1. Chapter 47
Thyroid Disease and Pregnancy
Shahla Nader, MD
Thyroid disorders are among the most common endocrinopathies in thyroid growth, differentiation, and all phases of iodine metabolism
young women of childbearing age. In large areas of the world, iodine from uptake of iodine to secretion of the two thyroid hormones. In
deficiency is the predominant cause of these disorders. In the Western the nonpregnant state, 80 to 100 μg of iodine are taken up by the gland
Hemisphere, these disorders are most often related to altered immu- daily. Dietary iodine is reduced to iodide, which is absorbed and cleared
nity. The hormonal and immunologic perturbations of pregnancy and by the kidney (80%) and thyroid (20%). Iodide is actively trapped by
the postpartum period and the dependence of the fetus on maternal the thyroid and is the rate-limiting step in hormone biosynthesis. The
iodine and thyroid hormone have profound influences on maternal iodide is converted back to iodine and organified by binding to tyrosyl
thyroid function and consequently on fetal well-being. Appropriate residues, which are part of the glycoprotein thyroglobulin. This process
antepartum and postpartum care requires a basic knowledge of thyroid requires the enzyme thyroid peroxidase. Iodination can give rise to
function, its alteration in pregnancy, and the more common thyroid monoiodotyrosine or diiodotyrosine, with the ratio depending on pre-
diseases afflicting women in the setting of pregnancy, all of which are vailing iodine availability. Coupling of two diiodotyrosine molecules
addressed in this chapter. The combination of thyroid disease and forms T4, and one diiodotyrosine and one monoiodotyrosine form T3.
pregnancy has been the topic of several reviews,1,2 and the Endocrine Thyroglobulin is extruded into the colloid space at the center of the
Society’s guidelines for management of thyroid dysfunction during follicle, and thyroid hormone is stored as colloid.
pregnancy and after delivery have recently been published.3 Hormone secretion by thyroid cells, which is also under TSH
control, involves digestion of thyroglobulin and extrusion of T4 and T3
into the capillaries. Daily secretion rates approximate 90 μg of T4 and
30 μg of T3. Both circulate highly bound to protein (mainly thyroxine-
Maternal-Fetal Thyroid binding globulin [TBG]), with less than 1% in free form (0.3% of T3
and 0.03% of T4). Other binding proteins include thyroxine-binding
Physiology prealbumin and albumin. It is the free hormone that enters cells and
is active.
Normal Thyroid Physiology Whereas T4 is completely thyroidal in origin, only approximately
The thyroid gland is located in the anterior neck below the hyoid bone 20% of T3 comes directly from the thyroid. Thyroxine is metabolized
and above the sternal notch. Consisting of two lobes and connected by in most tissues (particularly in the liver and kidneys) to T3 by deiodin-
the isthmus, it weighs approximately 20 to 25 g. Each lobe is divided ation. It is also metabolized to reverse T3, a metabolically inactive
into lobules, each of which contains 20 to 40 follicles. The follicle hormone. Removal of an iodine by 5′ monodeiodination from the
consists of follicular cells, which surround a glycoprotein material outer ring of T4 results in T3, which is metabolically active. When iodine
called colloid. is removed from the inner ring, reverse T3 is produced (Fig. 47-1)
The hypothalamic-pituitary axis governs the production of thyroid Monodeiodinase type I and type II catalyze the formation of T3, whereas
hormone by the follicular cells. Tonic stimulation of thyrotropin- reverse T3 is catalyzed by monodeiodinase type III. Normally, approxi-
releasing hormone (TRH) is required to maintain normal thyroid mately 35% of T4 is converted to T3, and 40% is converted to reverse
function, and hypothalamic injury or disruption of the stalk results in T3, but this balance is shifted in favor of the metabolically inert reverse
hypothyroidism. TRH, a tripeptide, is produced in the paraventricular T3 in illness, starvation, or other catabolic states.4,5 About 80% of cir-
nucleus of the hypothalamus, and its local production as determined culating T3 is derived from peripheral conversion. The half-life of T4 is
by mRNA is inversely related to concentrations of circulating thyroid 1 week; 5 to 6 weeks are necessary before a change in dose of T4 therapy
hormones. Traversing the pituitary stalk, TRH is delivered to the pitu- is reflected in steady-state T4 values. The half-life of T3 is 1 day.
itary thyrotroph by the pituitary portal circulation, and it affects Free thyroid hormone enters the cell and binds to nuclear receptors
the production and release of thyrotropin (i.e., thyroid-stimulating and in this way signals its cellular responses.6 The affinity of T3 for
hormone [TSH]). A glycoprotein, TSH is composed of α and β sub- nuclear receptors is tenfold that of T4, which helps to explain the
units, and the β subunit confers specificity. Control of TSH secretion greater biologic activity of T3. Thyroid hormone receptors belong to a
occurs by negative feedback (from circulating thyroid hormone, soma- large superfamily of nuclear-hormone receptors that include the
tostatin, dopamine) or by stimulation by TRH. steroid hormone, vitamin D, and retinoic acid receptors. Thyroid hor-
Thyroid gland production of thyroxine (T4) and triiodothyronine mones have diverse effects on cellular growth, development, and
(T3) is regulated by TSH. On binding to its receptor, TSH induces metabolism. The major effects of thyroid hormones are genomic,

2. 996 CHAPTER 47 Thyroid Disease and Pregnancy
I I NH2
3′ 3′
T4 HO 5′
O 5′
CH2 CH COOH
I I
I I NH2 I I NH2
T3 HO O CH2 CH COOH rT3 HO O CH2 CH COOH
I I
FIGURE 47-1 Iodine removal. Removal of an iodine atom by 5′-monodeiodination from the outer ring of
thyroxine (T4) results in the formation of metabolically active triiodothyronine (T3). Removal of an iodine atom
from the inner ring results in formation of the metabolically inactive reverse triiodothyronine (rT3).
stimulating transcription and translation of new proteins in a concen- state of iodine sufficiency. This does not apply when thyroid function
tration- and time-dependent manner. is compromised or iodine supply is insufficient.
Maternal Thyroid Physiology Iodine Deficiency and Goiter
Pregnancy alters the thyroidal economy, and the hormonal changes of Increased vascularity and some glandular hyperplasia can result in
pregnancy result in profound alterations in the biochemical parame- mild thyroid enlargement, but frank goiter occurs because of iodine
ters of thyroid function. This section reviews maternal thyroid physiol- deficiency or other thyroidal disease. Although iodine deficiency is
ogy, the role of maternal hormones in fetal growth and development, usually not a problem in the United States, Japan, and parts of Europe,
and the development of the fetal hypothalamic-pituitary-thyroid axis. 1 to 1.5 billion people in the world are at risk, with 500 million living
This topic was reviewed by Glinoer.7 in areas of overt iodine deficiency. The World Health Organization
Three series of events occur at different times during gestation. recommends 150 μg iodine per day for adults and 200 μg for pregnant
Starting in the first half of gestation and continuing until term, there women. There is increased renal iodine clearance during pregnancy,
is an increase in TBG, a direct effect of increasing circulating estrogen and in the latter part of gestation, a significant amount of iodine is
concentrations. Basal levels increase twofold to threefold. This increase diverted toward the fetoplacental unit to allow the fetal thyroid to
is accompanied by a trend toward lower free hormone concentrations produce its own thyroid hormones. This physiologic adaptation occurs
(T4 and T3), which results in stimulation of the hypothalamic- easily with minimal hypothyroxinemia and no goiter formation in
pituitary-thyroid axis. Under conditions of iodine sufficiency, the areas of iodine sufficiency. Through hypothalamic-pituitary feedback,
decrease in free hormone levels is marginal (10% to 15% on average). borderline iodine intake chronically enhances thyroid stimulation.
When the supply of iodine is insufficient, more pronounced effects The iodine deficiency manifests as greater hypothyroxinemia, which
occur, and these are addressed in later sections. There is usually a trend increases TSH and thyroglobulin levels and produces thyroid hyper-
toward a slight increase in TSH between the first trimester and term. trophy (Fig. 47-4).
