chorionic gonadotropin (hCG) and its free α and β subunits, in relation to maternal thyroid stimulation during
normal pregnancy. J Endocrinol Invest 1993; 16:881.
9. Grün JP, Meuris S, DeNayer P, et al: The thyrotropic role of human chorionic gonadotropin (hCG) in the early stages of twin (versus single) pregnancy. Clin
Endocrinol 1997; 46:719.
10. Burrow GN, Fisher DA, Larsen PR: Maternal and fetal thyroid function. N Engl J Med 1994; 331:1072.
11. Glinoer D, De Nayer P, Delange F, et al: A randomized trial for the treatment of mild iodine deficiency during pregnancy: Maternal and neonatal effects. J Clin Endocrinol
Metab 1995; 80:258.
12. Glinoer D: The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997; 18:404.
13. Levy RP, Newman M, Rejah LS, et al: The myth of goiter in pregnancy. Am J Obstet Gynecol 1980; 137:701.
14. Nelson M, Wickos GG, Caplan RH, et al: Thyroid gland size in pregnancy. J Reprod Med 1987; 32:888.
15. Brander A, Kivsaari L: Ultrasonography of the thyroid during pregnancy. J Clin Ultrasound 1989; 17:403.
16. Halnan KE: The radioiodine uptake of the human thyroid in pregnancy. Clin Sci 1958; 17:281.
17. Abdoul-Khair SA, Crooks J, Turnbull AC, et al: The physiological changes in thyroid function during pregnancy. Clin Sci 1964; 27:195.
18. Ferris TF: Renal disease. In: Burrow GN, Ferris TF, ed. Medical Complications During Pregnancy, Philadelphia: WB Saunders; 1988:277.
19. Beckers C: Iodine economy in and around pregnancy. In: Beckers C, Reinwein D, ed. 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 2000; 10:871.
//References
21. Radunovic N, Domez Y, Mandelbrot L, et al: Thyroid function in fetus and mother during the second half of normal pregnancy. Biol Neonate 1991; 59:139.
22. LaFranchi S: Thyroid function in the preterm infant. Thyroid 1999; 9:71.
23. Fisher DA: Hypothyroxinemia in premature infants: Is thyroxine treatment necessary?. Thyroid 1999; 9:715.
24. Bernal J, Perkonen F: Ontogenesis of the nuclear 3,5,3′-triiodothyronine receptor in the human fetal brain. Endocrinology 1984; 114:677.
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 1999; 84:493.
26. Vulsma T, Gons MH, de Vijlder JJ: Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J
Med 1989; 321:13.
27. Delange F, de Vilder JJ, Morreale de Escobar G, et al: Significance of early diagnostic data in congenital hypothyroidism: Report of the Subcommittee on Neonatal
Hypothyroidism of the European Thyroid Association. In: Delange F, Fisher DA, Glinoer D, ed. Research in Congenital Hypothyroidism, New York: Plenum Press; 1989:225-234.
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 2004; 9:3117.
29. Fisher DA, Polk DH: Development of the thyroid. Baillieres Clin Endocrinol Metab 1989; 3:627.
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 1977; 3:59.
31. Polk DH: Thyroid hormone effects on neonatal thermogenesis. Semin Perinatol 1988; 12:151.
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 1996; 443:821.
33. Vulsma Y, Kok JK: Prematurity-associated neurological and development abnormalities and neonatal thyroid function. N Engl J Med 1996; 3343:857.
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 2005; 90:4599.
35. Burrow GN, May PB, Spaulding SW, et al: TRH and dopamine interactions affecting pituitary hormone secretion. J Clin Endocrinol Metab 1977; 45:65.
36. Roti E, Gnudi A, Braverman LE: The placental transport, synthesis and metabolism of hormones and drugs, which affect thyroid function. Endocr Rev 1983; 4:131.
37. Ballard RA, Ballard PL, Creasy RK, et al: Respiratory disease in very- low-birthweight infants after prenatal thyrotropin-releasing hormone and
glucocorticoid. Lancet 1992; 339:510.
38. Romaguera J, Ramirez M, Adamsons K: Intra-amniotic thyroxine to accelerate fetal maturation. Semin Perinatol 1993; 17:260.
39. Davies TF: The thyroid immunology of the postpartum period. Thyroid 1999; 9:675.
