Taken in aggregate, these are common in young women and thus frequently managed in pregnancy.

There is an intimate relationship between maternal and fetal thyroid function, and drugs that affect
the maternal thyroid also affect the fetal gland. Moreover, thyroid autoantibodies have been
associated with increased early pregnancy wastage, and uncontrolled thyrotoxicosis and untreated
hypothyroidism are both associated with adverse pregnancy outcomes. Finally, there is evidence
that autoimmune thyroid disorder severity may be ameliorated during pregnancy, only to be
exacerbated postpartum.

Thyroid Physiology and Pregnancy

Maternal thyroid changes are substantial, and normally altered gland structure and function are
sometimes confused with thyroid abnormalities. These alterations are discussed in detail in Chapter
4 (p. 68), and normal hormone level values are found in the Appendix (p. 1290). First, maternal
serum concentrations of thyroid-binding globulin are increased concomitantly with total or bound
thyroid hormone levels (Fig. 4-17, p. 69). Second, thyrotropin, also called thyroid-stimulating
hormone (TSH), currently plays a central role in screening and diagnosis of many thyroid disorders.
Serum TSH levels in early pregnancy decline because of weak TSH-receptor stimulation from massive
quantities of human chorionic gonadotropin (hCG) secreted by placental trophoblast. Because TSH
does not cross the placenta, it has no direct fetal effects. During the first 12 weeks of gestation,
when hCG serum levels are maximal, thyroid hormone secretion is stimulated. The resulting
increased serum free thyroxine levels act to suppress hypothalamic thyrotropinreleasing hormone
(TRH) and in turn limit pituitary TSH secretion (Fig. 58-1). Accordingly, TRH is undetectable in
maternal serum. Conversely, beginning at midpregnancy TRH becomes detectable in fetal serum, but
levels are static and do not increase with advancing gestation.

Throughout pregnancy, maternal thyroxine is transferred to the fetus (Calvo, 2002).

Maternal thyroxine is important for normal fetal brain development, especially before development
of fetal thyroid gland function (Bernal, 2007). And even though the fetal gland begins concentrating
iodine and synthesizing thyroid hormone after 12 weeks’ gestation, maternal thyroxine contribution
remains important. In fact, maternal sources account for 30 percent of thyroxine in fetal serum at
term (Thorpe-Beeston, 1991; Vulsma, 1989). Developmental risks associated with maternal
hypothyroidism after midpregnancy, however, remain poorly understood (Morreale de Escobar,
2004).

Hyperthyroidism

The incidence of thyrotoxicosis or hyperthyroidism in pregnancy is varied and complicates

between 2 and 17 per 1000 births when gestational-age appropriate TSH threshold values are used
(Table 58-1). Because normal pregnancy simulates some clinical findings similar to thyroxine (T4)
excess, clinically mild thyrotoxicosis may be difficult to diagnose. Suggestive findings include
tachycardia that exceeds that usually seen with normal pregnancy, thyromegaly, exophthalmos, and
failure to gain weight despite adequate food intake. Laboratory confirmation is by a markedly
depressed TSH level along with an elevate serum free T4 (fT4) level. Rarely, hyperthyroidism is
caused by abnormally high serum triiodothyronine (T3) levels—socalled T3-toxicosis.
 Treatment

Thyrotoxicosis during pregnancy can nearly always be controlled by thionamide drugs.

Propylthiouracil (PTU) has been historically preferred because it partially inhibits the conversion of
T4 to T3 and crosses the placenta less readily than methimazole. The latter has also been associated
with a rare methimazole embryopathy characterized by esophageal or choanal atresia as well as
aplasia cutis, a congenital skin defect. Yoshihara and associates (2012) analyzed more than 5000
Japanese women with first-trimester hyperthyroidism and found a twofold increased risk of major
fetal malformations in pregnancies exposed to methimazole compared with the risk from PTU.
Specifically, seven of nine cases with aplasia cutis and the only case of esophageal atresia were in
the group of methimazole-exposed infants.

Until recently, PTU has been the preferred thionamide in the United States (Brent, 2008). In
2009, however, the Food and Drug Administration issued a safety alert on PTUassociated
hepatotoxicity. This warning prompted the American Thyroid Association and the American
Association of Clinical Endocrinologists (2011) to recommend PTU therapy during the first trimester
followed by methimazole beginning in the second trimester. The obvious disadvantage is that this
might lead to poorly controlled thyroid function. Accordingly, at Parkland Hospital we continue to
prescribe PTU treatment throughout pregnancy.

