Learning Objectives:After participating in this continuing education activity, the provider should be better able to:
1. Diagnose hypothyroidism and hyperthyroidism.
2. Develop treatment plans for both hypo- and hyperthyroidism in pregnancy.
3. Treat postpartum thyroiditis.
Thyroid hormone plays a critical role in growth, development, and metabolism. Dysfunction of the thyroid gland may result in an array of clinical sequelae, with significant morbidity and mortality if inadequately treated. Furthermore, antenatal hypothyroidism and hyperthyroidism affect both maternal and neonatal outcomes; thus, an understanding of basic thyroid pathophysiology and appropriate treatment options is necessary for providers caring for women in pregnancy.
Thyroid Physiology
Hypothalamic thyrotropin-releasing hormone (TRH) regulates pituitary thyroid-stimulating hormone (TSH), which in turn stimulates the synthesis and secretion of both thyroxine (T4) and triiodothyronine (T3). First, iodide is transported from the circulation by a sodium-iodide symporter at the basal surface of the cell and then moved to the apex of the cell. Catalyzed by thyroid peroxidase (TPO) enzyme, the process of iodination of tyrosine residues present in thyroglobulin molecules, known as organification, produces monoiodotyrosine (MIT) or diiodotyrosine (DIT). MIT and DIT then undergo coupling, again catalyzed by TPO, to form T3 and T4, which are stored in colloid. Under regulation of TSH, thyroid hormone is released into the circulation from the basal surface of the cell. Most of thyroid hormone in circulation is bound by proteins including thyroid-binding globulin (TBG); only a small fraction of hormone circulates in the unbound state, free for tissue uptake. The majority of bioactive T3 arises from peripheral conversion from T4 by 5'-deiodinase. Thyroid hormone diffuses into cells to act on nuclear receptors within the peripheral tissue.1
Changes in Thyroid Physiology With Pregnancy
The thyroid gland undergoes physiologic changes in pregnancy. The gland grows in size during pregnancy, and thyroid hormone production increases by 50% beginning in early pregnancy.1 Increased circulating estrogen during pregnancy results in increased hepatic synthesis of TBG. This elevation in TBG results in an increase in total T4 and total T3. The rise in human chorionic gonadotropin (hCG) in early pregnancy weakly stimulates TSH receptors resulting in transient increases in free T4 and decreases in TSH and TRH levels. This suppression of TSH is most pronounced in the first trimester, but slight suppression compared with nonpregnant levels often persists throughout pregnancy. This accounts for the downward shift in both the lower and upper limits of the TSH reference range in each trimester of pregnancy. Of note, the physiologic increase in thyroid hormone in response to hCG may be more pronounced in hyperemesis gravidarum. The markedly high hCG levels result in undetectable TSH, which resolves in the second trimester.
Increased fetal use and increased maternal renal clearance results in decreased plasma iodide levels in pregnancy. Given this increase in metabolism paired with increased utilization of iodine for thyroid hormone production, the Institute of Medicine recommends dietary iodine supplementation with 150 [micro]g prepregnancy, 220 [micro]g during pregnancy, and 290 [micro]g during lactation. Iodine supplementation in geographic areas of endemic deficiency has been associated with improved pregnancy outcomes.2
Maternal TRH level, iodine, TSH receptor immunoglobulins, thionamides, and small amounts of T3 and T4 are able to cross the placenta; maternal TSH does not cross the placenta. Transfer of maternal thyroid hormone across the placenta to the fetus is particularly important in the first trimester. By 10 to 12 weeks of gestation, the fetal thyroid begins concentrating iodine for fetal thyroid hormone production. Fetal pituitary TSH controls the fetal thyroid gland around 20 weeks of gestation, and thyroid hormone concentrations reach adult levels by 36 weeks.3
Thyroid Screening Recommendations
Although overt thyroid dysfunction may have serious sequelae if uncontrolled in pregnancy, the American Thyroid Association, Endocrine Society, American College of Obstetricians and Gynecologists, and American Society for Reproductive Medicine all recommend against universal screening for thyroid disease in pregnancy.3-6 One large randomized controlled trial assessing the utility of antenatal thyroid testing demonstrated no improvement in cognitive function in 3-year-old children of mothers who tested positive for thyroid dysfunction and were treated with levothyroxine accordingly.7 A subsequent follow-up study of the same children demonstrated no difference in cognitive function at 9.5 years of age.8 These studies support the society recommendations against universal screening of thyroid function in pregnancy. However, women with symptoms, signs, or risk factors for overt thyroid disease warrant assessment of thyroid function. The first-line test to screen for thyroid disease is serum TSH level. The measurement of free T4 may not be as reliable in pregnancy; trimester-specific reference ranges for both TSH and free T4 levels must be employed when interpreting results of thyroid function tests in pregnancy.