40. Weetman AP: The immunology of pregnancy. Thyroid 1999; 9:643.
41. Nelson JL, Hughes KA, Smith AG, et al: Maternal fetal disparity in HLA class II alloantigens and the pregnancy induced amelioration of rheumatoid arthritis. N Engl J
Med 1993; 329:466.
42. Buyon JP, Nelson JL, Lockshine MD: The effects of pregnancy on autoimmune thyroid diseases. Clin Immunol Immunopathol 1996; 79:99.
43. Confavreuz C, Hutchinson M, Hours MH, et al: Rate of pregnancy related relapse in multiple sclerosis. New Engl J Med 1998; 339:285.
//References
44. Piccinini MP, Giudizi MG, Biagiotti R, et al: Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and
membrane CD30 expression in established Th1 cell clones. J Immunol 1995; 155:128.
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 1987; 65:689.
46. Dashe JS, Casey BM, Wells CE, et al: Thyroid stimulating hormone in singleton and twin pregnancy: Importance of gestational age-specific reference ranges. Obstet
Gynecol 2005; 106:753.
47. Glinoer D, Soto MF, Bouroux P, et al: Pregnancy in patients with mild thyroid abnormalities: Maternal and neonatal repercussions. J Clin Endocrinol Metab 1991; 73:421.
48. Weintraub BD: Inappropriate secretion of thyroid-stimulating hormone. Ann Intern Med 1981; 95:339.
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 2001; 86:4273.
50. Anselmo J, Cao D, Karrison T, et al: Fetal loss associated with excess thyroid hormone exposure. JAMA 2004; 292:691.
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 1989; 50:573.
52. Learoyd DL, Fund HYM, McGregor AM: Postpartum thyroid dysfunction. Thyroid 1992; 2:73.
53. Weetman AP, McGregor AM: Autoimmune thyroid disease: Further developments in our understanding. Endocr Rev 1994; 15:788.
54. Bartalena L, Bogazzi F, Braverman LE, et al: Effect of amiodarone administration during pregnancy on neonatal thyroid function and subsequent neurodevelopment. J Endocrinol
Invest 2001; 24:116.
55. Wartofsky L, Burman KD: Alterations in thyroid function in patients with systemic illness: The “euthyroid sick syndrome.”. Endocr Rev 1982; 3:164.
56. Brent GA, Hershman JM: Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. J Clin Endocrinol Metab 1986; 63:1.
57. Winters SJ, Berga SL: Gonadal dysfunction in patients with thyroid disease. Endocrinologist 1997; 7:167.
58. Krassas GE: Thyroid disease and female reproduction. Fertil Steril 2000; 74:1063.
59. Trokoudes KM, Skordis N, Picolos MK: Infertility and thyroid disorders. Curr Opin Obstet Gynecol 2006; 18:446.
60. Krassas GE, Pontikides N, Kaltsas TH, et al: Menstrual disturbances in thyroidism. Clin Endocrinol 1994; 40:641.
61. Akande EO, Hockaday TD: Plasma estrogen and luteinizing hormone concentrations in thyrotoxic menstrual disturbances. Proc R Soc Med 1972; 65:789.
62. Tanaka T, Tamin H, Kuma K, et al: Gonadotropin response to luteinizing hormone releasing hormone in hyperthyroid patients with menstrual
disturbances. Metabolism 1981; 30:323.
63. Wilansky DL, Greisman B: Early hypothyroidism in patients with menorrhagia. Am J Obstet Gynecol 1989; 160:673.
64. Del Pozo E, Wyss H, Tolis G, et al: Prolactin and deficient luteal function. Obstet Gynecol 1979; 53:282.
65. Thomas R, Reid RL: Thyroid disease and reproductive dysfunction. Obstet Gynecol 1987; 70:789.
66. Wasserstrum N, Anania CA: Perinatal consequences of maternal hypothyroidism in early pregnancy and inadequate replacement. Clin Endocrinol 1997; 42:343.
//References
67. Brent GA: Diagnosing thyroid dysfunction in pregnant women: Is case finding enough?. J Clin Endocrinol Metab 2007; 92:39.
68. Montoro MN: Management of hypothyroidism during pregnancy. Clin Obstet Gynecol 1997; 40:65.
69. Negro R, Fomoso G, Manieri T, et al: Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: Effects on obstetrical complications. J Clin
Endocrinol Metab 2006; 91:2587.
70. Glinoer D: Miscarriage in women with positive anti-TPO antibodies: Is thyroxine the answer [editorial]?. J Clin Endocrinol Metab 2006; 91:2500.
