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Medical Disorders and Pregnancy

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Thyroid Disease in Pregnancy

WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).

Thyroid disease is the second most common endocrine disease affecting women of reproductive age; obstetricians often care for patients who have been previously diagnosed with alterations in thyroid gland function. In addition both hyperthyroidism and hypothyroidism may initially manifest during pregnancy. The interactions between pregnancy and the thyroid gland are fascinating from at least three aspects: pregnancy induces increased thyroid-binding globulin, intimate relationship between maternal and fetal thyroid function, and a number of related abnormal pregnancy and thyroid conditions that at least appear to interact.

The purpose of this document is to review the thyroid-related patho-physiologic changes created by pregnancy, and the maternal-fetal impact of thyroid disease.

Definitions:

Thyrotoxicosis is the clinical and biochemical state that results from an excess production of and exposure to thyroid hormone from any etiology. Hyperthyroidism is thyrotoxicosis caused by hyperfunctioning of the thyroid gland. Graves' disease is an autoimmune disease characterized by production of thyroid-stimulating immunoglobulin (TSI) and thyroid-stimulating hormone-binding inhibitory immunoglobulin (TBII) that act on the thyroid-stimulating hormone (TSH) receptor to mediate thyroid stimulation or inhibition, respectively. Thyroid storm is characterized by a severe, acute exacerbation of the signs and symptoms of hyperthyroidism.

Hypothyroidism is caused by inadequate thyroid hormone production. Postpartum thyroiditis is an autoimmune inflammation of the thyroid gland that presents as new-onset, painless hypothyroidism, transient thyrotoxicosis, or thyrotoxicosis followed by hypothyroidism within 1 year postpartum (1).

Changes in Thyroid Function during Pregnancy and in Thyroid Disease:

Source: ACOG Practice Bulletin No. 37, August 2002

Maternal Status TSH FT4 FTI TT4 TT3 RT3U
Pregnancy No Change No Change No Change Increase Increase Decrease
Hyperthyroidism Decrease Increase Increase Increase Increase or
No change		 Increase
Hypothyroidism Increase Decrease Decrease Decrease Decrease or
No Change		 Decrease

Abbreviations: TSH, thyroid-stimulating hormone; FT4, free thyroxine; FTI, free thyroxine index; TT4, total thyroxine; TT3, total triiodothyronine; RT3U, resin T3 uptake.

Thyroid Function and the Fetus:

The fetal thyroid begins concentrating iodine at 10-12 weeks of gestation and is controlled by pituitary TSH by approximately 20 weeks of gestation. Fetal serum levels of TSH, TBG, FT4, and free triiodothyronine (FT3) increase throughout gestation, reaching mean adult levels at approximately 36 weeks of gestation. Thyroid stimulating hormone does not cross the placenta, and only small amounts of thyroxine (T4) and triiodothyronine (T3) cross the placenta. In neonates with congenital hypothyroidism, enough maternal thyroid hormone crosses the placenta to prevent the overt stigmata of hypothyroidism at birth and maintain cord blood thyroid hormone levels at 25-50% of normal. However, thyrotropin-releasing hormone (TRH), iodine, and TSH receptor immunoglobulins do cross the placenta, as do the thioamides propylthiouracil (PTU) and methimazole (2).

Hyperthyroidism

Signs and Symptoms: Hyperthyroidism occurs in 0.2% of pregnancies; Grave's disease accounts for 95% of these cases. The signs and symptoms of hyperthyroidism include nervousness, tremors, tachycardia, frequent stools, excessive sweating, heat intolerance, weight loss, goiter, insomnia, palpitations, and hypertension. Distinctive symptoms of Graves' disease are ophthalmopathy (signs including lid lag and lid retraction) and dermopathy (signs include localized or pretibial myxedema). Serum thyroid function tests differentiate thyroid disease from non-thyroid disease. Differential diagnosis of hyperthyroidism is generally made by documenting thyroid function tests and by presence or absence of nodular goiter or thyroid mass. Graves' disease is the most common cause of thyrotoxicosis; other etiologies of thyrotoxicosis are excess production of TSH, gestational trophoblastic neoplasia, hyperfunctioning thyroid adenoma, toxic multinodular goiter, subacute thyroiditis, and extra-thyroid source of thyroid hormone.