Universal thyroid antibody screening is also not routinely recommended. Thyroid peroxidase antibody testing may be indicated in women with TSH values persistently above 2.5 mIU/L or other risk factors for overt thyroid disease to assess need for treatment.4
Hypothyroidism
Hypothyroidism is defined by inadequate thyroid hormone production. Hypothyroidism affects 0.3% of pregnant women.9 Although uncommon in the United States, iodine deficiency is the most common etiology of hypothyroidism worldwide. Hashimoto's disease is the most common cause of hypothyroidism in pregnancy in the United States; this occurs as a result of glandular destruction by antithyroid peroxidase antibodies. Other causes include subacute thyroiditis, radioactive iodine treatment, and thyroidectomy.
Signs and symptoms of hypothyroidism include fatigue, constipation, cold intolerance, muscle cramps, weight gain, edema, dry skin, hair loss, prolonged relaxation phase of deep tendon reflexes, palpable goiter, and, in severe cases, myxedema coma. Diagnosis of primary hypothyroidism is confirmed with thyroid function testing demonstrating low free T4 with elevation in TSH level. Suppressed TSH level in the setting of hypothyroidism may imply more rare etiologies involving the pituitary or hypothalamus.
Levothyroxine supplementation is the standard treatment for hypothyroidism. Starting dose is usually 1.6 [micro]g/kg per day based on ideal body weight or 100 [micro]g per day. TSH levels should be checked every 4 to 6 weeks and the levothyroxine dose titrated by 25 to 50 [micro]g to achieve goal TSH level, according to trimester-specific reference ranges. Women with a history of hypothyroidism may anticipate increased requirements in pregnancy; therefore, the levothyroxine dose may be empirically increased by 25% to 30% upon diagnosis of pregnancy.3,6
In women with overt hypothyroidism, TSH level should be maintained below 2.5 mIU/L before pregnancy. In pregnancy, TSH level should be assessed at initiation of prenatal care, and then may be checked once per trimester, if stable. Reference ranges for TSH level in pregnancy are as follows: 0.1 to 2.5 mIU/L in first trimester, 0.2 to 3.0 mIU/L in second trimester, 0.3 to 3.0 mIU/L in third trimester.5
Inadequate treatment of hypothyroidism in pregnancy has consequences on the pregnancy, fetus, and neonate. One cohort study noted an increase in low birth weight secondary to preterm delivery for gestational hypertension in women with overt and subclinical hypothyroidism.10 Another observational study demonstrated an increase in gestational diabetes, pregnancy-induced hypertension, intrauterine growth restriction, and intrauterine fetal demise in women with hypothyroidism; an increase in neonatal complications including neonatal intensive care unit admission, jaundice, and hypoglycemia was also noted in women with hypothyroidism.11 Impaired neurologic function of the child is of greatest concern for women with inadequately controlled hypothyroidism in pregnancy. A retrospective cohort study demonstrated lower intelligence quotient scores in children of mothers with elevated TSH level in the second trimester.12 Given the impact of overt hypothyroidism on pregnancy outcomes, close surveillance of thyroid function and adequate treatment in pregnancy are critical.