71. Greig WR: Radioactive iodine therapy for thyrotoxicosis. Br J Surg 1973; 758:765.
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 1975; 292:167.
73. Sioka C, Kouaklis G, Zafirakis , et al: Menstrual cycle disorders after therapy with iodine-131. Fertil Steril 2006; 86:625.
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 1994; 1:128.
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 1996; 37:606.
76. Gorman CA: Radio iodine and pregnancy. Thyroid 1999; 9:721.
77. Berlin L: Malpractice issues in radiology. Iodine 131I and the pregnant patient. Am J Radiol 2001; 176:869.
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 1998; 4:97.
79. Seely BL, Burrow GN: Thyrotoxicosis in pregnancy. Endocrinologist 1991; 7:409.
80. Costagliola S, Morgenthaler NG, Hoermann R, et al: Second generation assay for thyrotoxicosis receptor and bodies has superior diagnostic sensitivity for Graves disease. J Clin
81. Varner MW: Autoimmune disorders and pregnancy. Semin Perinatol 1991; 15:238.
82. Davis LE, Lucas MJ, Hankins GDV, et al: Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 1989; 160:63.
83. Momotani N, Ito K: Treatment of pregnant patients with Basedow's disease. Exp Clin Endocrinol 1991; 97:268.
84. Millar LK, Wing DA, Leung AS, et al: Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 1994; 84:946.
85. Cooper DS: Antithyroid drugs. N Engl J Med 2005; 352:905.
86. Clark SM, Saade GR, Sodgrass WR, et al: Pharmacokinetics and pharmacotherapy of thionamides in pregnancy. Ther Drug Monit 2006; 28:477.
87. Momotani N, Noh J, Oyanagi H, et al: Antithyroid drug therapy for Graves' disease during pregnancy. N Engl J Med 1986; 315:24.
88. Kung AWC, Jones BM: A change from stimulatory to blocking antibody activity in Graves' disease during pregnancy. J Clin Endocrinol Metab 1998; 8:514.
89. Cooper DS, Goldminz D, Levin AA, et al: Agranulocytosis associated with antithyroid drugs. Ann Intern Med 1983; 98:26.
90. Mortimer RH, Cannell GR, Addison RS, et al: Methimazole and propylthiouracil equally cover the perfused human term placental lobule. J Clin Endocrinol Metab 1997; 82:3099.
//References
91. Milham S, Elledge W: Maternal methimazole and congenital defects in children. Teratology 1972; 5:525.
92. Van Djihe UP, Heydendael RJ, De Kleine MR: Methimazole, carbimazole and congenital skin defects. Ann Intern Med 1987; 106:60.
93. Martinez-Frias ML, Cereijo A, Rodriguez-Pinella E, et al: Methimazole in animal feed and congenital aplasia cutis. Lancet 1992; 399:742.
94. Johnsson E, Larsson G, Ljunggren M: Severe malformations in infants born to hyperthyroid women on methimazole. Lancet 1997; 350:1520.
95. Clementi M, DiGianantonio E, Pelo E, et al: Methimazole embryopathy: Delineation of the phenotype. Am J Med Genet 1999; 83:43.
96. Di Gianantonio E, Schaefer C, Mastroiacovo PP, et al: Adverse effects of prenatal methimazole exposure. Teratology 2001; 64:262.
97. Wolf D, Foulds N, Daya H: Antenatal carbimazole and choanal atresia: A new embryopathy. Arch Otolaryngol Head Neck Surg 2006; 132:1009.
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
99. Mitsuda N, Tamaki H, Amino N, et al: Risk factors for development disorders in infants born to women with Graves' disease. Obstet Gynecol 1992; 80:359.
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 1994; 170:90.
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 1991; 324:532.
102. Kampmann JP, Johansen K, Hansen JM, et al: Propylthiouracil in human milk: Revision of a dogma. Lancet 1980; 1:736.
103. Azzizi F: Effect of methimazole treatment of maternal thyrotoxicosis on thyroid function in breast-feeding infants. J Pediatr 1996; 128:855.
104. Isley WL, Dahl S, Gibbs H: Use of esmolol in managing a thyrotoxic patient needing emergency surgery. Am J Med 1990; 89:122.
105. Burrow GN: The management of thyrotoxicosis in pregnancy. N Engl J Med 1985; 313:562.