The second event takes place transiently during the first trimester In a study of otherwise healthy pregnant women living under con-
and is a consequence of thyroid stimulation by increasing concentra- ditions of relative iodine restriction, thyroid volume, as assessed by
tions of human chorionic gonadotropin (hCG). As hCG peaks late in ultrasonography, increased an average of 30% during pregnancy.11 In
the first trimester, there is partial inhibition of the pituitary and tran- a selected group of these women with goitrogenesis, follow-up a year
sient lowering of TSH between 8 and 14 weeks’ gestation (Fig. 47-2). after delivery did not show a return of thyroid volumes to those found
In about 20% of women, TSH falls below the lower limit of normal, in early pregnancy. Iodine intake should also be increased after deliv-
and these women often have significantly higher hCG concentrations.8 ery, especially in breastfeeding women. Ultrasonography of neonates
The stimulatory action of hCG has been broadly quantified; an revealed that thyroid volume was 38% larger in neonates of untreated
increment of 10,000 IU/L is associated with a lowering of basal mothers compared with neonates of mothers treated with iodine
TSH of 0.1 mU/L. In most normal pregnancies, this is of minor supplementation.12
consequence.9 Other than iodine deficiency, goiter in pregnancy can be related to
In the third series of events, alterations in the peripheral metabo- the following:
lism of thyroid hormone occur throughout pregnancy but are more
prominent in the second half. Three enzymes deiodinate thyroid hor- Graves disease
mones: deiodinase types I, II, and III. Type I is not significantly modi- Hashimoto thyroiditis
fied. Type II, which is expressed in the placenta, can maintain T3 Excessive iodine intake
production locally, which can be critical when maternal T4 concentra- Lymphocytic thyroiditis
tions are reduced. Type III is also found abundantly in the placenta, Thyroid cancer
and it catalyzes the conversion of T4 to reverse T3 and conversion of T3 Lymphoma
to T2; this abundance may explain the low T3 and high reverse T3 con- Therapy with lithium or thionamides
centrations characteristic of fetal thyroid hormone metabolism.10
These physiologic adaptations to pregnancy, depicted in Figure In the United States, clinical studies of pregnant women and non-
47-3, are attained without difficulty by the normal thyroid gland in a pregnant controls have not revealed an increase in goiter during preg-

3. CHAPTER 47 Thyroid Disease and Pregnancy 997
Mother
Hypothalamus
TBG
TRH
Total T4
Pituitary
TSH
hCG
Free T4
hCG Thyroid
Thyrotropin
T4, T3
Liver
Fetus
TBG Free hormones
TBG
Estrogen
Total T4
Placenta Placental Deiodinases
Type II - T4 to T3
Thyrotropin Type III - T4 to reverse T3
Free T4
Total T3
Free T3
FIGURE 47-3 Physiologic adaptation to pregnancy. Schematic
representation of the physiologic adaptation to pregnancy shows
10 20 30 40 increased thyroxine-binding globulin (TBG) concentrations, increased
Week of pregnancy levels of human chorionic gonadotropin (hCG) with its thyrotropin-like
activity, and alterations in the peripheral metabolism of thyroid
FIGURE 47-2 Relative changes in maternal and fetal thyroid hormones in the placenta. TRH, thyrotropin-releasing hormone; TSH,
function during pregnancy. The effects of pregnancy on the thyroid-stimulating hormone, T4, thyroxine, T3, triiodothyronine.
mother include a marked and early increase in hepatic production of (Adapted from Glinoer D: What happens to the normal thyroid during
thyroxine-binding globulin (TBG) and placental production of human pregnancy? Thyroid 9:631, 1999.)
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 of increased renal blood flow and an increase in glomerular filtration
maternal secretion of thyrotropin. (Reprinted by permission from rate of as much as 50%.18 If iodine excretion is greater than 100 μg
Burrow GN, Fisher DA, Larsen PR: Maternal and fetal thyroid in a 24-hour period, the patient’s iodine intake is assumed to be
function. N Engl J Med 331:1072, 1994.) sufficient.19f
nancy.13 Ultrasound studies from other areas replete with iodine have
confirmed these findings.14,15 Placental-Fetal Thyroid
Physiology
Iodine Metabolism in Pregnancy The thyroid gland forms as a midline outpouching of the anterior
Although radioactive iodine is absolutely contraindicated in preg- pharyngeal floor, migrates caudally, and reaches its final position by 7
nancy, early studies using 132I showed a threefold increase in thyroidal weeks’ gestation. Lateral contributions from the fourth and fifth pha-
iodine clearance in pregnant women. Another set of studies enrolling ryngeal pouches give it its bilateral shape by 8 to 9 weeks’ gestation.
25 pregnant women also revealed increased radioactive iodine uptake Active trapping of iodide is detectable by week 12, and the first indica-
during pregnancy compared with the nonpregnant or postpartum tion of T4 production is detectable by week 14. Hypothalamic TRH is
state.16,17 The mean renal iodine clearance almost doubles because detectable at weeks 8 to 9, and the pituitary portal circulation is func-

4. 998 CHAPTER 47 Thyroid Disease and Pregnancy
It appears that the first phase of maximum growth velocity of
20
developing brain structures—neuronal multiplication and organiza-
tion occurring during the second trimester—corresponds to a phase
during which the supply of thyroid hormones to the fetus is almost
exclusively of maternal origin.20 In the second phase of maximum fetal
15 brain growth velocity, occurring from the third trimester to 2 to 3 years
Thyroid hypertrophy (%)
postnatally, the supply of thyroid hormone is of fetal and neonatal
origin. Low maternal thyroxine concentrations in the second trimester
can result in irreversible neurologic deficit in offspring. When it occurs
10 later, the damage to the fetal brain is less and is partially reversible. The
need for T3 by mid-gestation for development of the human cerebral
cortex was also demonstrated by Kester and associates.28 Concentra-
tions of TSH, T4, T3, and reverse T3 are measurable in the amniotic
5 fluid and correlate with the fetal rather than maternal serum.
Neonatal Thyroid Function
Immediately after birth, there is a surge of TRH and TSH that is fol-
0
5 5 10 10 lowed by an increase in T3 (from increased T4 to T3 conversion) and a
Urinary iodide (μg/dL) moderate increase in T4.10 Within a few days, the increased TSH falls
to adult levels through T4 and T3 negative-feedback inhibition. Neona-
FIGURE 47-4 Iodine deficiency can manifest as thyroid tal T4 and T3 concentrations return to normal adult levels within 4 to
hypertrophy. The percentage of maternal thyroid hypertrophy 6 weeks.29 The transient hyperthyroxinemia can be triggered by neo-
(thyroid volume > 18 mL) is plotted against the urinary iodine natal cooling and may represent an adaptation of thermogenesis to
concentration measured during the first trimester of pregnancy. extrauterine life.30,31
(Reprinted by permission from Caron P, Hoff M, Bassi S, et al: Urinary In premature neonates, free T4 levels are low, TSH levels are normal
iodine excretion during normal pregnancy in healthy women living in
(adult), and T4 levels are related to gestational age. The clinical conse-
the southwest of France: Correlation with maternal thyroid
quence of this transient hypothalamic hypothyroidism is unknown,
parameters. Thyroid 7:749, 1997.)