Maternal and Neonatal Effects: Inadequate treated maternal thyrotoxicosis is associated with a greater risk of miscarriages, preterm delivery, severe preeclampsia and heart failure than treated, controlled maternal thyrotoxicosis. Fetal and neonatal risks associated with Graves' disease are related either to the disease itself or to thioamides treatment of the disease. The possibility of fetal thyrotoxicosis should be considered in all women with a history of Graves' disease. If fetal thyrotoxicosis is diagnosed, consultation with a clinician with expertise in such conditions is warranted (3). Maternal antibodies are cleared less rapidly than thioamides in the neonate, resulting in a sometimes delayed presentation of neonatal Graves' disease. The incidence of neonatal Graves' disease is unrelated to maternal thyroid function. The neonates of women who have been treated surgically or with radioactive iodine 131 (I-131) prior to pregnancy and require no thioamide treatment are at higher risk for neonatal Graves' disease because they lack supportive thioamide.

Hypothyroidism

Sings and Symptoms: It is well accepted that having one autoimmune disease increases the likelihood of developing another; autoimmune thyroid dysfunction is no exception. Hypothyroid disease occurs in 5-8% patients with type I (insulin-dependent) diabetes and women with type I diabetes also have a 25% risk of developing postpartum thyroid dysfunction. The classic signs and symptoms of hypothyroidism are fatigue, constipation, intolerance to cold, muscle cramps, hair loss, dry skin, prolonged relaxation phase of deep tendon reflexes, and carpel tunnel syndrome. If left untreated, hypothyroidism will progress to myxedema and myxedema coma. It is unusual for advanced hypothyroidism to present in pregnancy. The most common etiologies of hypothyroidism in pregnant or postpartum women are Hashimoto's disease, subacute thyroiditis, thyroidectomy, radioactive iodine treatment, and iodine deficiency. Both Hashimoto's disease and iodine deficiency are associated with goiter, while subacute thyroiditis is not associated with goiter.

Maternal and Neonatal Effects: Untreated hypothyroidism is associated with an increased risk of preeclampsia, recurrent pregnancy loss and preterm delivery. High incidence of low birth weight babies because of intrauterine growth restriction, placental abruption and premature labor is seen. Women with iodine-deficient hypothyroidism are at significant risk of having babies with congenital cretinism (growth failure, mental retardation, and other neuro-psychologic deficits). In an iodine-deficient population, treatment with iodine in the first and second trimesters of pregnancy significantly reduces the incidence of the neurologic abnormalities of cretinism (4).

Untreated congenital hypothyroidism also results in cretinism. The incidence of congenital hypothyroidism is 1 per 4,000 newborns, and only 5% of neonates are identified by clinical symptoms at birth, likely because of the ameliorative effects of maternal thyroid hormone. If identified and treated within the first few weeks of life, near-normal growth and intelligence can be expected.

Which pregnant patients should be screened for Thyroid Dysfunction?

It is appropriate to perform indicated testing of thyroid function in women with a personal history of thyroid disease or symptoms of thyroid disease. The performance of thyroid function tests in asymptomatic pregnant women who have a mildly enlarged thyroid is not warranted. Development of a significant goiter or distinct nodules should be evaluated as in any patient. The available data are consistent with the possibility that maternal hypothyroidism is associated with a decrement in some neuro-psychologic testing. It is premature to recommend universal screening for hypothyroidism during pregnancy.

Medications can be used to treat hyperthyroidism and hypothyroidism in pregnancy:

Hyperthyroidism in pregnancy is treated with thioamides, specifically propylthiouracil (PTU) and methimazole, which decrease thyroid hormone synthesis by blocking the organification of iodide. PTU also reduces the peripheral conversion of T4 to T3 and thus may have a quicker suppressant effect than methimazole. Traditionally PTU is preferred in pregnant patient because it was believed that PTU crossed the placenta less well than methimazole and because methimazole was associated with fetal aplasia cutis (a congenital skin defect of scalp). Thioamide treatment of Graves' disease can suppress fetal and neonatal thyroid function. However, it is usually transient and rarely requires therapy. Fetal goiter also has been associated with thioamide treatment for Graves' disease, presumably caused by drug-induced fetal hypothyroidism. Fetal thyrotoxicosis secondary to maternal antibodies is rare, but all fetuses of women with Graves' disease should be monitored for appropriate growth and normal heart rate. All neonates of women with thyroid disease are at risk for neonatal thyroid dysfunction, and the neonate's pediatrician should be aware of the maternal diagnosis.

Women taking PTU may breastfeed, because only small amounts of the medication cross into breast milk. Studies have demonstrated that thyroid function tests results were normal in neonates after 1-8 months of breastfeeding from women taking PTU (5). The goal of management of hyperthyroidism in pregnancy is to maintain the FT4 or FTI in high normal range using the lowest possible dosage of thioamides to minimize fetal exposure to thioamides. Once treatment is started, it may be helpful to measure FT4 or FTI every 2-4 weeks and titrate the thioamide until FT4 or FTI are consistently in the high normal range.

