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Thirteen million Americans are affected with thyroid disease. Thyroid disease
often manifests itself during the reproductive period of a womans life and is the
second most common endocrinopathy that affects women of childbearing age.
The physiologic changes of pregnancy can mimic thyroid disease or cause a true
remission or exacerbation of underlying disease. In addition, thyroid hormones
are key players in fetal brain development.
Maternal, fetal and neonatal thyroid are discussed here. Moreover, this article
serves as a review of the more common thyroid diseases that are encountered
during pregnancy and the postnatal period, their treatments, and their potential
effects on pregnancy.
Maternal physiology
Normal thyroid physiology
The thyroid gland is composed of two lobes that are connected by the isthmus.
Each lobe is divided into lobules; each lobule contains 20 to 40 follicles. Each
follicle consists of colloid, a glycoprotein-rich material, which is surrounded by
follicular cells that produce thyroid hormone.
The hypothalamic pituitary axis is responsible for the maintenance of thyroid
hormone production. Thyrotropin-releasing hormone (TRH) is produced in a
* Corresponding author.
E-mail address: donna.neale@yale.edu (D. Neale).
0889-8545/04/$ see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.ogc.2004.09.001
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Maternal T4 and T3 cross the placenta, whereas maternal TSH does not. It is
believed that enough maternal T4 crosses the placenta to sustain fetal thyroid
function because it was shown that umbilical cord T4 levels in neonates who have
congenital hypothyroidism are up to 50% of the normal [9]. There also is transplacental transfer of TRH, iodine, thyroid stimulatory immunoglobulin (TSI),
propylthiouracil (PTU), methimazole, and b- blockers. Amniotic fluid measurements of TSH, T4, and T3 levels reflect fetal serum levels.
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Graves disease
Graves disease accounts for 95% of cases of thyrotoxicosis during pregnancy.
This is an organ-specific autoimmune disease that is mediated by thyroid
stimulatory immunoglobins. These autoantibodies mimic TSH and its ability to
stimulate thyroid function. They are responsible for thyroid hyperfunction and
thyroid gland hypertrophy. There does not seem to be any clinical correlation
between levels of antibody activity and disease severity. These antibodies,
however, can cross the placenta and cause neonatal Graves disease. In addition
to the traditional signs and symptoms of hyperthyroidism that were outlined
above, proptosis and external ocular muscle palsies along with localized or
pretibial myxedema are distinctive symptoms of Graves disease.
The goal of treatment of hyperthyroidism during pregnancy is to keep the
patient euthyroid with the free T4 in the upper limit of normal range so as not to
cause fetal or neonatal hypothyroidism. In the United States, PTU is the drug of
choice, whereas in Canada and Europe, methimazole or carbimazole (metabolized to methimazole) often are used. Both are thionamides, which inhibit
iodination of thyroglobulin and thyroglobulin synthesis by competing with iodine
for the enzyme peroxidase [15]. PTU also blocks the conversion of T4 and T3.
PTU is started at dosages of 100 mg to 150 mg every 8 hours (total daily dose
should be 300 mg450 mg, depending on severity of disease). It may take 6 to
8 weeks to see a clinical change. Free T4 levels should be monitored monthly.
After the mother is euthyroid, the dosage of PTU should be tapered. The side
effects of PTU include rash (5%), pruritus, hepatitis, lupus-like syndrome, drug
fever, and bronchospasm. The risks of uncontrolled thyroid disease outweigh these
risks, so daily dosages of up to 600 mg can be used. An alternative thionamide also
can be tried, but there is a 50% cross sensitivity. Agranulocytosis is a rare, but
serious, side effect that occurs in 0.1% of patients; it is seen particularly in older
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Thyroid storm
Thyroid storm during pregnancy is an obstetric emergency that is marked
by an extreme metabolic state. It occurs in only 10% of pregnant women who
have hyperthyroidism, but is associated with a high risk of maternal cardiac failure.
This diagnosis is suspected when patients present with a combination of fever,
change in mental status, seizures, nausea, diarrhea, and cardiac arrhythmias. An
inciting event (eg, infection, surgery, labor/delivery) can be identified and a source
of infection always should be excluded; however, after the diagnosis is suspected,
treatment should begin immediately, even if the results of serum free T4, free T3,
and TSH levels are not known. The consequences of untreated thyroid storm
can be shock, stupor, and coma.
Adequate treatment of thyroid storm is achieved using a combination of
pharmacologic agents with maternal supportive measures (eg, oxygen, IV fluids,
electrolyte replacement, antipyretics, cooling blankets) and fetal assessment.
These patients should be cared for in labor and delivery or in an ICU.
Each pharmacologic agent that is used has a synergistic role in the suppression
of thyroid function. PTU or methimazole blocks additional synthesis of thyroid
hormone by inhibiting the iodination of thyroglobulin. In addition, PTU blocks
the peripheral conversion of T4 to T3. If the patient is not able to take the
medication by mouth, methimazole rectal suppositories can be used. SSKI and
sodium iodide block the release of thyroid hormone from the thyroid gland.