but it has been associated with impaired neurologic and mental
development.32-34
tional by weeks 10 to 12. Until mid-gestation, fetal TSH and T4 con-
centrations remain low. At 18 to 20 weeks’ gestation, the fetal thyroid
gland’s iodine uptake and serum T4 concentrations begin to increase.20
Placental Transfer of Drugs Affecting
Concentrations of T4 increase from 2 μg /dL at 20 weeks to 10 μg/dL Thyroid Function
at term, with increasing TBG concentrations contributing to this rise. The potential influence of the placenta on fetal thyroid and neurologic
Similarly, free fetal T4 concentrations increase from 0.1 ng/dL at 12 development is evident by the ready transfer of several agents that
weeks’ gestation to 1.5 ng/dL near term. Increases in T3 and free T3 are affect thyroid function.35,36 These agents include the following:
smaller, presumably because of the availability of placental type III
deiodinase, which converts T4 rapidly to reverse T3. Fetal serum T3 Iodine
increases from 6 ng/dL at 12 weeks’ gestation to 45 ng/dL near term. Thionamides
Fetal serum TSH increases from 4 to 8 mU/L between weeks 12 and β-Adrenergic receptor blockers
term.21,22 In summary, most fetal T4 is inactivated to reverse T3. The T3 Somatostatin
(from T4 conversion or direct fetal thyroid secretion) has limited avail- Exogenous TRH
ability. Fetal tissues that depend on T3 for development (e.g., brain Dopamine agonists and antagonists
structures) are supplied by local T4 to T3 conversion by means of deio- Thyroid-stimulating immunoglobulins and other antibodies
dinase type II.22
TSH does not cross the placenta. TRH and corticosteroid adminis-
tered antenatally before 32 weeks’ gestation stimulates T4 release and
Placental Transfer of decreases the frequency of chronic lung disease among neonates.37
Thyroid Hormones Intra-amniotic administration of T4 in the preterm setting increases
Although earlier studies suggested only limited T4 and T3 transfer fetal maturation, as reflected by an increase in the lecithin-to-
through the placenta, later studies have shown that T4 can be found in sphingomyelin ratio and decrease in respiratory distress syndrome
first-trimester celomic fluid by 6 weeks’ gestation. Nuclear T3 receptors of the newborn.38
can be identified in the brain of 10-week-old fetuses, and they increase
tenfold by 16 weeks’ gestation before the fetal thyroid becomes fully
functional.24 These studies suggest that maternal T4 transfer occurs
early in gestation and that low levels of T4 are sustained in the fetus at Pregnancy, the Immune
this time.25 Vulsma and colleagues26 reported that cord serum T4 levels
in hypothyroid neonates with glandular agenesis represented as much
System, and Thyroid Disease
as 30% of normal circulating values, a strong indication of maternal Chapter 6 offers a detailed review of pregnancy immunology. The
T4 transfer, although this has not been a uniform finding.27 fetus, with its complete set of paternal antigens, survives because of

5. CHAPTER 47 Thyroid Disease and Pregnancy 999
adjustments in the maternal-placental-fetal immune systems. This TABLE 47-1 FACTORS INFLUENCING
immunologic compromise of pregnancy is orchestrated primarily by THYROXINE-BINDING GLOBULIN
the placental tissues and passaged fetal cells that are able to modulate
the local and systemic maternal immune responses.39,40 Autoimmune Factors Increasing TBG Levels Factors Decreasing TBG Levels
responses are usually reduced in pregnancy, as evidenced by ameliora-
Oral contraceptives Testosterone
tion of Graves disease, rheumatoid arthritis, and multiple sclerosis.41-43
Pregnancy Nephrotic syndrome
Although there is a shift from proinflammatory TH1 cytokines to TH2 Estrogen Cirrhosis
cytokines, driven perhaps by progesterone,44 it is occurring against a Hepatitis Glucocorticoids
background of reduced B-cell reactivity. The reduced B-cell responses Acute intermittent porphyria Severe illness
are likely orchestrated by placental sex steroids, which are powerful Inherited defect Inherited defect
negative regulators of B-cell activity. Whereas most of the immune
changes in pregnancy return to normal by 12 months after delivery, TBG, thyroxine-binding globulin.
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 early in pregnancy because of the stimulatory effects of hCG. Free T4
levels rise above pre-pregnancy levels during the first 6 months after levels tend to fall through the rest of pregnancy and occasionally to
delivery, suggesting continuing nonspecific immune stimulation.39 levels below those of nonpregnant women.2 Free hormone levels then
fall through the rest of the pregnancy but usually not below the lower
limit of normal.47 Table 47-1 outlines factors that influence TBG and
Laboratory Evaluation therefore total hormone concentrations.
Resistance to thyroid hormone is a rare condition encompassing a
of Thyroid Function number of different defects. The pituitary and other peripheral tissues
can manifest this resistance. These patients present with an increased
during Pregnancy free T4 concentration along with an inappropriately elevated or non-
suppressed TSH, and they may have goiters. Whereas patients with
Thyrotropin and Thyroid Hormones thyroid hormone resistance have normal α-subunit concentrations,
Total T4 and total T3 are elevated because of increased TBG production patients with TSH-secreting tumors (i.e., differential diagnosis of
and reduced clearance induced by the hyperestrogenic state of preg- thyroid hormone resistance) often have elevated serum α-subunit
nancy.45 The normal reference range for total T4 should be adjusted by levels.48 In a case reported by Anselmo and colleagues,49 transient thy-
a factor of 1.5 for pregnant patients.2 The T3 resin uptake (i.e., indirect rotoxicosis occurred during pregnancy in a woman with resistance to
laboratory measure of available TBG binding sites) is reduced in preg- thyroid hormone caused by a mutation in the thyroid receptor β gene.
nancy because increased TBG binding sites take up more of the added This thyrotoxicosis manifested clinically by hypermetabolic features
T3, leaving less to bind to resin. The free thyroxine index, which is and paralleled the rise and peak of hCG concentrations. Symptoms
a product of the total T4 and T3 resin uptake, usually falls to within ameliorated and thyroid hormone concentrations declined as preg-
the normal range in pregnancy. Because free T4 can be determined, nancy progressed and hCG concentrations fell.
however, third-generation TSH and free T4 assessments are the best Concern has been raised regarding unaffected fetuses of mothers
ways to evaluate thyroid function in pregnancy. However, automated with thyroid hormone resistance. Outcomes of pregnancies in an
free T4 assays are sensitive to alternations in binding proteins as occurs extended Azorean family with resistance to thyroid hormone were
in pregnancy. Because these proteins change, they can falsely elevate or analyzed; miscarriages were found to be more common, and unaf-
lower the free T4 assay result. The free T4, as measured by equilibrium fected infants born to affected mothers had lower birth weights, dem-
dialysis, is not affected by these protein changes. Trimester-specific onstrating a direct toxic effect of thyroid hormone excess on the
normative data for iodine-sufficient women using specific commer- fetus.50
cially available assays is not available. This topic is discussed further in
the section on Subclinical Hypothyroidism and Hypothyroxinemia.
If the TSH is suppressed, suggesting overproduction of thyroid Thyrotropin Receptor Antibodies
hormones, free T3 can be determined. The third-generation TSH assays Several functional types of TSH receptor antibodies are recognized.
can differentiate profound from marginal suppression. Trimester- Some antibodies promote gland function (i.e., thyroid-stimulating
specific TSH concentrations were obtained by Dashe and colleagues,46 immunoglobulins [TSIs]), some inhibit binding of TSH to its receptor
who determined these concentrations at each point during gestation (i.e., thyroid-binding inhibitory immunoglobulins [TBIIs]), and some
in singleton and twin pregnancies. They constructed nomograms for enhance or inhibit thyroid growth. These antibodies can be measured
both using regression analysis and showed significantly lower TSH by a variety of bioassays and receptor assays. For example, maternal
concentrations in the first trimester. These levels were lower in twin production of TSIs causes maternal Graves disease, is transferred
pregnancies, as would be expected from the known effects of hCG. across the placenta, and can lead to neonatal Graves disease. Excess
Values were converted to multiples of the median for singleton preg- TBIIs can cause maternal and neonatal hypothyroidism.
nancies at each week of gestation, and they suggested that values
expressed this way might facilitate comparison across laboratories and
populations. In another study, using sensitive TSH assays, 9% of non- Antithyroid Antibodies
symptomatic first-trimester women were found to have TSH values Patients with autoimmune thyroid disease commonly develop anti-
higher than 0.05 mU/L (i.e., lower limit of assay detection) but less bodies to thyroid antigens. The two most commonly determined
than 0.4 mU/L, and another 9% had TSH values below the detection antibodies are those to thyroglobulin and to thyroid peroxidase
limit.8 Free T3 and T4 concentrations can be in the high-normal range (anti-TPO).51 Among nonpregnant women, the incidence of anti-TPO

6. 1000 CHAPTER 47 Thyroid Disease and Pregnancy
TABLE 47-2 EFFECTS OF DRUGS ON THYROID short term with thyroid hormones. Only two newborns had transient
HORMONES AND FUNCTION hyperthyroxinemia. Although breastfeeding resulted in substantial
infant amiodarone ingestion, it did not cause major changes in neonatal
TEST RESULTS
thyroid function. The study authors concluded that amiodarone should
Inhibition of thyroid function be used only when tachyarrhythmias are unresponsive to other drugs
Iodine and are life threatening and that hypothyroid neonates (and perhaps
Lithium the fetus in utero) should be treated. It is prudent to monitor the infants
Inhibition of T4 to T3 conversion of breastfeeding mothers who continue to use the medication.54
Glucocorticoid
Ipodate
Propranolol Nonthyroidal Illness and
Amiodarone
Propylthiouracil
Thyroid Function
Increased level of TSH Nonthyroidal illness has been the topic of various reviews and com-
Iodine mentaries.4,5,55 Severely ill patients can manifest thyroid function test
Lithium abnormalities that may correlate with functional inhibition of the
Dopamine antagonists hypothalamic-pituitary-thyroid axis, impaired T4 to T3 conversion (a
Decreased level of TSH constant accompaniment of nonthyroidal illness), and abnormalities
Glucocorticoids in binding and clearance of thyroid hormone. Reverse T3 levels are
Dopamine agonists
substantially elevated because of increased T4 to reverse T3 conversion
Somatostatin
and impaired metabolic clearance of reverse T3. TSH concentrations
Inhibition of T4 and T3 binding to binding proteins
Phenytoin can be low, normal, or elevated, although seldom higher than 20 mU/
Salicylates L.55 The more severe the illness, the lower the T4 values, and this rela-
Sulfonylureas tionship has been used as a prognostic indicator, because a high cor-
Inhibition of gastrointestinal absorption of thyroid hormone relation has been found between a low T4 value and a fatal outcome.56
Ferrous sulfate The best test for assessing thyroid function in severely or chronically
Sucralfate ill patients is the free T4 concentration. Despite the low T3 and total T4
Cholestyramine state, this situation does not represent true hypothyroidism, but rather
Aluminum hydroxide an adaptation to stress, and it should not be treated.
