Antenatal thyroid disease and pharmacotherapy in pregnancy


Thyroid function and physiology in pregnancy

In pregnancy, abnormalities of the thyroid gland can be easily overlooked due to the normal physiologic changes of pregnancy often mimicking disturbances of thyroid gland function. As a result, basic knowledge of thyroid gland function and the changes the thyroid gland undergoes during the course of pregnancy are essential. Regulation of the thyroid gland and its hormones is controlled through an endocrine feedback loop that includes the hypothalamus and anterior pituitary [ ]. The hypothalamus initiates this feedback loop with the release of thyrotropin-releasing hormone, which in turn regulates the release of thyroid-stimulating hormone (TSH) from thyrotrope cells in the anterior pituitary. TSH then prompts the release of thyroid hormones T4 and T3 from the thyroid gland. Abnormal production of T4 and T3 occurs with hyperthyroidism and hypothyroidism in the pregnant patient, with various etiologies accounting for the observed abnormal levels (see Table 19.1 ).

Table 19.1
Maternal thyroid function testing and associated physiologic alterations in normal pregnancy.
Increased Decreased No change
Thyroid-binding globulin (TBG) TSH Free T3 (FT3)
Total T3 (TT3) Plasma iodide Free T4 (FT4)
Total T4 (TT4) Hepatic clearance
Thyroid gland size
hCG
Albumin

The physiologic changes of normal pregnancy affect thyroid function in numerous ways. The thyroid gland itself increases in size and can be newly palpable on physical examination. This increase in size is due to an increase in thyroid volume, the formation of new thyroid nodules, and/or increased iodine turnover [ , ]. In fact, the maternal thyroid volume is 30% larger in the third trimester than in the first trimester [ ]. Although the formation of thyroid nodules can occur during pregnancy, any palpable nodule should be evaluated with an ultrasound of the thyroid gland [ ]. Overall, these changes normally occur without any significant change in thyroid hormone levels, but physical examination of the thyroid gland during pregnancy is important on entry to prenatal care, especially if the patient is exhibiting potential signs or symptoms of thyroid gland dysfunction (see Table 19.2 ).

Table 19.2
Maternal signs and symptoms of hyperthyroidism and hypothyroidism.
Hyperthyroidism Hypothyroidism
Nervousness Fatigue
Tremors Constipation
Tachycardia Cold intolerance
Frequent stools
Excessive sweating
Muscle cramps
Weight gain
Heat intolerance
Weight loss
Goiter
Insomnia
Edema
Dry skin
Hair loss
Prolonged relaxation phase of reflexes
Palpitations
Hypertension
Lid lag and lid retraction
Localized or pretibial myxedema

The observed increase in iodine turnover and subsequent depletion of the maternal iodine pool is predominantly the result of a reduction in serum iodine due to fetal use of maternal iodine and increased maternal renal clearance of iodine, which also causes an increase in thyroid gland size in 15% of pregnant women [ ]. As pregnancy progresses, maternal renal clearance of iodine increases due to an increase in renal blood flow and glomerular filtration rate, which further increases iodine clearance [ ]. The American Thyroid Association (ATA) recommends a daily allowance of iodine of 150 mcg for nonpregnant adults, 220–250 mcg in pregnant women, and 250–290 mcg in breastfeeding women. As a result, women should take multivitamins containing 150 mcg of iodine daily in the form of potassium iodine during the preconception period, pregnancy, and lactation [ ].

The physiologic changes of thyroid gland function, particularly during the first trimester of pregnancy, are well documented. TSH and human chorionic gonadotropin (hCG) are glycoproteins that share similar alpha subunits. This similarity between the alpha subunits results in negative feedback on the pituitary by hCG and decreased TSH production [ , , , ]. As hCG levels continue to rise during the first trimester, TSH levels decline by approximately 20%–50% reaching a maximal decrease at 8–14 weeks' gestation [ , , ]. In fact, TSH levels may decrease below the lower limit of normal in up to 20% of women with little clinical consequence [ ]. As a result of this decrease in TSH, the levels of FT4 and FT3 may slightly increase and even reach high-normal levels. The observed changes in TSH, FT4, and FT3 are referred to as transient subclinical hyperthyroidism or gestational transient thyrotoxicosis (GTT). GTT affects 1%–5% of pregnant women and typically does not require treatment since it is not due to intrinsic thyroid disease [ , ]. In the second and third trimesters, TSH levels will start to rise due to the increased renal clearance of iodine and placental degradation of thyroid hormone, and a decrease in FT4 and FT3 levels back into normal range will follow [ ] (see Table 19.3 ).