106. Burch HB, Wartofsky L: Life threatening thyrotoxicosis: Thyroid storm. Endocrinol Metab Clin North Am 1993; 22:263.
107. Waltman PA, Brewer JM, Lobert S: Thyroid storm during pregnancy. A medical emergency. Crit Care Nurse 2004; 24:74.
108. Sheffield JS, Cunningham FG: Thyrotoxicosis and heart failure that complicate pregnancy. Am J Obstet Gynecol 2004; 190:211.
109. Casey BM, Dashe JS, Wells CE, et al: Clinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol 2006; 107:337.
110. Zimmerman D: Fetal and neonatal hyperthyroidism. Thyroid 1999; 9:727.
111. Clavel S, Madec A, Bornet H, et al: Anti TSH-receptor antibodies in pregnant patients with autoimmune thyroid disorder. BJOG 1990; 97:1003.
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 1983; 57:1036.
113. Becks GP, Burrow G: Thyroid disease and pregnancy. Med Clin North Am 1991; 75:121.
114. Houck JA, Davis RE, Sharma HM: Thyroid-stimulating immunoglobulin as a cause of recurrent intrauterine fetal death. Obstet Gynecol 1988; 71:1018.
115. Yoshimoto M, Nakayama Itoi , Baba P, et al: A case of neonatal McCune-Albright syndrome with Cushing syndrome and hyperthyroidism. Acta Pediatr Scand 1991; 89:984.
//References
116. Kopp P, Van Sande J, Parmer J, et al: Brief report: Congenital hyperthyroidism caused by a mutation in the thyrotropin receptor gene. N Engl J Med 1995; 322:150.
117. Hershman JM: Human chorionic gonadotropin and the thyroid: Hyperemesis gravidarum and trophoblastic tumors. Thyroid 1999; 9:653.
118. Talbot JA, Lambert A, Anobile LJ, et al: The nature of human chorionic gonadotropin glycoforms in gestational thyrotoxicosis. Clin Endocrinol 2001; 55:33.
119. Bashiri A, Neumann L, Maymon E, et al: Hyperemesis gravidarum: Epidemiologic features, complications and outcome. Eur J Obstet Gynecol Reprod Biol 1995; 63:135.
120. Goodwin TM, Montoro M, Mestman JH: The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum. J Clin Endocrinol Metab 1992; 75:1333.
121. Goodwin TM, Montoro M, Mestman JH: Transient hyperthyroidism and hyperemesis gravidarum: Clinical aspects. Am J Obstet Gynecol 1992; 167:648.
122. Wilson R, McKillop JH, MacLean M, et al: Thyroid function tests are rarely abnormal in patients with severe hyperemesis gravidarum. Clin Endocrinol (Oxf) 1992; 37:331.
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 Endocrinol Metab 1993; 76:70.
124. Morgan LS: Hormonally active gynecologic tumors. Semin Surg Oncol 1990; 6:83.
125. Nader S, Mastrobattista J: Recurrent hyperthyroidism in consecutive pregnancies characterized by hyperemesis. Thyroid 1996; 6:465.
126. Rodien P, Bremont C, Sanson M-LR, et al: Familial gestational hyperthyroidism caused by a mutant thyrotropic receptor hypersensitive to human chorionic gonadotropin. N Engl
J Med 1998; 339:1823.
127. Mariotti S, Martino E, Cupini C: Low serum thyroglobulin as a clue to the diagnosis of thyrotoxicosis factitia. N Engl J Med 1982; 307:410.
128. Lazarus JH: Thyroid hormone and intellectual development: A clinician's view. Thyroid 1999; 9:659.
129. Glinoer D: Pregnancy and iodine. Thyroid 2001; 11:471.
130. Dunn JT, Delange F: Damaged reproduction: The most important consequence of iodine deficiency. J Clin Endocrinol Metab 2001; 86:2360.
131. Delange F, de Benoist B, Pretell E, et al: Iodine deficiency in the world: Where do we stand at the turn of the century?. Thyroid 2001; 11:437.
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 1998; 83:3401.
133. Pharoah PQ, Butterfield IH, Hetzel BS: Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet 1971; 1:308.
134. Vanderpas JB, Contempré B, Dvale NL, et al: Iodine and selenium deficiency associated with cretinism in Northern Zaire. Am J Clinic Nutr 1990; 52:1087.
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 Deficiency,
New York: Cognizant Communication; 1994:195.
136. Xue-Yi C, Xin-Min J, Zhi-Hong D, et al: Time of vulnerability of the brain to iodine deficiency in endemic cretinism. N Engl J Med 1994; 331:1739.