TSH, thyroid-stimulating hormone; T3, l-triiodothyronine; T4,
l-thyroxine.
Thyroid Dysfunction and
antibodies is about 3%, with the incidence ranging from 5% to 15%
among pregnant women. A substantial proportion of women with
Reproductive Disorders
positive anti-TPO antibodies in early pregnancy develop postpartum Thyroid hormones are important for normal reproductive function.
thyroiditis.52,53 Deficiency of thyroid hormone can result in delayed sexual develop-
ment. As reviewed by Winters and Berga57 and Krassas,58 all women
with infertility and menstrual disturbances should have thyroid func-
Drugs and Thyroid Function tion tests, usually T4, T3, and TSH. Women with type 1 diabetes, who
Table 47-2 outlines drug effects on thyroid function and metabolism, have a relatively high incidence of hypothyroidism, should probably
absorption of thyroid hormones, and interpretation of thyroid func- undergo screening before conception. This topic has been reviewed by
tion tests. Iodine and lithium inhibit thyroid function. Propranolol and Trokoudes and coworkers.59
ipodate block T4 to T3 conversion, as do glucocorticoids; however,
glucocorticoids also reduce release of TSH from the pituitary, as do
dopamine, dopamine agonists, and somatostatin. The antiseizure med- Hyperthyroidism
ication phenytoin reduces total T4 levels (up to 30%) by inhibiting the Hyperthyroidism has been linked to oligomenorrhea, hypomenorrhea,
binding of thyroid hormones to binding proteins and increasing T4 amenorrhea, and infertility, although many thyrotoxic women remain
clearance. Ferrous sulfate, aluminum hydroxide, and sucralfate may ovulatory. In one survey, only 21.5% of 214 thyrotoxic patients had
inhibit thyroid hormone absorption substantially—an important menstrual disturbances, compared with 50% to 60% in older series.60
interaction in pregnant women who are taking both iron and thyroid Thyroxine upregulates the production of sex hormone–binding globu-
hormones. lin. Elevated levels of circulating testosterone and estrogen may be
Amiodarone, an iodine-rich drug, has been used in pregnancy for observed, and the clearance of testosterone is reduced. Gonadotropin
maternal or fetal tachyarrhythmias. Amiodarone and the iodine are concentrations can be tonically elevated.61,62 The substantial weight loss
transferred across the placenta, exposing the fetus to the drug and iodine seen in some hyperthyroid patients can affect the hypothalamic-
overload. This iodine overload can cause fetal or neonatal hypothyroid- pituitary-gonadal axis and can contribute to the infertility of severe
ism and goiter, because the fetus acquires the capacity to escape from hyperthyroidism.
the acute Wolff-Chaikoff effect (i.e., decrease in 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 Hypothyroidism
progeny developed hypothyroidism (goitrous and nongoitrous). Hypo- Hypothyroidism in fetal life does not affect the development of the
thyroidism was transient, although a few of the infants were treated reproductive tract, but during childhood, it leads to sexual immaturity

7. CHAPTER 47 Thyroid Disease and Pregnancy 1001
and usually a delay in puberty, followed by anovulatory cycles. Almost
25% of women with untreated hypothyroidism have menstrual irregu-
larities. Menorrhagia occurs frequently and can reflect interference Hyperthyroidism and
with the endometrial maturational process and response to ovarian
steroids; it usually responds to thyroxine treatment.63 The increased Pregnancy
miscarriage rate seen in hypothyroid patients may reflect disrupted
endometrial maturation. Hypothyroidism, through increased TRH, Signs and Symptoms
can be associated with hyperprolactinemia, which itself can disrupt The prevalence of hyperthyroidism in pregnant women ranges from
reproductive function and menstrual cyclicity,64 leading to oligomen- 0.05% to 0.2%.78 The signs and symptoms of mild to moderate hyper-
orrhea or amenorrhea. Galactorrhea can sometimes be seen in this thyroidism—heat intolerance, diaphoresis, fatigue, anxiety, emotional
setting, as can elevated levels of luteinizing hormone, possibly through lability, tachycardia, and a wide pulse pressure—can be mimicked by
diminished dopamine secretion.65 the hypermetabolic state of normal pregnancy. However, weight loss,
Women with hypothyroidism have diminished rates of metabolic tachycardia greater than 100 beats/min, and diffuse goiter are features
clearance of androstenedione and estrone and an increase in peripheral that may suggest hyperthyroidism. Graves ophthalmopathy can be
aromatization. Whereas plasma concentrations of testosterone and helpful but does not necessarily indicate active thyrotoxicosis.79 Gas-
estradiol are decreased because of diminished binding activity, their trointestinal symptoms such as severe nausea and excessive vomiting
unbound fractions are actually increased. Several studies have sug- can accompany thyrotoxicosis in pregnancy, as can diarrhea, myopathy,
gested increased risk of miscarriage in the presence of thyroid anti- lymphadenopathy, and congestive heart failure.
bodies, even in the face of a euthyroid status. Although previous studies
did not demonstrate benefit in using T4 to treat euthyroid women with
recurrent spontaneous abortions,66-68 benefit was shown by Negro and Diagnosis
colleagues69 in a group of 115 antibody-positive women, one half of Biochemical confirmation of the hyperthyroid state can be obtained
whom received thyroxine. Treatment decreased miscarriages and pre- through laboratory measurement of free T4, free T3, and TSH. Typi-
maturity by 75% and 69%, respectively. In a thoughtful accompanying cally, elevated values of free T4 and T3 and greatly suppressed TSH
editorial, Glinoer70 stated that the statistical strength of the association values are found, but a normal free T4 level can be seen in cases of T3
between miscarriages and autoimmune thyroid disease has been largely toxicosis. Other laboratory features include normochromic, normocytic
confirmed, with a threefold increase in the overall miscarriage rate. anemia; mild neutropenia; elevated levels of liver enzymes and alkaline
Because there is no reason to believe that thyroxine treatment altered phosphatase; and mild hypercalcemia. Patients may test positive for anti-
autoimmunity, it was thought that the subtle deficiency in thyroid thyroid antibodies (i.e., antithyroglobulin and antithyroid peroxidase),
hormone concentration or reduced ability of maternal thyroid func- but they are not specific to Graves disease. TSIs are considered to be
tion to adapt adequately in women with autoimmune thyroid disease the antibodies specific to Graves disease and can be measured by bioas-
was the main reason for the beneficial effects of thyroid hormone says or receptor assays.80
administration.