Table 19.3
Maternal thyroid disease and relation to TSH and FT4.
TSH FT4
Subclinical hyperthyroidism (or GTT) Decreased Normal to high normal
Hyperthyroidism Decreased Increased
Subclinical hypothyroidism Increased Normal to low normal
Hypothyroidism Increased Decreased

Although circulating T4 and T3 are predominantly bound (>99%) to the carrier proteins TBG and albumin, it is the free hormone (<1%) that is biologically active. During pregnancy, serum TBG levels increase 2–3-fold due to increased TBG synthesis through the effects of increased estrogen and decreased hepatic clearance [ , , , , ]. Increased TBG leads to a rise in TT4 and TT3 concentrations by approximately 50% starting at 6 weeks of gestation without significantly altering FT4 and FT3 concentrations [ , , ]. In addition, the thyrotrophic effect of hCG likely further contributes to the increase in TT4 and TT3 concentrations [ ].

Since FT4 and FT3 are the biologically active hormones, unaltered levels of FT4 and FT3 ideally allow the pregnant patient to remain euthyroid during this time. Although there can be a transient rise in FT4 during the first trimester due to increasing levels of hCG and its thyrotropic effect, TSH will start to increase in the latter trimesters resulting in a fall in FT4 as previously mentioned [ ]. Overall, the FT4 levels should remain within normal to high-normal range, and FT3 levels will parallel that of FT4 and remain in the normal reference range as well [ ] (see Table 19.1 ).

Hyperthyroidism in pregnancy

Hyperthyroidism occurs in 0.2% of pregnant women, or 1 in every 1000–2000 pregnancies [ , , , ]. The causes of hyperthyroidism are multiple and include autoimmune disease, nodular goiter, solitary toxic adenoma, gestational trophoblastic disease, subacute and lymphocytic thyroiditis, and tumors of the pituitary gland or ovary [ ].

Graves' disease is the most common cause in pregnancy, occurring in 85%–95% of all pregnant patients with hyperthyroidism [ , ]. It is an autoimmune disease caused by autoantibodies that activate the TSH receptor and stimulate the thyroid to produce an excessive amount of thyroid hormone [ , ]. TSH (thyrotropin) receptor antibodies (TRAb) can be stimulating, blocking, or neutral. The thyroid-stimulating antibodies (TSAb) cause hyperthyroidism, while the thyroid-blocking antibodies (TBAb) cause hypothyroidism. The receptor assays that measure TSH receptor–binding inhibitory immunoglobulins measure antibodies that block binding of TSH to an in vitro TSH receptor preparation and do not differentiate between TSAb and TBAb [ , ]. These TRAb cause thyroid hyperfunction and thyroid gland hypertrophy, although there is no correlation between levels of antibody activity and disease severity [ ]. Of note, Graves' disease may also be caused by TSH receptor–blocking antibodies as well.

TRAb are measurable in around 95% of patients with active Graves' hyperthyroidism [ ]. Furthermore, elevated TRAb levels carry a prognostic value for fetal and neonatal thyrotoxicosis as TRAb can cross the placenta resulting in neonatal thyrotoxicosis in 1%–5% of neonates of mothers with Graves' disease [ , ]. If high titers persist in the third trimester, fetal or neonatal hyperthyroidism is more likely to develop [ , ]. Such a complication is more likely if maternal Graves' disease has been difficult to control or there has been a delay in diagnosis [ , ]. Once the diagnosis of hyperthyroidism is established, consideration for evaluation of TRAb levels in early pregnancy and again in the third trimester to assess for the potential of neonatal disease is recommended by some [ , ]. The ATA recommends evaluation of TRAb since levels greater than >5 IU/L, or 3 times the upper level of normal in the latter half of pregnancy, predicted neonatal hyperthyroidism with 100% sensitivity and 43% specificity [ ] (see Table 19.4 ).