Dexamethasone decreases thyroid hormone release and blocks the peripheral
conversion of T4 to T3. b-blockers are used to treat the adrenergic effects of the
excessive thyroid hormone. If the patient has a contraindication to b-blockade
(ie, history of severe bronchospasm) then Reserpine or Diltiazem can be used
instead. Phenobarbital has been used to reduce extreme agitation and it may
increase the catabolism of thyroid hormone [24].
Assessment of intravascular volume status is crucial. Invasive central
monitoring and continuous maternal cardiac monitoring may be indicated. The
perceived underlying cause of the thyroid storm should be treated. Fetal status
should be assessed with ultrasound, biophysical profile, or nonstress test,
depending on the gestational age of the fetus. Delivery should be reserved for
fetal indications that outweigh the risks to the woman.
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Hypothyroidism in pregnancy
Hypothyroidism was reported to occur in 0.05% of pregnancies [25]; however,
population-screening studies have suggested a higher incidence. In a U.S. study,
49 of 2000 women who had their serum TSH levels checked between 15 and
18 weeks of gestation had levels that were elevated to 6 mU/L or greater. Of these
49 women, 58% had positive thyroid antibodies compared with an 11% rate in the
group that was euthyroid [26]. In a more recent study that examined midtrimester
TSH levels in pregnant women, only 75 of the 25,215 women (0.30%) had elevated TSH levels [27]. The urge to determine the true incidence of hypothyroidism
in pregnancy is driven by the knowledge that these women have increased rates of
miscarriage, preeclampsia, placental abruption, growth restriction, prematurity
and stillbirths and their fetuses are at risk for impaired neurologic development.
Symptoms of hypothyroidism often can be masked by the hypermetabolic
state of pregnancy. Mild symptoms include modest weight gain, lethargy, decrease in exercise capacity, and intolerance to cold. In more symptomatic women,
constipation, hoarseness, hair loss, brittle nails, dry skin, goiter, or delay in the
relaxation phase of the deep tendon reflexes may been appreciated. Patients who
undergo thyroidectomy for Graves disease may become hypothyroid if not
supplemented with thyroid hormone postoperatively. Therefore, in patients who
have a thyroidectomy scar together with the above symptoms, the diagnosis of
hypothyroidism should be entertained. In normal pregnancy, TSH and free T4
levels should not change. In hypothyroidism, TSH can be elevated with or
without suppressed levels of free T4.
Frequently, antithyroid autoantibodies (eg, antithyroglobulin, antithyroid peroxidase) are present in cases of hypothyroidism. Other laboratory abnormalities
include elevated creatine phosphokinase, cholesterol, and liver function tests. Because having an autoimmune disease increases the likelihood of developing another, some patients present with type I diabetes mellitus. There is a 5% to 8%
prevalence of hypothyroidism in type I diabetes mellitus and women who have type
I diabetes have a 25% risk of developing postpartum thyroid dysfunction [28].
Causes of hypothyroidism
Worldwide, the most common cause of hypothyroidism is iodine deficiency.
One to 1.5 billion people are at risk; 500 million live in areas of overt iodine
deficiency [29]. Because the transplacental passage of maternal T4 is necessary for
fetal brain development early in the first trimester before the development of the
fetal thyroid gland, lack of iodine during this time may lead to impaired neurologic
development. Moreover, even when the fetal thyroid gland has developed, if there
is no iodine substrate for the gland to use, then the fetus is unable to synthesize
its own thyroid hormones. The result of severe iodine deficiency (intake of 20
25 mg/dg) is endemic cretinism. These infants are characterized by severe mental
retardation, deafness, muteness, and pyramidal or extrapyramidal syndromes; the
most common cause of mental retardation worldwide is iodine deficiency.
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Thyroid cancer
Thyroid tumors are the most common endocrine neoplasms. Most of the
nodules are benign hyperplastic (or colloid) nodules. The actual rate of malignancy is low; thyroid cancer accounts for 1% of all cancers. Three out of four
tumors occur in women; half present during the reproductive years. Therefore,
whenever a solitary or dominant nodule is found within the thyroid gland, biopsy
is recommended. Serum TSH and free T4 levels should be obtained. Radionucleotide scanning is contraindicated during pregnancy; however, ultrasonography can be used to characterize the lesion. Fine needle aspiration can be
performed safely during pregnancy. A benign lesion can be followed conservatively and reaspirated if it enlarges again. If a lesion is frankly malignant or
suspicious for papillary cancer, surgery should ensue at the earliest safe period.
There is no evidence that pregnancy causes a reactivation of thyroid cancer or
that exposure to radioactive iodine poses a risk to future pregnancies [41].
Patients should be maintained on thyroid replacement therapy with monitoring
of TSH and free T4 levels every 8 weeks.
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