Differential Diagnosis
Causes of hyperthyroidism are outlined in Table 47-3. Approximately
Radioiodine and Gonadal Function 90% to 95% of hyperthyroid pregnant women have Graves disease, and
The prevalence of infertility, premature births, miscarriage, and genetic this can be diagnosed with certainty in a thyrotoxic pregnant woman
damage in the offspring of women treated with radioactive iodine who has diffuse thyromegaly with a bruit and ophthalmopathy.
for thyrotoxicosis does not seem to be increased.71,72 Although thyroid Whereas excess circulating thyroid hormones cause lid retraction and
cancer doses of 131I may be associated with subsequent menstrual lid lag, proptosis and external ocular muscle palsies reflect infiltrative
irregularities, exposure to radioiodine does not appear to reduce ophthalmopathy of Graves disease. Graves disease is an autoimmune
fecundity.73 In a study of 32 women who conceived after 131I treatment disease mediated by antibodies (i.e., TSIs) that activate the TSH recep-
for thyroid cancer (resulting in 60 term deliveries), two children
conceived within a year of 131I therapy had birth defects, but no
anomalies were seen in the remaining 58.74 Contraception has been
recommended for 1 year after 131I treatment. In a large study, TABLE 47-3 CAUSES OF HYPERTHYROIDISM
Schlumberger and associates75 obtained data on 2113 pregnancies IN PREGNANCY
conceived after exposure to 30 to 100 mCi of radioiodine given for
Graves disease
thyroid cancer. The incidences of stillbirths, preterm labor, low birth Toxic adenoma
weight, congenital malformations, and death during the first year of Toxic multinodular goiter
life were not significantly different between pregnancies conceived Hyperemesis gravidarum
before or after radioiodine therapy. Miscarriages were more common Gestational trophoblastic disease
for the women treated with 131I in the year preceding conception TSH-producing pituitary tumor
(40%). Metastatic follicular cell carcinoma
All women need pregnancy tests before 131I treatment. Treatment Exogenous T4 and T3
late in the first trimester and in the second trimester may result De Quervain (subacute) thyroiditis
in irreversible hypothyroidism in the fetus. Lactating mothers Painless lymphocytic thyroiditis
Struma ovarii
who have received diagnostic or therapeutic doses of 131I should not
breastfeed their infants. These topics are reviewed by Gorman76 and TSH, thyroid-stimulating hormone; T3, l-triiodothyronine; T4,
Berlin.77 l-thyroxine.

8. 1002 CHAPTER 47 Thyroid Disease and Pregnancy
tor and stimulate the thyroid follicular cell. It affects 3% of women of directly to the control and severity of the hyperthyroidism. In a study
reproductive age.81 of hyperthyroid pregnant women, the odds ratio for low birth weight
was 2.4 for those treated during pregnancy and 9.2 for those uncon-
trolled during pregnancy compared with a group who was euthyroid
Treatment and remained so. Similarly, prematurity was more common in the
The outcome of treatment before pregnancy is better than that of hyperthyroid group; the odds ratio was 2.8 for the controlled group
treatment in pregnancy,82 and hyperthyroidism is therefore best treated and 16.5 for the uncontrolled group. Similar findings related to pre-
before conception. If untreated or treated inadequately, women may eclampsia, with an odds ratio of 4.7 for the controlled group.84 This
have more complications during pregnancy and delivery. Very mild was confirmed by a later study.98 In other reports, higher frequencies
cases of hyperthyroidism, with adequate weight gain and appropriate of small-for-gestational-age births, congestive heart failure, and
obstetric progress, may be followed carefully, but moderate or severe stillbirths have been found.82,99 It is uncertain whether untreated
cases must be treated. In a retrospective study of 60 thyrotoxic preg- Graves disease is associated with a higher frequency of congenital
nant women, preterm delivery, perinatal mortality, and maternal heart malformation.87,100
failure were significantly increased among women who remained thy- Infants of mothers receiving thionamides should be evaluated
rotoxic. Thyroid hormone status at delivery correlated directly with ultrasonographically for signs of hypothyroidism, such as goiter, bra-
pregnancy outcome.82 In another study by Momotani and Ito,83 hyper- dycardia, and intrauterine growth restriction. If needed, cordocentesis
thyroidism at conception was associated with a 25% rate of abortion may be performed and fetal thyroid function determined; reference
and 15% rate of premature delivery, compared with 14% and 10%, ranges have been reported.101 Doses of PTU should be adjusted to keep
respectively, for euthyroid patients. Preeclampsia has also been associ- free T4 level in the upper normal range and TSH level less than 0.5 mU/
ated with uncontrolled hyperthyroidism.84 L during pregnancy to avoid hypothyroidism in the fetus. PTU often
can be stopped in late gestation.
Thionamide Therapy PTU is not significantly concentrated in breast milk (10% of serum)
Thionamide therapy has been reviewed by Cooper85 and Clark and and does not appear to affect the infant’s thyroid hormone levels in
associates.86 The thionamides inhibit the iodination of thyroglobulin any major way. Methimazole also does not appear to affect subsequent
and thyroglobulin synthesis by competing with iodine for the enzyme somatic or intellectual growth in children exposed to it during lacta-
peroxidase. Propylthiouracil (PTU) is more frequently prescribed in tion.87,102,103 Antithyroid medication should be taken just after breast-
the United States. Carbimazole (a drug metabolized to methimazole) feeding, allowing a 3- to 4-hour interval before the woman lactates
and methimazole itself are used often in Europe and Canada. PTU (but again.
not methimazole) also inhibits the conversion of T4 to T3. The goal of
therapy is to control the hyperthyroidism without causing fetal or b-Blockers
neonatal hypothyroidism.87 Maternal free T4 should be maintained in β-Blockers are useful for the control of adrenergic symptoms, particu-
the high-normal range. PTU is given every 8 hours at doses of 100 to larly maternal heart rate. Propranolol is commonly used in doses of 20
150 mg (300 to 450 mg total daily dosage) according to thyrotoxicosis to 40 mg two or three times daily, and it inhibits T4 to T3 conversion.
severity. The occasional patient may require higher doses (e.g., 600 mg Alternatively, atenolol (50 to 100 mg daily) may be used, and in an
or more) because the risk of uncontrolled maternal hyperthyroidism emergency, esmolol, an ultra-short-acting cardioselective intravenous
is greater than that of high-dose PTU.82 It can take 6 to 8 weeks for β-blocker, has been used successfully.104 Prolonged therapy with β-
major clinical effects to manifest. After the patient is euthyroid blockers can be associated with intrauterine growth restriction, fetal
(reflected by monthly free T4 and free T3 values), the dose of PTU bradycardia, and hypoglycemia.
should be tapered (e.g., halved), with further reduction as the preg-
nancy progresses. For many patients, PTU can be discontinued by 32 Iodides
to 36 weeks’ gestation, because remission of Graves disease during Iodides decrease circulating T4 and T3 levels by up to 50% within 10
pregnancy is commonly observed, often with relapse after delivery. It days by acutely inhibiting the release of stored hormone. Their use
has been suggested that a change from stimulatory to blocking anti- is appropriate in combination with thionamides (which should
body activity may contribute to this remission.88 be started before the iodide) and β-blockers in patients with
Maternal side effects of PTU treatment can include rash (≈5%), severe thyrotoxicosis or thyroid storm. Potassium iodide (SSKI, 5
pruritus, drug-related fever, hepatitis, a lupus-like syndrome, and drops every 8 hours) is given. Sodium ipodate, a radiographic
bronchospasm. An alternative thionamide can be used, although cross- contrast agent, is an alternative and has the added benefit of inhibiting
sensitivity occurs in 50% of patients. Agranulocytosis, which is the conversion of T4 to T3. Its safety in pregnancy has not been
most serious side effect, develops in only 0.1%, occurring especially in documented.
older women and those receiving higher doses.89 All patients experi- Because iodides cross the placenta readily, they should be used for
encing fever or unexpected sore throat on therapy should discontinue no longer than 2 weeks, or fetal goiter can result. Inadvertent use of
the drug and have white blood cell count monitoring. Agranulocytosis iodides also follows use of Betadine cleansing solutions, iodine-con-
is a contraindication to further thionamide therapy; the blood count taining bronchodilators, and the drug amiodarone.
131
gradually improves over days or weeks. I thyroid ablation is contraindicated in pregnancy because the
Methimazole is not used in the United States. Although the trans- radioactive iodine is concentrated in the fetal thyroid after 10 to 12
placental passage is similar,90 methimazole may cause cutis aplasia, a weeks’ gestation. If a woman inadvertently receives 131I during preg-
scalp deformity.91-93 Although rare, there are reports of methimazole nancy, SSKI should be given immediately, along with PTU, to block
and carbimazole embryopathy, with choanal atresia, tracheoesopha- organification and reduce radiation exposure to the fetal thyroid by a
geal fistula, and facial anomalies.94-97 factor of 100 and to the fetal whole body by a factor of 10. To be of
The risks of untreated hyperthyroidism need to be considered in benefit, SSKI and PTU treatment must be given within 7 to 10 days of
relation to the risk of antithyroid medications. They appear to relate exposure.76

9. CHAPTER 47 Thyroid Disease and Pregnancy 1003
Surgery among these women, and it was recommended that treatment in preg-
In select cases of thyrotoxicosis with severe complications or noncom- nancy was unwarranted.
pliance, surgery can be performed in the pregnant patient. Two weeks
of low-dose iodine therapy, such as one or two drops of SSKI daily, can
reduce gland vascularity preoperatively. Surgery is best performed in
the second trimester, although it can be done in the first or third tri- Fetal and Neonatal
mester.105 The risks are those of anesthesia, hypoparathyroidism, and
recurrent laryngeal nerve paralysis.
