Thyroid Diseases in Pregnancy

Graves disease is described as an autoimmune dysfunction of the thyroid gland. The sera of patients with Graves disease is thought to contain a factor that stimulated the murine thyroid gland. This factor had a longer duration of action than that of thyrotropin (i.e. thyroid-stimulating hormone [TSH]), the long-acting thyroid stimulator.

Further studies revealed that these long-acting thyroid stimulators are autoantibodies directed against the TSH receptor. The activating versions of the TSH receptor are the thyroid-stimulating autoantibodies, which activate adenylate cyclase and which stimulate thyroid function.

In terms of histologic features, the thyroid glands of patients with Graves disease show follicular hypertrophy and hyperplasia.

Hashimoto thyroiditis is also known as goitrous chronic thyroiditis. Almost all patients with this disease have positive test results for the thyroid peroxidase antibody (anti-TPO), an autoantibody against thyroid peroxidase enzyme. Of these patients, 50-70% also have positive results for antithyroglobulin antibodies.

Classic histologic findings of Hashimoto thyroiditis are

• Extensive lymphocytic infiltration
• Follicular rupture
• Eosinophilia
• Various degrees of hyperplasia, and
• Fibrosis.

Atrophic chronic thyroiditis is a rare autoimmune cause of hypothyroidism. This condition is characterized by the presence of blocking autoantibodies to the TSH receptors.

PPT is a variant of chronic autoimmune thyroiditis (Hashimoto thyroiditis).

PTT is characterized by the presence of anti-microsomal antibodies. Histologic examination of PTT-affected thyroid glands affected reveals destructive lymphocytic thyroiditis.

Maternal Complications: Uncontrolled hyperthyroidism, especially in the second half of pregnancy, can lead to numerous complications. The complications include

Miscarriage,

Infection,

Preeclampsia,

Preterm delivery,

Congestive heart failure (CHF),

Thyroid storm, and

Placental abruption.

Fetal and neonatal complications include:

• Prematurity,
• Small size for gestational age,
• Intrauterine fetal death,
• Fetal or neonatal goiter, and/or
• Thyrotoxicosis.

Overtreatment may cause iatrogenic fetal hypothyroidism.

When maternal thyroid antibody titers are greater than 300% of the normal upper limit, the fetus is at risk of fetal hyperthyroidism and should be evaluated by ultrasound for evidence of hyper- or hypothyroidism.

Fetal hyperthyroidism effects can include

• Tachycardia,
• Accelerated maturation of bone,
• Goiter,
• Growth restriction, and
• Congestive heart failure.

Maternal complications of untreated hypothyroidism include:

• Microcytic anemia,
• Preeclampsia,
• Placental abruption,
• Postpartum hemorrhage,
• Cardiac dysfunction, and
• Miscarriage.

Fetal or neonatal complications include:

• Prematurity,
• Low birth weight,
• Congenital anomalies,
• Stillbirth, and
• Poor neuropsychological development.

The fetal thyroid does not begin to concentrate iodine until 10-12 weeks of gestation. Therefore, before this time, the mother must provide for all of the fetus' thyroxine (T4) requirements.

Subclinical hypothyroidism may be associated with an increased risk of adverse pregnancy complications such as spontaneous abortions, fetal loss, and preterm labor.

Complications associated with PPT: These are maternal, and depression is common. Permanent hypothyroidism occurs in as many as 20-40% of women. These patients are also at high risk for recurrent PPT with subsequent pregnancies.

Patients with hyperthyroidism usually report loss of concentration, nervousness, and emotional lability.

Tremor, heat intolerance, excessive sweating, palpitations, and hyper-defecation are also common findings.

Patients may report having difficulty with climbing stairs; this is a sign of proximal muscle weakness.

Some patients may report that their neck is getting bigger than it was before. This change is caused by the enlarged thyroid gland.

Untreated patients with moderate-to-severe hypothyroidism have impaired fertility. As a result, women with this disease are rarely pregnant at the time of presentation.

Symptoms of mild hypothyroidism can mimic those of normal pregnancy, making diagnosis difficult.

Lethargy, weight increase, and constipation are commonly reported.