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
138. Utiger RD: Iodine nutrition: More is better. N Engl J Med 2006; 354:26.
139. Klein RZ, Haddow JE, Faix JD, et al: Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol 1991; 35:41.
//References
140. Kamijo K, Saito T, Saito M, et al: Transient subclinical hypothyroidism in early pregnancy. Endocrinol Jpn 1990; 37:387.
141. Leung AS, Millar LK, Koonings PP, et al: Perinatal outcome in hypothyroid patients. Obstet Gynecol 1993; 81:349.
142. Davis LE, Leveno KJ, Cunningham FG: Hypothyroidism complicating pregnancy. Obstet Gynecol 1988; 72:108.
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 1988; 159:442.
144. Werner S: Modification of the classification of eye changes of Graves' disease: Recommendation of the Ad Hoc Committee of the American Thyroid Association. J Clin
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 2004; 351:241.
146. Mandel SJ, Larsen PR, Seely EW, et al: Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990; 323:91.
147. Kaplan MM: Monitoring thyroxine treatment during pregnancy. Thyroid 1992; 2:147.
148. Kaplan MM: Management of thyroxine therapy during pregnancy. Endocr Pract 1996; 2:281.
149. Mestman JH: Thyroid disease in pregnancy other than Graves' and post partum thyroid dysfunction. Endocrinologist 1999; 9:294.
150. Brent GA: Maternal hypothyroidism recognition and management. Thyroid 1999; 9:661.
151. Haddow JE, Palomaki GE, Alan WC, et al: Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J
Med 1999; 341:549.
152. Klein RZ, Mitchell ML: Maternal hypothyroidism and child development. Horm Res 1999; 52:55.
153. Man EB, Jones WS: Thyroid function in human pregnancy. V. Incidence of maternal serum low butanol-extractable iodines and of normal gestational TBG and TBPA capacities:
Retardation of 8-month old infants. Am J Obstet Gynecol 1969; 104:898.
154. Matsuura N, Konishi J: Transient hypothyroidism in infants born to mothers with chronic thyroiditis'a nationwide study of 23 cases. Endocrinol Jpn 1990; 37:767.
155. Fukushi M, Honma IC, Fujita K: Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child [letter]. N Engl J Med 1999; 341:556.
156. Pop VJM, deVries E, van Baar AL, et al: Maternal thyroid peroxidase antibodies during pregnancy: A marker of impaired child development?. J Clin Endocrinol
Metab 1995; 80:3561.
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 concentrations during early pregnancy associated with impaired psychomotor development in infancy. Clin
159. Casey BM, Dashe JS, Wells CE, et al: Clinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005; 105:239.
160. Casey BM: Subclinical hypothyroidism and pregnancy. Obstet Gynecol Surv 2006; 61:415.
161. Gharib H, Cobin RH, Dickey RA: Subclinical hypothyroidism during pregnancy: Position statement from the American Association of Clinical Endocrinologists. Endocr
Pract 1999; 5:367.
//References
162. Vaidya B, Anthony S, Bilous M, et al: Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high risk case finding. J Clin Endocrinol
Metab 2007; 92:203.
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
164. Demers L, Spencer CA: Laboratory medicine practice guidelines: Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13:6.
165. Glinoer D, De Nayer P, Bourdoux P, et al: Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 1990; 71:276.
166. Mandel SJ, Spencer CA, Hollowell JG: Are detection and treatment of thyroid insufficiency in pregnancy feasible?. Thyroid 2005; 15:44.
167. Morreale de Escobar G, Obregon MJ, Escobar del Rey F: Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia?. J Clin
168. Larsen PR: Detecting and treating hypothyroidism during pregnancy. Nat Clin Pract Endocrinol Metab 2006; 2:59.
169. Dussault JH, Rousseau F: Immunologically mediated hypothyroidism. Endocrinol Metab Clin North Am 1987; 16:417.