Hyperthyroidism
The topic of fetal and neonatal hyperthyroidism has been reviewed
Thyroid Storm by Zimmerman.110 Hyperthyroidism in fetuses and neonates is usually
Thyroid storm is a life-threatening exacerbation of thyrotoxicosis. Cri- produced by transplacental passage of TSIs. Although they are a
teria for its diagnosis have been introduced,106 and the classic findings common component of active Graves disease, the antibodies can con-
are various degrees of thermoregulatory dysfunction, central nervous tinue to be present in the maternal circulation after surgical (Fig. 47-5)
system effects (e.g., agitation, delirium, coma), gastrointestinal dys- or radioactive iodine ablation or even in patients with Hashimoto
function, and cardiovascular problems manifesting as tachycardia or thyroiditis. Fetal hyperthyroidism occurs when TSIs cross the placenta
heart failure. For example, a patient with a temperature of 102°F who and activate the fetal thyroid; this occurs in 1% of infants born to these
is agitated and tachycardic with a pulse rate exceeding 130 beats/min women.
would be diagnosed with thyroid storm. Although rare in pregnancy, Maternal TSI levels in excess of 300% of control values are
it may be seen and can be precipitated by labor and delivery, cesarean predictive of fetal hyperthyroidism99 and should be measured at 28 to
section, infection, or preeclampsia.107 Thyrotoxic cardiomyopathy may 30 weeks. The assay used should be a functional one, because TSH-
also lead to heart failure in pregnancy.108 Intensive care treatment with receptor antibodies are heterogeneous and can stimulate or block the
fluid and nutritional support is necessary for thyroid storm and heart TSH receptor.99,111 Neonatal syndromes have been caused by transpla-
failure. A loading dose of PTU of 600 mg may be given orally or cental passage of stimulating and blocking antibodies.112
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 Fetal Thyrotoxicosis
sodium iodide every 8 hours) to inhibit thyroid hormone release. If Features of fetal thyrotoxicosis include a heart rate greater than 160
the patient is iodine allergic, lithium (300 mg every 6 hours) is an beats/min, growth retardation, advanced bone age, and craniosynos-
alternative. Dexamethasone (2 mg every 6 hours) is also given to block tosis, all of which can be detected by ultrasound examination.113 Occa-
T4 to T3 conversion. For tachycardia exceeding 120 beats/min, β- sionally, nonimmune fetal hydrops and fetal death occur with associated
blockers such as propranolol, labetalol, or esmolol may be used.1 diminished subcutaneous fat and thyroid enlargement. In utero, most
Table 47-4 summarizes the management of thyroid storm. cases are likely treated by the PTU given to the mother. This problem
can arise if the mother is euthyroid but has elevated levels of TSIs.114
Cordocentesis can be used for diagnosis and for monitoring therapy.
Subclinical Hyperthyroidism A combination of PTU and T4 treats the fetal hyperthyroidism while
keeping the mother euthyroid.
Subclinical hyperthyroidism, as defined by suppressed TSH and normal
free T4 and free T3 levels, is also seen in pregnancy. In a study by Casey
and associates,109 1.7% of women screened had subclinical hyperthy- Neonatal Thyrotoxicosis
roidism, which they defined as TSH values at or below the 2.5th per- Features of thyrotoxicosis in the neonate include hyperkinesis, diar-
centile for gestational age and a free T4 level of 1.75 ng/dL or less. rhea, poor weight gain, vomiting, exophthalmos, arrhythmias, cardiac
Pregnancy complications, morbidity, and mortality were not increased failure, hypertension (systemic and pulmonary), hepatosplenomegaly,
TABLE 47-4 TREATMENT OF THYROID STORM
Treatment Rationale and Cautions Dosage
General care Intensive management achieved with intravenous
fluid hydration and nutritional support
Propylthiouracil Initial: 600 mg orally or crushed and given by NG tube
Maintenance: 200-300 mg every 6 hr given orally or by NG tube
Iodide Initial dose to be given 1 hr after start of PTU 5 drops of supersaturated solution of potassium iodide every 8 hr or
500-1000 mg of intravenous sodium iodide infusion every 12 hr
Lithium carbonate Used if patient is allergic to iodine 300 mg every 6 hr
Dexamethasone Given to block T4 to T3 conversion 2 mg every 6 hr for four doses
β-Blockers Given to control tachycardia ≥ 120 beats/min IV propranolol at 1 mg/min up to several doses until blockade is
(use cautiously if patient in heart failure) achieved and concurrent 60 mg of propranolol (PO or NG tube)
every 6 hours or
IV loading dose of 250-500 μg/kg of esmolol, followed by infusion
at 50-100 μg/kg/min
IV, intravenous; NG, nasogastric; PO, orally; PTU, propylthiouracil.

10. 1004 CHAPTER 47 Thyroid Disease and Pregnancy
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.
thrombocytopenia, and craniosynostosis. The infant should be exam- production can suppress the TSH to low or suppressed values in up to
ined immediately after birth. Cord blood reflects the in utero environ- 20% of normal pregnancies. Twin pregnancies can be associated with
ment, and by day 2 of life, the maternal antithyroid drug effects have biochemical hyperthyroidism,9 as may pregnancies complicated by
receded. Affected neonates are treated with PTU, β-blockers, iodine, trophoblastic disease. Several clinical scenarios can arise and are
and glucocorticoids and digoxin, as needed. Ipodate may be preferable described in the following sections.
because it blocks T4 to T3 conversion. Remission by 20 weeks is
common, and it usually occurs by 48 weeks; occasionally, there is
persistent disease when there is a strong family history of Graves Gestational Transient Thyrotoxicosis
disease. Gestational transient thyrotoxicosis (GTT) occurs in the first trimester
Other mechanisms of fetal and neonatal hyperthyroidism include in women without a personal or family history of autoimmune disease.
activating mutations of the stimulatory G protein in McCune-Albright It results directly from hCG stimulation of the thyroid. Glinoer and
syndrome and activating mutations of the TSH receptor.115,116 colleagues8 found an overall prevalence of GTT in 2.4% in a prospec-
tive cohort study between 8 and 14 weeks’ gestation. Symptoms com-
patible with thyrotoxicosis were often present, and elevated free T4
concentrations were found. The GTT was transient, paralleled the
Hyperthyroidism Related decline in hCG, and usually did not require treatment. The thyroid
gland was not enlarged. Occasionally, β-blockers were used. GTT was
to Human Chorionic not associated with a less favorable outcome of pregnancy.