Patients frequently report having cold intolerance, stiffness, muscle cramping, carpal tunnel syndrome

PPT has 3 phases:

1. Hyperthyroid phase, when thyroid hormones are being released because of thyroid destruction
2. Hypothyroid phase
3. Resolution, or euthyroid, phase

The most common time for women present with PPT is 1-8 months after delivery, with a peak incidence at 6 months. This timing is important because the process may overlap with the next pregnancy in women who have short pregnancy intervals.

Depending on the stage of disease at the time of presentation, patients may have symptoms of hyperthyroid or hypothyroid, as outlined above.

Subclinical hypothyroidism affects 2-3% of women in pregnancy.

The symptoms of subclinical hypothyroidism are vague and nonspecific.

The diagnosis is based on a normal level of free thyroxine (FT4) and an elevated TSH level.

General appearance:

• In general, patients with hyperthyroidism are restless, anxious, and fidgety.

Skin and hair:

• The skin is warm and moist, with a velvety texture, and their hair is fine and silky.

Eyes:

• The eyes usually have a characteristic stare, with a widened palpebral fissure.
• Lid lag and failure to wrinkle the brow during the upward gaze.
• With careful observation, infrequent blinking is noted.
• Potential ophthalmological findings include proptosis, ophthalmoplegia, chemosis, conjunctivitis, periorbital swelling, corneal ulceration, optic neuritis, and optic dystrophy.

Thyroid:

• A goiter is present in almost every pregnant patient with Graves’ disease.
• The gland is diffusely enlarged, usually 2-4 times normal.
• The gland can be soft or firm, and it is seldom tender to palpation.
• A thrill or bruit may be present.
• The presence of a nodule requires further workup during pregnancy to rule out malignancy.

Heart:

• Findings on cardiac examination include a wide pulse pressure due to increased systolic pressure and decreased diastolic pressure.
• Sinus tachycardia is common. A resting tachycardia greater than 100 bpm that does not change with Valsalva is helpful in distinguishing hyperthyroid tachycardia from that of pregnancy.
• Atrial arrhythmias can also be found on examination. These usually occur in the form of atrial fibrillation.
• Other findings are systolic murmurs, an increased intensity of the apical first sound, cardiac enlargement, and cardiac failure.

Nails:

• Separation of the nail from the distal nail bed, known as onycholysis or Plummer nail, can often be found when the extremities are examined. The ring fingers are most commonly affected.
• Fine tremor of the fingers and hyperreflexia can also be noted.

Fetal thyroid dysfunction in Hyperthyroidism

Suggestive findings

• Fetal tachycardia (fetal heart rate >160 bpm)
• Intrauterine growth restriction
• Fetal goiter
• Hydrops

Causes

• The risk of fetal or neonatal thyrotoxicosis is related to the mother's level of thyroid receptor–stimulating antibodies because the antibodies freely cross the placenta.
• Foetal or neonatal hypothyroidism may also be due to maternal use of antithyroid drugs (ATDs), as these cross the placenta.

Diagnosis and screening in the Fetus

Fetal diagnosis may rarely require umbilical cord sampling to differentiate hyperthyroidism from hypothyroidism. Amniotic fluid levels can be used for diagnosis.

In women with a past or current history of autoimmune thyroid disease, thyroid antibody values should be checked at the end of the first pregnancy. For those with positive results for thyroid receptor–stimulating antibodies or those taking ATDs, fetal ultrasonography should be performed at least monthly after 20 weeks of gestation.

Treatment

Fetal thyroid dysfunction is treated with adjustment of maternal ATD therapy.

Fetal hypothyroidism may require intra-amniotic administration of T4.

Motor function and cognition: Patients with hypothyroidism appear to have slowing of speech and movement. They can also be forgetful and exhibit difficulty with concentration.

Skin:

• The skin is usually dry, pale, and yellowish.

Hair:

• Hair is thin, brittle, and sparse.

Head, eyes, ears, nose, and throat

• Auditory acuity may be decreased.
• Eye examination may reveal periorbital puffiness.
• A large tongue and an expressionless face can be observed in patients with severe disease.

Thyroid gland

• A goitre associated with Hashimoto thyroiditis is firm, diffusely enlarged, and usually painless to palpation.
• In patients with atrophic chronic thyroiditis, the thyroid gland may be normal or not palpable.

Heart

• A low-normal heart rate is common.
• The heart can be enlarged if it is dilated.
• Pericardial effusion is present in severe cases.