Side Effects of Thioamide: Agranulocytosis occurs in about 0.1%-0.4%, and is usually presents as fever and sore throat. If a patient on thioamide develops these symptoms, a complete blood cell count should be done and the medication should be discontinued. Other major side effects of thioamide are: thrombocytopenia, hepatitis, and vasculitis, rash, nausea, arthritis, anorexia, fever and loss of taste or smell.

Beta-blockers may be used during pregnancy to ameliorate the symptoms of thyrotoxicosis until thioamides decreases thyroid hormone levels. Propranolol is the most common beta-blocker used for this indication. Thyroidectomy should be reserved for women in whom thioamide treatment is unsuccessful.

Iodine 131 is contraindicated in pregnancy because of fetal thyroid ablation and women should avoid pregnancy for 4 months after I-131 treatment.

Treatment of Thyroid Storm in Pregnant Women (6):

  1. Propylthiouracil (PTU), 600-800 mg orally, stat, then 150-200 mg orally every 4-6 hours. If oral administration is not possible, use methimazole rectal suppositories.
  2. Starting 1-2 hours after PTU administration, saturated solution of potassium iodide (SSKI), 2-5 drops orally every 8 hours, or sodium iodide, 0.5-1.0 g IV every 8 hours, or Lugol's solution, 8 drops every 6 hours, or lithium carbonate, 300 mg orally every 6 hours.
  3. Dexamethasone 2 mg IV or IM every 6 hours for 4 doses
  4. Propranolol 20-80 mg orally every 4-6 hours, or propranolol 1-2 mg IV every 5 minutes for a total of 6 mg, then 1-10 mg intravenously every 4 hours. If the patient has history of severe bronchospasm: Reserpine 1-5 mg IM every 4-6 hours, Guanethidine 1 mg/kg orally every 12 hours, Diltiazem 60 mg orally every 6-8 hours.
  5. Phenobarbital 30-60 mg orally every 6-8 hours as needed for extreme restlessness.

Hypothyroidism in pregnant women is the same as for non-pregnant women and involves administering levothyroxine at sufficient dosages to normalize TSH levels. It takes approximately 4 weeks for the thyroxine therapy to alter the TSH levels. Therefore, levothyroxine therapy should be adjusted at 4 week intervals until TSH levels are stable. In stable patients, it is prudent to check TSH levels every trimester in pregnant women with hypothyroidism (7).

Thyroid Nodule or Thyroid Cancer in Pregnancy:

The incidence of thyroid cancer in pregnancy is 1 per 1,000. Any thyroid nodule discovered during pregnancy should be diagnostically evaluated, because malignancy will be found in up to 40% of these nodules. Pregnancy itself does not appear to alter the course of thyroid cancer. If a diagnosis of cancer is made, a multidisciplinary treatment plan should be determined. The options are pregnancy termination, treatment during pregnancy, and preterm or term delivery with treatment after pregnancy. This decision will be affected by the gestational age at diagnosis and the tumor characteristics. Definitive treatment for thyroid cancer is thyroidectomy and radiation. Thyroidectomy can be performed during pregnancy, preferably in the second trimester, but radiation should be deferred until after pregnancy. Breastfeeding should be avoided for at least 120 days after I-131 treatment.

Postpartum Thyroiditis:

It occurs in about 5% of women who do not have a history of thyroid disease. Studies have found that approximately 44% of women with postpartum thyroiditis have hypothyroidism, while the remaining women are evenly split between thyrotoxicosis and thyrotoxicosis followed by hypothyroidism. The diagnosis of postpartum thyroiditis is made by documenting new-onset abnormal levels of TSH or FT4 or both. If the diagnosis is in doubt, measuring antimicrosomal or thyroperoxidase antithyroid peroxidase antibodies may be useful to confirm the diagnosis.

Current concepts in managing patients with thyroid disease:

Women with inadequately treated hypothyroidism are reported to have a higher incidence of low-birth-weight infants and preeclampsia. Women who have iodine-deficient hypothyroidism -- the most common type -- are at significant risk of having babies with congenital cretinism. Ensuring appropriate iodine replacement for iodine-deficient populations in the first and second trimester significantly reduces the incidence of neurologic abnormalities of cretinism. Current guidelines are (8):

  • Pregnant women should take 220 mcg of iodine-containing multivitamins daily, while breastfeeding women should take 290 mcg daily. Other women of childbearing age should take 150 mcg daily of iodine-containing multivitamins.
  • Women should avoid taking levothyroxine and multivitamin and iron supplementation at the same time of the day. These supplements interfere with the absorption of levothyroxine.
  • A majority of women with preexisting hypothyroidism will need to increase their dose of levothyroxine and have the dose monitored during pregnancy. Postpartum, they can return to their pre-pregnant dose.
  • Pregnant women on antithyroid drugs for the treatment of hyperthyroidism should receive frequent monitoring to ensure appropriate treatment.