Gonadotropin
When hyperthyroidism is diagnosed during the first trimester, the Hyperemesis Gravidarum
physician has a challenging differential diagnosis, usually that of Graves Hyperemesis gravidarum is a serious pregnancy complication associ-
disease versus hCG-mediated hyperthyroidism. The hCG has TSH-like ated with weight loss and severe dehydration, often necessitating hos-
stimulatory activity, which can result in overproduction of thyroid pitalization.119 Biochemical hyperthyroidism is found in most women
hormone when the concentrations are high or when there is a change with this condition.120,121 Whereas Goodwin and colleagues120,121 found
in its molecular structure. Molecular variants of hCG with increased that the severity of disease varied directly with the hCG concentration,
thyrotropic potency include basic molecules with reduced sialic acid Wilson and associates122 did not find such a correlation. As in the
content, truncated molecules lacking the C-terminal tail, or molecules case of GTT, certain hCG fractions may be more important than total
in which the 47-48 peptide bond in the β-subunit loop is nicked.117 hCG as thyroid stimulators.123 The duration of the hyperthyroidism
This relationship is further complicated by differences in clearance varies widely from 1 to 10 weeks but is usually self-limited. Vomiting
rates of different hCG glycoforms.118 In vivo thyrotropic activity is and normalization of T4 levels occur by 20 weeks, though TSH may
regulated by the glycoforms and the plasma half-life. remain suppressed a little longer. Treatment is usually supportive, with
The hCG concentrations peak at 6 to 12 weeks and then decline to correction of dehydration, antiemetics, and occasionally, parenteral
a plateau after 18 to 20 weeks. The stimulation of thyroid hormone nutrition. The vomiting may not be controlled by normalization of

11. CHAPTER 47 Thyroid Disease and Pregnancy 1005
Clinical Disorders
Defective
ontogenesis Iodine
Fetus Normal Normal
(congenital deficiency
hypothyroidism)
Iodine Hypothy-
Mother Normal Normal
deficiency roxinemia
Thyroxinemia
in the fetus
Contribution arising
from maternal
hormone transfer
Conception
Mid-
gestation
Term
FIGURE 47-6 Thyroid function disorders. Schematic representation of the three sets of clinical
conditions that can affect thyroid function in the mother alone, in the fetus alone, or in the fetomaternal
unit shows the relative contributions of impaired maternal or fetal thyroid function that may eventually lead
to alterations in fetal thyroxinemia. (Reprinted by permission from Glinoer D, Delange F: The potential
repercussions of maternal, fetal and neonatal hypothyroxinemia on the progeny. Thyroid 10:871, 2000.)
thyroid hormones. In patients who require treatment, PTU therapy adenoma. If either of these entities is diagnosed during pregnancy, the
can be attempted if tolerated; methimazole suppositories can also be correct treatment is control of hyperthyroidism with antithyroid drugs
used. until definitive treatment (i.e., surgery or radioactive iodine) can be
administered after delivery.
Even less common causes of hyperthyroidism in pregnancy are
Gestational Trophoblastic Disease listed in Table 47-3. They include TSH-producing pituitary tumors,
Both hydatidiform mole and choriocarcinoma can be associated with metastatic follicular thyroid cancer, viral (de Quervain) thyroiditis, and
hCG levels that are greater than 1000 times normal and thus can cause struma ovarii, which is an ovarian dermoid tumor in which more than
hyperthyroidism (biochemically seen in approximately 50% of such 50% of the neoplasm consists of thyroid tissue.
women). The thyroid is usually not enlarged. Treatment of the hyda-
tidiform mole or choriocarcinoma restores thyroid function to normal.
Treatment with antithyroid drugs and β-blockers is frequently neces-
sary, however, before surgical treatment of the mole.124 Iodine Deficiency,
Hypothyroidism,
Recurrent Gestational Hyperthyroidism and Pregnancy
Cases of recurrent gestational hyperthyroidism have been described.125,126
In the case described by Rodien and colleages,126 the hyperthyroidism A schematic representation of the clinical conditions that can affect
was caused by a mutant TSH receptor that was hypersensitive to thyroid function in the mother, fetus, or fetomaternal unit is provided
hCG. 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
Other Causes of Hyperthyroidism areas of overt iodine deficiency. Worldwide, it is the most common
Much less common causes of hyperthyroidism include thyrotoxicosis cause of mental retardation.
factitia (i.e., ingestion of exogenous hormone surreptitiously); in such In the past few decades, the physiology of maternal and fetal iodine
cases, serum thyroglobulin, which is produced by the thyroid, is sup- metabolism, thyroid hormone metabolism, and fetal brain develop-
pressed.127 Women with large nodular goiters may have hyperthyroid- ment and the pathophysiology of iodine deficiency have been unrav-
ism from autonomously functioning nodules within such goiters. eled. These findings have revealed a fascinating aspect of pregnancy
Alternatively, women can have hyperthyroidism from a single toxic physiology. Iodine deficiency and hypothyroidism in pregnancy con-

12. 1006 CHAPTER 47 Thyroid Disease and Pregnancy
tinue to be a worldwide problem worthy of resolution. This topic also of iodine deficiency, it appeared to be responsible for an IQ loss of 13.5
has been a subject of numerous reviews.128-131 Even in the United States, points.135 Even borderline iodine deficiency, as seen in Europe, can be
iodine intake has declined, and 15% of women of childbearing age and accompanied by impaired school achievements by apparently normal
7% of pregnant women were found to have urinary iodine excretions children, as reviewed by Glinoer.129
below 50 μg/L, indicative of moderate iodine deficiency.132 Actions taken to eradicate iodine deficiency have prevented the
Pregnancy is an environmental trigger for the thyroid machinery, occurrence of mental retardation in millions of infants throughout
inducing changes in people who live in geographic areas that have the world. In a study by Xue-Yi and coauthors136 of a severely iodine-
iodine deficiency. Four biochemical markers are useful for following deficient area of the Xinjiang region of China, iodine was administered
the changes induced: to pregnant women. The prevalence of moderate or severe neurologic
abnormalities among 120 infants whose mothers received iodine in the
1. Relative hypothyroxinemia first or second trimester was 2%, compared with 9% (of 952 infants)
2. Preferential T3 secretion as reflected by an elevated T3/T4 molar when the mothers received iodine in the third trimester (P = .008).
ratio Although treatment in the third trimester did not improve neurologic
3. Increased TSH after the first trimester, progressing until term status, head growth and developmental quotients improved slightly.
4. Supranormal thyroglobulin concentrations correlating with gesta- The importance of thyroid hormone to fetal and neonatal well-
tional goitrogenesis being and development was highlighted by a remarkable case of an
infant born to a mother with strongly positive TSH receptor-blocking
Goitrogenesis also occurs in the fetus, indicating the exquisite sen- antibodies. The mother was profoundly hypothyroid when tested after
sitivity of the fetal thyroid gland to the consequences of maternal delivery. The infant was delivered by cesarean section because of bra-
iodine deficiency. This process can start during the earliest stages of dycardia. She was also profoundly hypothyroid and required intuba-
fetal thyroid development. It occurs against a background of low initial tion. Her brain size was reduced, and her auditory brainstem response
maternal intrathyroidal iodine stores, the increased need for iodine was absent at age 2 months. The audiogram at age 4 years revealed
after pregnancy occurs, and the insufficiency of iodine intake through- sensorineural deafness. At age 6 years, motor development was the
out the gestation. same as at age 4 months. She required T4 for 8 months until the anti-
It appears that maternal thyroxine, traversing the placenta during body effect had worn off. Her physical growth was normal. The
the first trimester and subsequently, is necessary for fetal brain devel- outcome of severe thyroid hormone deficiency in utero was fetal dis-
opment. Even before fetal thyroid hormone synthesis, T3 receptors are tress, permanent auditory deficit, brain atrophy, and severely impaired
found in fetal brain tissues, and local conversion of T4 to T3 can occur. neuromotor development despite adequate neonatal treatment.137
Iodine deficiency perpetuates the process, because the fetus is less The Institute of Medicine of the National Academy of Sciences has
able to synthesize thyroid hormones even when the fetal thyroid has set the iodine requirement as 110 μg for infants 0 to 6 months, 130 μg
developed. for infants 7 to 12 months, 90 μg for children 1 to 8 years, 120 μg for
In severe iodine deficiency (intake of 20 to 25 μg/day), a condition those 9 to 13 years, and 150 μg for those older than 13 years. The rec-
known as endemic cretinism occurs, with a prevalence up to 15% in ommended intake for pregnancy and lactation is 200 μg/day. Even
severely affected populations. These infants are characterized by severe higher intakes (300 to 400 μg/day) have been suggested.138
mental retardation with a neurologic picture including deaf-mutism,
squint, and pyramidal and extrapyramidal syndromes. There are few
clinical signs of thyroid failure. A remarkable exception to this picture
has emerged from Africa, where the cretins have less mental retarda- Hypothyroidism
tion and less in the way of neurologic deficits. The clinical picture is
that of severe thyroid failure with dwarfism, delayed sexual maturation, Signs and Symptoms
and myxedema. Thyroid function is grossly impaired. Hypothyroidism occurs with a frequency of 1 case in 1600 to 2000
The consensus is that the neurologic picture of endemic cretinism deliveries.67 Population screening studies have revealed a higher inci-
results from insults to the developing brain, occurring perhaps during dence. In a study in the United States, serum TSH levels were deter-
the first trimester (in the case of deafness) and mostly during the mined in 2000 women between gestational weeks 15 to 18; 49 (2.5%)
second trimester, with the cerebellar abnormalities resulting from had TSH levels greater than or equal to 6 mU/L, and positive thyroid
postnatal insult. This is supported by the observation that the full antibodies were found in 58% of these 49 women, compared with 11%
picture can be prevented only when the iodine deficiency is corrected of control euthyroid pregnant women.139 In a Japanese study, only
before the second trimester and, optimally, even before conception.133 0.29% had an elevated TSH level.140 In another U.S. study, 1 infant in
In Africa, iodine deficiency is complicated by selenium deficiency. The 1629 deliveries had hypothyroidism.141
deficiency of selenium leads to accumulation of peroxide, and excess Women with hypothyroidism have higher pregnancy complication
peroxide leads to destruction of thyroid cells and hypothyroidism.134 rates. As well as miscarriages, complications include preeclampsia, pla-
Selenium deficiency also induces monodeiodinase I (a selenoenzyme) cental abruption, low birth weight, prematurity, and stillbirths.142
deficiency, resulting in reduced T4 to T3 conversion and increased avail- These outcomes can be improved with early therapy. Gestational
ability of maternal T4 for the fetal brain. This protective mechanism hypertension is also more common.141
may prevent the development of neurologic cretinism, and the com- The symptoms of hypothyroidism are insidious and can be masked
bined iodine-selenium deficiency prevalent in Africa may help explain by the hypermetabolic state of pregnancy. Symptoms can include
the predominance of the myxedematous type observed there. modest weight gain, decrease in exercise capacity, lethargy, and intoler-
The neurologic abnormalities and mental retardation depend ulti- ance to cold. In moderately symptomatic patients, constipation,
mately on the timing and severity of the brain insult. Endemic cretin- hoarseness, hair loss, brittle nails, and dry skin also can occur. Physical
ism constitutes only the extreme expression of the spectrum of physical signs may include a goiter, a thyroidectomy scar, and delay in the
and intellectual abnormalities. In a meta-analysis of 18 studies in areas relaxation phase of deep tendon reflexes.