170. Bogner U, Gruters A, Sigle B, et al: Cytotoxic antibodies in congenital hypothyroidism. J Clin Endocrinol Metab 1989; 68:671.
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 2001; 16:47.
172. Kung A, Chau M, Lao T, et al: The effect of pregnancy on thyroid nodule formation. J Clin Endocrinol Metab 2002; 87:1010.
173. Hay ID: Nodular thyroid disease diagnosed during pregnancy: How and when to treat. Thyroid 1999; 9:667.
174. Tan GH, Gharib H, Goellner JR, et al: Management of thyroid nodules in pregnancy. Arch Intern Med 1996; 156:2317.
175. Marley EF, Oertil YC: Fine needle aspiration of thyroid lesions in 57 pregnant and postpartum women. Diagn Cytopathol 1997; 16:122.
176. Moosa M, Mazzaferri EL: Outcome of differentiated thyroid cancer diagnosed in pregnant women. J Clin Endocrinol Metab 1997; 82:2862.
177. Herzon FS, Morris DM, Segal MN, et al: Coexistent thyroid cancer and pregnancy. Arch Otolaryngol Head Neck Surg 1994; 120:1191.
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
179. Amino N, Tada H, Hidaka Y, et al: Therapeutic controversy. Screening for postpartum thyroiditis. J Clin Endocrinal Metab 1999; 84:1813.
180. Lazarus JH: Clinical manifestations of postpartum thyroid disease. Thyroid 1999; 9:685.
181. Lucas A, Pizarro E, Granada ML, et al: Postpartum thyroiditis: Epidemiology and clinical evolution in a non-selected population. Thyroid 2000; 10:71.
182. Stagnaro-Green AS: Recognizing, understanding and treating postpartum thyroiditis. Endocrinol Metab Clinics NA 2000; 29:417.
183. Pearce EN, Farwell AP, Braverman LE: Thyroiditis [published erratum appears in N Engl J Med 349:62, 2003]. N Engl J Med 2003; 348:2646.
184. Stagnaro-Green AS: Postpartum thyroiditis: Prevalence, etiology, and clinical implications. Thyroid Today 1993; 16:1.
185. Gerstein HC: Incidence of postpartum thyroid dysfunction in patients with type I diabetes mellitus. Ann Intern Med 1993; 188:419.
//References
186. Alvarez-Marfany M, Roman SH, Drexler AJ, et al: Long-term prospective study of postpartum thyroid dysfunction in women with insulin dependent diabetes mellitus. J Clin
187. Adams H, Jones MC, Othman S, et al: The sonographic appearances in postpartum thyroiditis. Clin Radiol 1992; l45:311.
188. Pedersen CA: Postpartum mood and anxiety disorders: A guide for the non-psychiatric clinician with an aside on thyroid associations with postpartum
mood. Thyroid 1999; 9:691.
189. Harris B, Fung H, Johns S, et al: Transient postpartum thyroid dysfunction and postnatal depression. J Affect Disord 1989; 17:243.
190. Pop VJM, de Rooy HAM, Vader HL, et al: Postpartum thyroid dysfunction and depression in an unselected population. N Engl J Med 1991; 324:1815.
191. Harris B, Othman S, Davies JA, et al: Association between postpartum thyroid dysfunction and thyroid antibodies and depression. BMJ 1992; 305:152.
192. Pop VJM, de Rooy HAM, Vader VL, et al: Microsomal antibodies during gestation in relation to postpartum thyroid dysfunction and depression. Acta Endocrinol 1993; 129:26.
193. Pop VJM, Maarteens LH, Levsink G, et al: Are autoimmune thyroid dysfunction and depression related?. J Clin Endocrinol Metab 1998; 83:3194.
194. Tachi J, Amino N, Tamaski H, et al: Long-term follow-up and HLA association in patients with postpartum hypothyroidism. J Clin Endocrinol Metab 1988; 66:480.
195. Othman S, Phillips DL, Parkes AB, et al: Long-term follow-up of postpartum thyroiditis. Clin Endocrinol 1990; 32:559.
196. Stagnaro-Green AS: Post-miscarriage thyroid dysfunction. Obstet Gynecol 1992; 803:490.
197. Marqusee E, Hill JA, Mandel SJ: Thyroiditis after pregnancy loss. J Clin Endocrinol Metab 1997; 82:2455.
198. Kampe O, Jansson R, Karlsson FA: Effects of L-thyroxine and iodide on the development of autoimmune postpartum thyroiditis. J Clin Endocrinol Metab 1990; 70:1014.
199. Weetman AP: Editorial: Insulin-dependent diabetes mellitus and postpartum thyroiditis: An important association. J Clin Endocrinol Metab 1994; 79:7.