GI tract

• Bowel sounds may be decreased or absent.
• Paralytic ileus has been reported in severe cases of hypothyroidism.

Extremities

• Examination of the extremities may reveal nonpitting edema and hyporeflexia, with prolongation of the relaxation phase of the reflex response.

Fetus:

• Fetal examination usually reveals normal findings in mild cases.

Presenting findings: Patients with PPT can present with symptoms of hyperthyroidism or hypothyroidism, depending on the stage of disease.

Phases of disease: As many as one third of women with PPT present with hyperthyroidism at 1-4 months after birth. This period is followed by a hypothyroid phase lasting as long as 2 months. Recovery then ensues.

Physical stigmata of Graves disease will be absent (goiter with a bruit, endocrine ophthalmopathy).

This condition is characterized by elevated FT4 values, suppressed TSH levels, minimal thyroid enlargement, variable evidence of clinical hyperthyroidism, and absent thyroid antibodies.

Gestational hyperthyroidism is due to the thyroid-stimulation effects of human chorionic gonadotropin (hCG) and is most likely to arise in the setting of elevated hCG concentrations (e.g., molar or multiple pregnancies). Treatment is usually not needed because spontaneous recovery occurs after the first trimester.

T3, T4, FT3, FT4, and TSH tests

• Total T3 and total T4 levels are increased due to a rise in the amount of thyroid-binding globulin. Free T3 (FT3) and FT4 levels are high-normal in the first trimester and return to normal by the second trimester.
• Total T4 values are not useful in pregnant women because they rise in response to the estrogen-induced increase in the amount of thyroid-binding globulin.
• FT3 values should be measured when the TSH value is suppressed but the FT4 level is normal. An elevated T3 level confirms T3 toxicosis, an early stage in the development of true hyperthyroidism.
• TSH concentrations fall during pregnancy, especially in the first trimester, because hCG cross-reacts with TSH receptors on the thyroid gland.
• Resin T3 update test: Resin T3 uptake is reduced because the number of unsaturated binding sites increases.
• Test for thyroid-stimulating immunoglobulins (TSIs), CBC, liver function test, and determination of calcium and magnesium levels and Anti-microsomal antibody test.

FT4 and TSH tests

Definitions of hypothyroidism and subclinical hypothyroidism in pregnancy:

• In primary hypothyroidism, TSH levels are elevated and the FT4 value or FT4 index should be low.
• With supra-thyroid hypothyroidism, the TSH level may be normal or low, and the FT4 level or FT4 index is low.
• In subclinical hypothyroidism, the FT4 value is normal, and the TSH level is elevated.

Elevations in serum TSH during pregnancy should be defined using pregnancy-specific reference ranges.

Hypothyroidism is defined as an elevated TSH (>2.5 mIU/L) in conjunction with a decreased FT4 concentration.

Women with TSH levels of 10.0 mIU/L or above, regardless of their FT4 levels, are also considered to have hypothyroidism.

Subclinical hypothyroidism is defined as a serum TSH between 2.5 and 10 mIU/L with a normal FT4 concentration.

Isolated hypothyroxinemia is defined as a normal maternal TSH concentration in conjunction with FT4 concentrations in the lower 5th or 10th percentile of the reference range.

Other tests for Hypothyroidism

• Tests for anti-TPO and antithyroglobulin antibodies
• Levels of anti-TPO and antithyroglobulin antibodies should be measured in pregnant women with possible hypothyroidism to determine if Hashimoto thyroiditis is the cause.
• Measurement of anti-TPO antibody concentrations is often sufficient because the results are almost always positive in patients with Hashimoto thyroiditis.
• CBC and liver function tests
• Consider ordering a CBC and liver function tests after hypothyroidism is diagnosed.
• Anemia is observed in as many as 30-40% of patients because erythropoiesis is decreased.
• Concomitant vitamin B-12 or folic acid deficiency should be considered if the anemia is macrocytic.
• Leukocyte and platelet counts are usually normal.

Generally, TSI is negative in PPT in the majority of cases, while it is positive with postpartum Graves disease. An elevated T4:T3 ratio suggests the presence of PPT.

The radioiodine uptake is elevated or normal in Graves disease and low in PPT.