13. CHAPTER 47 Thyroid Disease and Pregnancy 1007
Laboratory confirmation is obtained from an elevated TSH level, the third trimester in about one third of patients.2 In a study of 12
with or without suppressed free T4. Test results for thyroid autoanti- pregnant women with hypothyroidism, 9 required a higher T4 dose,
bodies (antithyroglobulin and antithyroid peroxidase) may be positive. with a mean dose increase of 45%.146 In a review of 77 pregnancies in
Other laboratory abnormalities can include elevated levels of creatine 65 hypothyroid women, serum TSH levels became abnormal in 70%
phosphokinase, cholesterol, and carotene and liver function abnor- of women with prior 131I ablation therapy and in 47% of women with
malities. Patients may have macrocytic or normochromic, normocytic chronic thyroiditis. When data from other studies were pooled, overall,
anemia. Hypothyroidism may occur more frequently in pregnant TSH levels increased above normal in 45% with a mean daily thyroxine
women with type 1 diabetes, and T4 replacement therapy can increase dose of 146 μg.147,148 It was estimated that the increment in dose could
insulin requirements.143 be predicted according to the TSH value at the first evaluation. The
TSH concentration should be determined again 4 to 6 weeks after dose
adjustment.
Differential Diagnosis The causes of increased T4 requirements include a real increased
Hashimoto thyroiditis, also known as chronic lymphocytic thyroiditis, demand for T4 in pregnancy149 in patients whose thyroid reserve is
an autoimmune disease, is the most common cause of hypothyroidism compromised and, in some cases, iron therapy. Ferrous sulfate inter-
and can occur in 8% to 10% of women of reproductive age. It is char- feres with T4 absorption and should be taken at a different time of day
acterized by the presence of antithyroid antibodies, and the patient from thyroxine therapy.150 Patients with thyroid cancer whose target
may have a goiter. Titers of antithyroglobulin are elevated in 50% to TSH concentration is below the normal range almost uniformly require
70% of patients, and almost all have antithyroid peroxidase anti- an increased dose to maintain their suppressed TSH levels, and they
bodies.53 The goiter is firm and diffusely enlarged and painless, and the should be followed closely.150 After delivery, the dose should be reduced
gland is infiltrated by lymphocytes and plasma cells. Many patients to pre-pregnancy levels in all patients, and the TSH concentration
with Hashimoto thyroiditis are actually euthyroid but can subsequently should be measured 6 to 8 weeks later.
develop hypothyroidism. The thyroid gland can be atrophic and the The topic of thyroid hormone and intellectual development has
test result for antibodies negative—so-called idiopathic hypothyroid- received widespread publicity and has been the subject of articles and
ism. Patients with other autoimmune disease also can develop Hashi- reviews in the past few years.128,151,152 In 1969, Man and Jones153 studied
moto thyroiditis. a cohort of 1349 children and concluded that mild maternal hypothy-
Other important and common causes of hypothyroidism include roidism alone was associated with lower IQ levels in the offspring. In
131
I therapy, ablation for Graves disease, and thyroidectomy (e.g., for 1990, Matsuura and Konishi154 documented that fetal brain develop-
thyroid cancer). Of patients who receive 131I therapy, 10% to 20% are ment is affected adversely when both mother and fetus have hypothy-
hypothyroid within the first 6 months, and 2% to 4% become hypo- roidism caused by chronic autoimmune thyroiditis. With the
thyroid each year thereafter.144 Hypothyroidism can result from sub- background of this information and the associations of iodine defi-
acute viral thyroiditis and, much less commonly, from suppurative ciency, its consequent maternal hypothyroxinemia, and abnormal fetal
thyroiditis. brain development, Haddow and associates151 conducted a study mea-
Drugs known to inhibit the synthesis of thyroid hormones include suring TSH levels from stored samples in more than 25,000 pregnant
thionamide, iodides, and lithium. Carbamazepine, phenytoin, and women. They located 62 women with high TSH levels and 124 matched
rifampin can increase thyroid clearance. Aluminum hydroxide, chole- women with normal values. Their 7- to 9-year-old children, none of
styramine, and, most important, ferrous sulfate and sucralfate can whom had hypothyroidism as newborns, underwent 15 tests relating
interfere with the intestinal absorption of thyroxine. to intelligence, attention, language, reading ability, school performance,
Hypothyroidism resulting from hypothalamic or pituitary disease and visual-motor performance. The full-scale IQ in children of hypo-
is rare but can occur in the setting of pituitary tumors, after pituitary thyroid women was 4 points lower (P = .06); 15% had scores of 85 or
surgery or irradiation, and in Sheehan’s syndrome and lymphocytic less compared with 5% of controls. The IQ of the children of 48
hypophysitis, an autoimmune disease with a predilection for women, women whose hypothyroidism was not treated averaged 7 points lower
especially in the setting of pregnancy (see Chapter 48). In secondary than the 124 controls (P = .005), and 19% had scores of 85 or lower.
hypothyroidism, the TSH level may be low or normal, but the free T4 The researchers concluded that undiagnosed hypothyroidism can
level is low. affect fetuses adversely and recommended screening for hypothyroid-
ism in pregnancy. Fukushi and coworkers155 reported on such screen-
ing in Japan and found hypothyroidism in 1 of 692 pregnancies.
Treatment In a study by Pop and colleagues,156 even the presence of antithyroid
Hypothyroidism must be treated promptly, and a dose of 0.1 to 0.15 mg peroxidase antibodies in the maternal circulation was shown to have
of T4 per day, should be initiated. The dose is adjusted every 4 weeks deleterious effects on child development. In two similar studies, thyroid
until the TSH concentration is in the lower end of the normal range. antibody–positive women had lower free T4 levels, and lower scores on
In women with little or no functioning thyroid tissue, a dose of 2 μg/ psychomotor tests were found in children of mothers whose free T4
kg/day may be required. Women who are euthyroid on T4 need to be value was below the 5th and 10th percentiles as measured at 12 weeks’
checked as soon as pregnancy is established; the dose should be adjusted gestation.157,158
and rechecked in 4 to 8 weeks,145 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 Subclinical Hypothyroidism
may depend on the cause. For example, women who have had total
thyroidectomy may need a greater increase than women with mild
and Hypothyroxinemia
hypothyroidism. Increased dosage requirements may plateau by the Subclinical hypothyroidism is defined as an elevated TSH level when
20th week,145 but the need for increased dosage may be seen as late as the free T4 level is in the normal range. More than 90% of hypothyroid-