The National Institute of Child Health and Human Developments Maternal-Fetal Medicine Network has an ongoing trial on this issue. Because uncontrolled hypothyroidism is associated with numerous adverse outcomes, including an increased risk of preeclampsia and mental deficits in the offspring, the trial aims to clarify whether treatment of women with subclinical hypothyroidism during pregnancy is associated with intellectual improvement in the offspring (9). Some studies have shown that women who used thyroid hormone therapy during pregnancy more often have diabetes and other comorbidities and use other medications such as cardiovascular drugs, systemic corticosteroids, psychiatric drugs, and drugs for asthma than those who did not use thyroid hormone therapy (10). In this group, sub-fertility, previous miscarriage, cesarean delivery, and induction of labor are more common than among non-users. For the most part, the infants are little affected, except for slight increase in cardiac and renal abnormalities. The finding that some infants experience thyrotoxicosis probably relates to the fact that some of the mothers also have this illness.

The offsprings in the First and Second Trimester Evaluation of Risk Consortium trial have not yet reached the age at which they can be evaluated and this information will be very important once it is available (11). A more important question is whether the early occurrence of subclinical hypothyroidism during the period when the fetal brain is developing but the fetus is not yet producing its own thyroxine may have an effect on neural development in later life.

A large study conducted on an unselected population of pregnant women, both with known diagnosis of hypothyroidism and those who were screened but not diagnosed; found a four-point difference in the intelligent quotient (IQ) levels of the offspring, raising the question of clinical significance (12). The endocrine community has accepted that subclinical hypothyroidism causes significant decrease in IQ score and has advocated for routine screening of pregnant women. However, obstetric authorities have cautioned that more research is needed before a causal relationship between subclinical hypothyroidism and lower IQ performance is verified.

Summary:

Levels of TSH or FT4/ FTI should be monitored to manage thyroid disease in pregnancy. Either PTU or methimazole can be used to treat pregnant women with hyperthyroidism. Thyroid function tests are not indicated in asymptomatic pregnant women with slightly enlarged thyroid glands. There is no need to measure thyroid function tests routinely in women with hyperemesis. There are insufficient data to warrant routine screening of asymptomatic pregnant women for hypothyroidism. The presence of maternal thyroid disease is important information for the pediatrician to have at the time of delivery. Thyroid nodules should be investigated to rule out malignancy.

Suggested Reading:

  1. World Health Organization
    Iodine Deficiency in Europe: A continuing public health problem
  2. Iodine in Drinking-water
  3. National Institutes of Health (NIH)
    Pregnancy and Thyroid Disease

References:

  1. Idris I, Srinivasan R, Simm A et al. Effects of maternal hyperthyroidism during early gestation on neonatal and obstetric outcome. Clin docrional 2006;65:133-135
  2. Girling JC. Thyroid disorders in pregnancy. Curr Obstet Gynecol 2006;16:47-53
  3. Creasy RK, Resnik R, Iams J. Maternal-Fetal Medicine. 5th ed. Philadelphia PA: Saunders Elsevier; 2004:1063-1082
  4. Alexander EK, Marqusee E, Lawrence J et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004;351:241-249
  5. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical management guidelines for obstetricians and gynecologists. Number 37, August 2002. Thyroid disease in pregnancy. Obstet Gyecol 2002;100:387-396
  6. Casey BM, Dashe JS, Wells CE et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105:239-245
  7. Kooisa L, Crawford S, van Baar AL et al. Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics 2006;117:161-167
  8. ACOG Committee Opinion. Subclinical hypothyroidism in pregnancy. Number 381; October 2007
  9. Gharib H, Tuttle RM, Baskin HJ et al. Consensus Statement # 1. Subclinical thyroid dysfunction: A joint statement on management from the American Association of Clinical Endocrinologists, The American Thyroid Association, and the Endocrine Society. Thyroid 2005;15:24-28
  10. Wikner BN, Sparre LS, Stiller CO et al. Maternal use of thyroid hormones in pregnancy and neonatal outcomes. Acta Obstet Gynecol Scand 2008;87:617-627
  11. Cleary-Goldman J, Malone FD, Lambert-Messerlian G et al. Thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008:112:85-92
  12. Gyamfi D, Wapner RJ, D'Alton ME. Thyroid dysfunction in pregnancy. Obstet Gynecol 2009;113:702-707

Published: 8 June 2009

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