Transient leukopenia can be documented in up to 10 percent of women taking antithyroid

drugs, but this does not require therapy cessation. In 0.3 to 0.4 percent, however, agranulocytosis
develops suddenly and mandates drug discontinuance. It is not dose related, and because of its
acute onset, serial leukocyte counts during therapy are not helpful. Thus, if fever or sore throat
develops, women are instructed to discontinue medication immediately and report for a complete
blood count (Brent, 2008).

As mentioned above, hepatotoxicity is another potentially serious side effect that develops
in 0.1 to 0.2 percent. Serial measurement of hepatic enzymes has not been shown to prevent
fulminant PTU-related hepatotoxicity. Also, approximately 20 percent of patients treated with PTU
develop antineutrophil cytoplasmic antibodies (ANCA). However, only a small percentage of these
subsequently develop serious vasculitis (Helfgott, 2002; Kimura, 2013). Finally, although thionamides
have the potential to cause fetal complications, these are uncommon. In some cases, thionamides
may even be therapeutic, because TSH-receptor antibodies cross the placenta and can stimulate the
fetal thyroid gland to cause thyrotoxicosis and goiter.

The initial thionamide dose is empirical. For nonpregnant patients, the American Thyroid
Association recommends that methimazole be used at an initial higher daily dose of 10 to 20 mg
orally followed by a lower maintenance dose of 5 to 10 mg. If PTU is selected, a dose of 50 to 150 mg
orally three times daily may be initiated depending on clinical severity (Bahn, 2011). At Parkland
Hospital, we usually initially give 300 or 450 mg of PTU daily in three divided doses for pregnant
women. Occasionally, daily doses of 600 mg are necessary. As discussed, we generally do not
transition women to methimazole during the second trimester. The goal is treatment with the
lowest possible thionamide dose to maintain thyroid hormone levels slightly above or in the high
normal range while TSH levels remains suppressed (Bahn, 2011). Serum free T4 concentrations are
measured every 4 to 6 weeks (National Academy of Clinical Biochemistry, 2002).

Subtotal thyroidectomy can be performed after thyrotoxicosis is medically controlled. This

seldom is done during pregnancy but may be appropriate for the very few women who cannot
adhere to medical treatment or in whom drug therapy proves toxic (Davison, 2001; Stagnaro-Green,
2012a). Surgery is best accomplished in the second trimester. Potential drawbacks of thyroidectomy
during pregnancy include inadvertent resection of parathyroid glands and injury to the recurrent
laryngeal nerve (Fitzpatrick, 2010).

Thyroid ablation with therapeutic radioactive iodine is contraindicated during pregnancy.

These doses may also cause fetal thyroid gland destruction. Thus, when given unintentionally, many
clinicians recommend abortion. Any exposed fetus must be carefully evaluated, and the incidence of
fetal hypothyroidism depends on gestational age and radioiodine dose (Berlin, 2001). Tran and
colleagues (2010) describe a case in which a relatively high dose (19.8 mCi) of radioiodine early in
the first trimester resulted in a normal euthyroid male infant assessed at 6 months. The authors
hypothesized that the exposure occurred well before thyroid embryogenesis. There is no evidence
that radioiodine given before pregnancy causes fetal anomalies if enough time has passed to allow
radiation effects to dissipate and if the woman is euthyroid (Ayala, 1998). The International
Commission on Radiological Protection has recommended that women avoid pregnancy for 6
months after radioablative therapy (Brent, 2008). Moreover, during lactation, the breast also
concentrates a substantial amount of iodide. This may pose neonatal risk due to 131 I-containing
milk ingestion and maternal risk from significant breast irradiation. To limit maternal exposure and
her cancer risks, a delay of 3 months between lactation and ablation will more reliably ensure
complete breast involution (Sisson, 2011).

Pregnancy Outcome.

Women with thyrotoxicosis have pregnancy outcomes that largely depend on whether
metabolic control is achieved. For example, as discussed in Chapter 18 (p. 353), excess thyroxine
may cause miscarriage (Anselmo, 2004). In untreated women or in those who remain hyperthyroid
despite therapy, there is a higher incidence of preeclampsia, heart failure, and adverse perinatal
outcomes (Table 58-2). A prospective cohort study from China reported that women with clinical
hyperthyroidism had a 12-fold increased risk of delivering an infant with hearing loss (Su, 2011).
Perinatal mortality rates varied from 6 to 12 percent in several studies.

