THYROID PHYSIOLOGY DURING PREGNANCY
The thyroid gland is under the influence of the hypothalamic-pituitary axis. Thyrotropin- releasing hormone, produced by the hypothalamus, induces secretion of thyroid- stimulating hormone (TSH) from the pituitary gland. The production of the 2 main thyroid hormones, thyroxine (T4) and triiodothyronine (T3), is induced when TSH binds to its receptors on the thyroid gland. T3 and T4 are mostly protein bound by thyroid- binding globulin (TBG), as only 0.04% of total T4 (TT4) and 0.5% of total T3 (TT3) are available in their free form (FT4 and FT3) in serum. The free hormone negatively feeds back on the pituitary gland to down-regulate TSH production.
TT4 and TT3 increase early in pregnancy due to greater production and decreased degradation of TBG. The high levels of estrogen associated with pregnancy stimulate the liver to produce TBG and extend its half-life as well, resulting in a significant increase in TBG levels (~200%). The high TBG levels plateau at 20 weeks' gestation and remain unchanged until delivery. With increased TBG levels, one would expect the levels of free thyroid hormones to decrease, as more would be protein bound. However, human chorionic gonadotropin (hCG) acts as a weak thyroid stimulator on the TSH receptor.
This TSH-like effect by hCG leads to enhanced production of T4 and TSH suppression. In fact, low TSH levels may be seen in 15% of normal pregnant women in the first trimester.1 The hCG effect may be more pronounced in multiple gestations. Thus, a suppressed TSH in the face of a normal FT4 level is consistent with normal pregnancy, and treatment is not warranted.
After the first trimester, as peak levels of hCG are reached, TSH suppression by hCG decreases and the TSH often normalizes. Currently, data support 2.5 mU/L as an upper limit of normal serum TSH in the first trimester. Of note, the thyrotropic properties of hCG (increased T4 production and TSH suppression) can make the diagnosis of hypothyroidism in early pregnancy difficult.
The free thyroxine index (FT4I) is not altered during pregnancy and may be used to estimate the FT4 if direct determination is not available. Due to inconsistencies among the various laboratories, it has been suggested that the FT4I may be a more reliable method if indirectly assessing the FT4 level. Another test, the resin T3 uptake test (RT3U), is an alternate way of indirectly determining FT4 levels by measuring unoccupied binding sites in the TBG molecule. The RT3U value is then multiplied by the TT4 (or TT3) concentration to obtain the FT4I (or FT3I). Table 1 summarizes the alterations in thyroid function testing seen during pregnancy.
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THYROID FUNCTION TESTING
The hypermetabolic state of pregnancy may mimic the symptomatology seen in hyperthyroidism. Thus, laboratory testing is the best diagnostic tool when considering hyperthyroidism. Periodic laboratory testing is also necessary when treatment with antithyroid medication has been initiated.
In a pregnant patient with suspected hyperthyroidism or hypothyroidism, both TSH and FT4 should be measured. Of note, a recent study questioned the diagnostic accuracy of FT4 immunoassays during pregnancy.2 FT3 is not measured routinely. However, FT3 assessment should be considered in patients with signs of thyrotoxicosis, a suppressed TSH and a normal FT4. An elevated FT3 indicates T3 thyrotoxicosis, which may occur before increased production of FT4.3
The clinical utility of evaluating thyroidstimulating immunoglobulin (TSI) levels during pregnancy is controversial. These autoantibodies are immunoglobulin G antibodies that can cross the placenta and stimulate the fetal thyroid gland. Fetal effects are not correlated with maternal disease, but high levels of TSI (≥200%-500%) increase the risk of fetal and neonatal hyperthyroidism. 4 The risk for neonatal Graves disease due to transplacental passage of TSI is 1% to 5%.3
Currently, ACOG does not endorse routine evaluation of TSI levels.5 However, in pregnant women with a history of Graves disease, TSI activity may decrease, leading to chemical remission.6,7 Recommendations for when to consider TSI measurements during pregnancy are listed in Table 2.
Gestational transient thyrotoxicosis is a biochemical hyperthyroidism specific to pregnancy that is associated with high hCG levels. It is commonly associated with hyperemesis gravidarum (HEG), although it can be seen in gestational trophoblastic disease. The high hCG levels lead to temporary hyperthyroidism due to TSH receptor stimulation. These patients are rarely symptomatic, and antithyroid treatment is not warranted. As pregnancy progresses past the first trimester, FT4 levels normalize, although TSH levels may remain suppressed for several weeks. In patients with HEG, routine assessment of thyroid function is not indicated unless clinical signs of hyperthyroidism are apparent.5 Table 3 lists the various clinical scenarios with corresponding laboratory results.
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The incidence of hypothyroidism in the general population is 1%, and 1 to 3 in 1,000 in pregnancy. It is seen with a greater frequency with concurrent autoimmune disease, such as type 1 diabetes mellitus (5%-8%).
In developed countries, the most common cause of hypothyroidism during pregnancy is Hashimoto thyroiditis, also known as chronic autoimmune thyroiditis. This condition is characterized by the presence of antithyroid antibodies, including antimicrosomal and antithyroglobulin antibodies. Rarely, these antibodies can cause neonatal hypothyroidism, which is transient.
Other causes of primary hypothyroidism include subacute viral thyroiditis, radioactive iodine treatment, thyroidectomy, and iodine deficiency. The latter is the most common cause of hypothyroidism worldwide. Hashimoto disease and iodine deficiency are associated with goiter. Certain medications, including lithium, iodine, and amiodarone, are uncommon causes of hypothyroidism.