Imaging modalities currently available for the evaluation of thyroid disease are ultrasonography, CT scanning, MRI, and radioactive iodine uptake testing.

Radioactive iodine uptake testing is contraindicated in pregnancy.

Ultrasonography is considered a safe test in pregnancy, and sonographic findings can help in differentiating a cystic nodule from a solid nodule.

Spectral Doppler ultrasound may be a useful adjunct to distinguish hyperthyroid and hypothyroid postpartum thyroiditis.

Thyroid biopsies are usually delayed until after pregnancy

Prenatal counseling and management of Graves disease

Women with hyperthyroidism should be treated either with ablative therapy (iodine radiation or surgery) or medical therapy and become euthyroid before attempting pregnancy. For ablative therapy, TSI titers tend to increase and remain elevated for many months.

A pregnancy test should be performed 48 hours before the iodine radiation ablation to avoid radiation exposure to the fetus. Conception should be delayed for 6 months post-ablation to allow time for the dose of T4 to be adjusted to obtain target values for pregnancy (serum TSH between 0.3 and 2.5 mIU/L).

If the patient chooses thioamide drugs (ATD therapy), propylthiouracil (PTU) should be used in the first trimester of pregnancy, because of the risk of methimazole (MMI) embryopathy; and consideration should be given to discontinuing PTU after the first trimester and switching to MMI in order to decrease the incidence of liver disease. Contraception should be used until normal thyroid function is achieved.

Pregnancy management

The goal of treatment is to maintain clinical euthyroidism, with the mother's FT4 level in the high-normal range.

In order to prevent overtreatment and possible neonatal hypothyroidism, the lowest dose possible should be used to keep maternal free T4 and free T3 in upper limit of the normal range.

Thioamide drugs (i.e., ATDs) are the first-line treatment in pregnancy. PTU, methimazole (MMI), and carbimazole (CMI) are the ATDs available in the United States. These drugs inhibit iodination of thyroglobulin and thyroglobulin synthesis by competing with iodine for the enzyme peroxidase. PTU, MMI, and CMI are equally effective.

Beta-blockers (e.g., atenolol, nadolol, propranolol) are valuable adjuncts to ATDs. These drugs effectively alleviate symptoms of hypermetabolic states. With prolonged use, beta-blockers are associated with foetal morbidity. Therefore, these drugs should be used for only a short period (i.e., 2 wk.) while one waits for the ATDs to take effect.

Use of radioactive iodine is contraindicated in pregnancy.

The goal of treatment is to normalize maternal TSH levels. (It should be remembered that iodine deficiency is an important cause of neonatal neurologic damage worldwide).

The recommended mean intake of iodine during pregnancy and lactation is approximately 250 mcg/d.

Thyroid hormone replacement using synthetic thyroxine (T4) is the treatment for patients with hypothyroidism, which should be corrected before pregnancy occurs.

A full replacement dosage of 1.6-2.0 mcg/kg/day should be started at the time of diagnosis. Preconception thyroid medication should be adjusted to achieve a TSH level of less than 2.5 mU/mL before pregnancy.

Other thyroid preparations, such as T3 or desiccated thyroid, are strongly discouraged. The goal of thyroid hormone treatment is to normalize maternal serum TSH values within the trimester-specific pregnancy reference range (first trimester, 0.1-2.5 mIU/L; second trimester, 0.2-3.0 mIU/L; third trimester, 0.3-3.0 mIU/L).

Hyperthyroidism

Subtotal thyroidectomy induces remission in most patients with Graves disease. Surgery should be used as the second line of treatment in pregnant women.

Surgery is reserved for patients who meet 1 of the following criteria:

• High doses of ATDs (PTU > 300 mg, MMI > 20 mg) are required.
• Clinical hyperthyroidism cannot be controlled.
• Fetal hypothyroidism occurs at the dosage needed for maternal control.
• The patient cannot tolerate ATDs.
• The patient is noncompliant.
• Malignancy is suspected.

When surgery is needed, it should be performed during the second trimester.

Hypothyroidism

• No surgical care is recommended.

The outcome of pregnancies affected by autoimmune thyroid disease depends on the degree of metabolic control. Women with euthyroid disease can expect satisfactory outcomes of their pregnancy. With close follow-up postpartum, medical therapy can be adjusted to ensure a euthyroid state. This helps ensure a good prognosis.