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/Thyroid Disease and Pregnancy/Maternal-Fetal Thyroid Physiology

Chapter 47 – Thyroid Disease and Pregnancy

Maternal-Fetal Thyroid Physiology

Normal Thyroid Physiology

Maternal Thyroid Physiology

Iodine Deficiency and Goiter

Iodine Metabolism in Pregnancy

Placental-Fetal Thyroid Physiology

Placental Transfer of Thyroid Hormones

Neonatal Thyroid Function

Placental Transfer of Drugs Affecting Thyroid Function

Pregnancy, the Immune System, and Thyroid Disease

Laboratory Evaluation of Thyroid Function during Pregnancy

Thyrotropin and Thyroid Hormones

TABLE 47-1 -- FACTORS INFLUENCING THYROXINE-BINDING GLOBULIN

TBG, thyroxine-binding globulin.

Thyrotropin Receptor Antibodies

Drugs and Thyroid Function

Increased level of TSH

Decreased level of TSH

Inhibition of T 4 and T 3 binding to binding proteins

Inhibition of gastrointestinal absorption of thyroid

TSH, thyroid-stimulating hormone; T 3, l-triiodothyronine; T 4, l-thyroxine.

Nonthyroidal Illness and Thyroid Function

Thyroid Dysfunction and Reproductive Disorders

Radioiodine and Gonadal Function

Hyperthyroidism and Pregnancy

Signs and Symptoms

TABLE 47-3 -- CAUSES OF HYPERTHYROIDISM IN PREGNANCY

TSH, thyroid-stimulating hormone; T 3, l-triiodothyronine; T 4, l-thyroxine.

TABLE 47-4 -- TREATMENT OF THYROID STORM

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

Fetal and Neonatal Hyperthyroidism

Hyperthyroidism Related to Human Chorionic Gonadotropin

Gestational Transient Thyrotoxicosis

Gestational Trophoblastic Disease

Recurrent Gestational Hyperthyroidism

Other Causes of Hyperthyroidism

Iodine Deficiency, Hypothyroidism, and Pregnancy

Signs and Symptoms

Subclinical Hypothyroidism and Hypothyroxinemia

Fetal and Neonatal Hypothyroidism

Thyroid Nodules, Malignant Tumors, and Nontoxic Goiter in Pregnancy

Postpartum Thyroid Disease

Postpartum Graves Disease

Depression and Postpartum Thyroiditis

Hypothyroidism and Postpartum Thyroiditis

Thyroiditis after Abortion

Prevention and Screening of Postpartum Thyroiditis

40. Weetman AP: The immunology of pregnancy. Thyroid 1999; 9:643.

85. Cooper DS: Antithyroid drugs. N Engl J Med 2005; 352:905.

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

129. Glinoer D: Pregnancy and iodine. Thyroid 2001; 11:471.

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