Fetal and Neonatal Effects

In most cases, the perinate is euthyroid. In some, however, hyper- or hypothyroidism can
develop with or without a goiter (Fig. 58-3). Clinical hyperthyroidism develops in approximately 1
percent of neonates born to women with Graves disease (Barbesino, 2013; Fitzpatrick, 2010; Luton,
2005). If fetal thyroid disease is suspected, nomograms are available for sonographically measured
thyroid volume (Gietka-Czernel, 2012; Ranzini, 2001).
 The fetus or neonate who was exposed to excessive maternal thyroxine may have any of
several clinical presentations. First, goitrous thyrotoxicosis is caused by placental transfer of
thyroidstimulating immunoglobulins. Nonimmune hydrops and fetal demise have been reported
with fetal thyrotoxicosis (Nachum, 2003; Stulberg, 2000). The best predictor of perinatal
thyrotoxicosis is presence of thyroid-stimulating TSH-receptor antibodies in women with Graves
disease. This is especially true if their levels are more than threefold higher than the upper normal
limit (Barbesino, 2013). In a study of 72 pregnant women with Graves disease, Luton and associates
(2005) reported that none of the fetuses in 31 low-risk mothers had a goiter, and all were euthyroid
at delivery. Low risk was defined by no antithyroid medications during the third trimester or absence
of antithyroid antibodies. Conversely, in a group of 41 women who either were taking antithyroid
medication at delivery or had thyroid receptor antibodies, 11 fetuses—27 percent—had sonographic
evidence of a goiter at 32 weeks’ gestation. Seven of these 11 were determined to be hypothyroid,
and the remaining fetuses were hyperthyroid. In response to such results, the American Thyroid
Association and American Association of Clinical Endocrinologists (2011) recommend routine
evaluation of TSH-receptor antibodies between 22 and 26 weeks’ gestation in women with Graves
disease. The American College of Obstetricians and Gynecologists (2013), however, does not
recommend such testing because management is rarely changed by the results. If the fetus is
thyrotoxic, treatment is by adjustment of maternal thionamide drugs even though maternal thyroid
function may be within the targeted range (Duncombe, 2001; Mestman, 2012). Occasionally,
neonatal thyrotoxicosis may also require short-course antithyroid drug treatment.

A second presentation is goitrous hypothyroidism caused by fetal exposure to maternally

administered thionamides (see Fig. 58-3). Although there are theoretical neurological implications,
reports of adverse fetal effects seem to have been exaggerated. Available data indicate that
thionamides carry an extremely small risk for causing neonatal hypothyroidism (Momotani, 1997;
O’Doherty, 1999). For example, of the 239 treated thyrotoxic women shown in Table 58-1, there was
evidence of hypothyroidism in only four infants despite relatively high maternal PTU doses.
Furthermore, at least four long-term studies report no abnormal intellectual and physical
development of these children (Mestman, 1998). If hypothyroidism is identified, the fetus can be
treated by a reduced maternal antithyroid medication dose and injection of intraamnionic thyroxine
if necessary

A third presentation, nongoitrous hypothyroidism, may develop from transplacental passage

of maternal TSH-receptor blocking antibodies (Fitzpatrick, 2010; Gallagher, 2001). And finally, fetal
thyrotoxicosis after maternal thyroid gland ablation, usually with 131I radioiodine, may result from
transplacental thyroid-stimulating antibodies. In the previously described case of early fetal
exposure to radioiodine, neonatal thyroid studies indicated transient hyperthyroidism from maternal
transfer of stimulating antibodies (Tran, 2010).

Fetal Diagnosis.

Evaluation of fetal thyroid function is somewhat controversial. Although fetal thyroid

sonographic assessment has been reported in women taking thionamide drugs or those with
thyroid-stimulating antibodies, most investigators do not currently recommend this routinely
(Cohen, 2003; Luton, 2005). Kilpatrick (2003) recommends umbilical blood sampling and fetal
antibody testing only if the mother has previously undergone radioiodine ablation. Because fetal
hyper- or hypothyroidism may cause hydrops, growth restriction, goiter, or tachycardia, fetal blood
sampling may be appropriate if these are identified (Brand, 2005). The Endocrine Society Clinical
Practice Guidelines recommend umbilical blood sampling only when the diagnosis of fetal thyroid
disease cannot be reasonably ascertained based on clinical and sonographic data (Garber, 2012).
Diagnosis and treatment are considered further in Chapter 16 (p. 324).