Table 19.4
Maternal thyroid antibodies and neonatal thyroid gland effects.
Hyperthyroidism Hypothyroidism
TSH receptor antibodies (TRAbs):

  • (Can be activating (TSI) or blocking (TBII))

  • Thyroid-stimulating antibodies (TSAbs)-Can cause neonatal thyrotoxicosis

  • Thyroid-blocking antibodies (TBAbs)-Can cause hypothyroidism or transient neonatal hypothyroidism

Thyroglobulin antibodies (TgAbs):

  • Do not affect fetal thyroid gland function

Thyroid peroxidase antibodies (TPOAbs):

  • Do not affect fetal thyroid gland function

As previously discussed, GTT can occur in the first trimester of pregnancy due to the cross-reactivity of the alpha subunits of TSH and hCG. During this period of gestation, differentiating between GTT and true Graves' disease is important as the former is expected to resolve spontaneously without intervention and the latter requires therapeutic intervention. The symptoms specific to hyperthyroidism should help to confirm the diagnosis of intrinsic thyroid disease versus normal physiologic changes of pregnancy (see Table 19.2 ).

In the first trimester, if the TSH is suppressed, FT4 is elevated, and the patient is symptomatic, the diagnosis of overt hyperthyroidism should be established. Laboratory assays of TRAb will likely be abnormal and are not necessary to make a diagnosis. If the TSH is suppressed, FT4 is normal to high normal, and the patient is symptomatic, laboratory assays of TRAb should be considered to help differentiate between a diagnosis of hyperthyroidism or GTT [ ]. If TRAb are normal, the diagnosis is GTT or subclinical hyperthyroidism. If elevated levels of TRAb exist, the diagnosis of hyperthyroidism is confirmed.

Once again, GTT (suppressed TSH and normal-high normal FT4) is the diagnosis if there are no TRAb, thyroid nodules, goiter, or orbitopathy present, and there is no prior maternal history of Graves' disease [ , ]. Once the diagnosis of GTT is confirmed, the patient can be reassured that symptoms and laboratory abnormalities will resolve without intervention. Of note, the increase in hCG that is associated with GTT is also a contributor to the development of hyperemesis gravidarum (HG), which is the more severe form of nausea and vomiting in pregnancy (NVP) typically seen in the first trimester. HG is defined as persistent nausea and vomiting resulting in greater than 5% weight loss, ketonuria, dehydration, and electrolyte imbalance [ , , ]. Abnormal thyroid function tests similar to that observed in GTT, including elevated FT4 into the high-normal range and suppressed or undetectable TSH, are found in about 60% of women with HG with levels typically normalizing after 16–20 weeks [ , ]. Finally, newly diagnosed cases of overt hyperthyroidism can present with HG or NVP, making thyroid function testing essential. In this scenario, once therapy is initiated, symptoms resolve with successful treatment of the disease [ ].

Uncontrolled or poorly controlled hyperthyroidism in pregnancy has significant maternal and fetal/neonatal effects. Maternal complications include insufficient weight gain, heart failure, preeclampsia, and thyroid storm, a true medical emergency that may be precipitated by labor and delivery, infection, or preeclampsia. When considering the fetus, there is an increase in fetal loss, low birth weight, preterm labor, and congenital malformations [ , , , ]. As stated earlier, the neonate can be affected by the transplacental transfer of TRAb [ , , ]. Furthermore, the fetus may also develop tachycardia and goiter in utero due to the presence of these antibodies, and in severe cases cardiac failure and fetal hydrops. There is not a general consensus on whether to routinely follow TRAb in a patient with Graves' disease. However, if the patient is poorly controlled, continues to be symptomatic, or is noncompliant with treatment, evaluation of TRAb should be considered. The 2017 guidelines of the ATA lists specific indications for ordering TRAb in pregnancy and recommends repeat testing at weeks 18–22 of pregnancy if the maternal TRAb concentration is elevated in early pregnancy or if treatment with antithyroid drugs (ATDs) is indicated [ ]. However, such rigorous use of TRAb testing in maternal thyroid disease has not been recommended by the American College of Obstetricians and Gynecologists (ACOG).

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