Signs and Symptoms of Hypothyroidism
Due to TSH suppression by hCG in early pregnancy and symptoms that mimic those commonly seen during pregnancy, the diagnosis of clinical hypothyroidism can be difficult. The classic symptoms of hypothyroidism include cold intolerance, dry skin, fatigue, constipation, hair loss, and muscle cramps. These may progress to weight gain, hair loss, insomnia, voice changes, carpal tunnel syndrome, and intellectual slowness. Hypothyroidism can lead to myxedema and coma if left untreated. It is unusual for uncontrolled hypothyroidism to present during pregnancy.
Maternal and Fetal Risks of Hypothyroidism
Well-controlled hypothyroidism has minimal impact upon pregnancy. Poorly or partially controlled thyroid disease may be associated with adverse pregnancy outcomes including preeclampsia, placental abruption, preterm birth, low birth weight, and fetal death.
Uncontrolled thyroid disease can also place the fetus at risk for neuropsychologic deficits. The fetus does not produce thyroid hormone until approximately 12 weeks' gestation, depending on maternal FT4 for brain development in the first trimester. Therefore, treatment should be initiated during pregnancy as early as possible.
Management of Hypothyroidism
At least 50% of patients diagnosed with hypothyroidism prior to pregnancy will need an increase in the thyroxine replacement dose during pregnancy. TSH and FT4 should be checked at the first prenatal visit. The goal of levothyroxine replacement is a TSH of 0.5 to 2 mU/L and FT4 in the normal range.
As it takes approximately 4 to 6 weeks for the TSH to reequilibrate to the new thyroid replacement dose, thyroid functions should be checked 4 weeks after any dose adjustment is made and every 4 weeks thereafter, until a stable TSH level is reached. Increasing the dose in 25- to 50-mcg increments is a reasonable approach. An elevated TSH warrants an increase in the levothyroxine dose, and labs should be rechecked in 4 weeks. Once a stable TSH is reached, thyroid functions should be checked at least every trimester.
For women diagnosed with hypothyroidism during pregnancy, the starting dose of levothyroxine ranges from 1 to 2 mcg/kg/day, or approximately 100 mcg/ day. In the unlikely event levothyroxine is unavailable, desiccated thyroid preparation such as Armour Thyroid can be used. The initial dose is 30 mg/day, increased incrementally by 15 mg every 2 to 3 weeks, until a maintenance dose of 60 to 120 mg/ day is reached. In stable patients, checking TSH/FT4 levels every trimester is prudent. Any dose adjustments warrant a recheck of thyroid functions in 4 weeks. Of note, certain medications can interfere with levothyroxine absorption (eg, ferrous sulfate, cholestyramine, aluminum hydroxide antacids) or metabolism (eg, phenytoin, carbamazepine, and rifampin).
Antepartum management includes serial ultrasounds to assess fetal growth. If the fetus is growing appropriately and the disease is well controlled, nonstress tests are not necessary. In poorly controlled disease, antepartum testing starting at 32 to 34 weeks should be considered.
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The topic of subclinical hypothyroidism (elevated TSH and normal FT4) has received considerable attention over the past few years. Based on observational data, 2 studies suggested a link between subclinical hypothyroidism and impaired neurocognitive development.8,9 The studies, both retrospective and noninterventional, showed a lower IQ in children born to mothers with an elevated TSH in mid-gestation.
These results led several national endocrine authorities, including the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society, to recommend routine screening and treatment for subclinical hypothyroidism during pregnancy.10 Specifically, they recommend screening TSH preconceptionally, or as soon as pregnancy is established, with a follow-up FT4 if the TSH is abnormal. However, the results must be interpreted with caution. There was no difference when the untreated hypothyroid patients were compared with treated hypothyroid patients, as the comparison group was normal controls. FT4 is necessary for fetal brain development and maturation, independent of the TSH level.8,11,12 Therefore, it is unclear how a normal thyroxine level, as noted in subclinical hypothyroidism, impacts fetal brain development. In fact, isolated hypothyroxinemia (normal TSH and low FT4) may be more of a concern.13,14 A large, multicentered, randomized clinical trial (clinicaltrials. gov identifier: NCT00388297) is in progress to help determine if screening and treatment of subclinical hypothyroidism and hypothyroxinemia will have a long-term effect on pediatric neurodevelopment. 14
To date, there have been no interventional studies to determine whether screening and treating pregnant patients for subclinical hypothyroidism will improve the neuropsychologic performance of their offspring. In contrast to the national endocrine authorities, ACOG does not recommend routine screening and treatment of subclinical hypothyroidism during pregnancy. 5 However, it is reasonable to have a low threshold to screen patients if risk factors are present (Table 4).
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All patients with thyroid disease requiring treatment during pregnancy should have follow-up thyroid function testing in the postpartum period. Postpartum thyroiditis represents an autoimmune inflammation of the thyroid gland that occurs within 1 year postpartum. It is seen in 5% of women who do not have a history of thyroid disease and can occur after pregnancy loss. The recurrence risk is 70%. The diagnosis is made by confirmation of new-onset abnormal levels of TSH, FT4, or both.
Clinically, 3 presentations are possible that can include hyperthyroidism or hypothyroidism. Symptoms are vague and nonspecific, including carelessness, memory impairment, and depression. If the diagnosis is in doubt, measurement of antimicrosomal or thyroid peroxidase antibodies can be useful. Treatment of postpartum thyroiditis is controversial, usually reserved for those with symptoms. Although often transient, a portion of women will develop permanent hypothyroidism.
Part 2 of "Thyroid Disease During Pregnancy" will focus on the diagnosis and management of hyperthyroidism.
The author reports no actual or potential conflict of interest in relation to this article.
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David E. Abel, MD, is a specialist in Maternal-Fetal Medicine, Deaconess Perinatal Services, Spokane, WA.