Subclinical Hypothyroidism
Subclinical hypothyroidism (SCH) is defined as an elevation in TSH level with a normal free T4 level in the absence of symptoms. SCH is estimated to affect 2.5% of pregnancies.9 Some studies have demonstrated an increase in pregnancy loss in women with SCH in pregnancy,13-15 whereas other studies have demonstrated no association of SCH with adverse outcomes.16 For this reason, treatment of SCH prenatally and antenatally is a topic of debate. One meta-analysis reported a decrease in miscarriage and preterm delivery rates with levothyroxine treatment in women with SCH.17 Treatment is recommended for women with SCH with TSH level above the pregnancy trimester-specific reference range and positive TPO antibodies.3,6 Treatment is also recommended for women with SCH, TSH level greater than 10mIU/L, and negative TPO antibodies.3
Thyroid Antibodies and Hypothyroidism
Autoimmune thyroid disease may occur in the presence of antibodies to thyroid antigens. Thyroid peroxidase antibodies have been associated with Hashimoto's thyroiditis. SCH is one indication for testing TPO antibodies. Along with thyroglobulin, antibodies to thyroglobulin are clinically useful for following patients with a history of thyroid cancer; outside of this context, however, thyroglobulin antibody is not indicated, as only thyroid peroxidase antibodies have clinical significance with respect to hypothyroidism.3
One prospective study by Negro et al18 demonstrated an increase in poor pregnancy outcomes in euthyroid women with positive TPO antibodies. However, a recent large randomized controlled trial assessed the need for treatment in pregnant euthyroid women with positive TPO antibodies with a history of infertility or recurrent pregnancy loss; no difference in pregnancy loss, preterm delivery, or live birth rates was noted in women who received levothyroxine treatment versus placebo.19 Given these data, close monitoring of TSH levels is appropriate in euthyroid women with TPO antibodies; treatment may be considered if TSH values are greater than 2.5 mIU/L.3,5
Hyperthyroidism
Hyperthyroidism in pregnancy, although less common than hypothyroidism in pregnancy, is important to recognize, as it poses several risks to mother and fetus. The overall incidence of hyperthyroidism in pregnancy is 0.1% to 0.4%, and 85% of these cases are attributable to maternal Graves' disease.6 Graves' disease is an organ-specific autoimmune process associated with thyroid-stimulating autoantibodies, which bind to and activate TSH receptors causing thyroid hyperfunction and growth.20 Nonimmune causes of hyperthyroidism in pregnancy include toxic multinodular goiter, toxic adenoma, TSH-secreting pituitary adenomas, and inappropriate exogenous thyroid hormone intake.3
Gestational transient thyrotoxicosis is another common form of hyperthyroidism in pregnancy that is typically associated with hyperemesis gravidarum, characterized by very high levels of hCG, which stimulate the TSH receptor.21 Gestational transient thyrotoxicosis generally is mild, resolves without treatment, and does not affect pregnancy outcomes. At symptom onset, it may be difficult to determine whether symptoms are due to transient gestational thyrotoxicosis or Graves' disease. Graves' disease usually has prominent features of an autoimmune component such as a goiter and presence of TSH receptor antibodies.6 Other conditions associated with hCG-induced thyrotoxicosis are hydatidiform mole, multifetal gestation, and choriocarcinoma.3
Signs and symptoms of hyperthyroidism include nervousness, tremors, frequent stools, excessive sweating, heat intolerance, tachycardia (exceeding what is normally seen in pregnancy), thyromegaly, exophthalmos, and weight loss or failure to gain weight in pregnancy despite adequate nutritional status.4,20 Of these signs, those that are most specific for Graves' disease are exophthalmos and dermopathy, such as localized pretibial myxedema.
Diagnosis
Due to the intrinsic thyrotropic activity of hCG, there is a normal suppression of TSH in pregnancy that may lead clinicians to misdiagnose subclinical hyperthyroidism.3,20 Accurate diagnosis of hyperthyroidism in pregnancy requires laboratory confirmation of a markedly decreased level of TSH in conjunction with an increased level of free T4, using trimester-specific reference ranges for TSH level.3
Treatment
Thionamide drugs, most commonly propylthiouracil (PTU) and methimazole, are the medications of choice for treatment of hyperthyroidism in pregnancy. The main mechanism of action of the thionamides is inhibition of thyroid peroxidase and inhibition of organic binding of thyroid iodide, thus inhibiting thyroid hormone synthesis. PTU has a shorter half-life and less bioavailability than methimazole and thus needs to be given in larger doses and more frequently (generally 2-3 times daily dosing).22-24 In general, the initial dose of methimazole in pregnancy is 5 to 30 mg/day (typical dose in an average patient, 10-20 mg) and that of PTU is 100 to 600 mg/day (typical dose in an average patient, 200-400 mg/day).22-24 When switching a patient from one medication to the other, generally the conversion of methimazole to PTU is 1:20 (5 mg of methimazole is equivalent to 100 mg of PTU).22-24
In the first trimester, PTU is the recommended drug of choice, as methimazole has been shown to be associated with congenital abnormalities due to interruption of organogenesis in the fetus.6 The American Thyroid Association recommends PTU use until 16 weeks' gestation and then medication can be switched to methimazole.3 In 2010, the FDA called attention to the risk of hepatotoxicity in patients exposed to PTU because it had been found to be third on the list of drugs leading to liver transplantation in the United States.25 Given this risk, PTU should not be continued past 16 weeks if the patient is able to take methimazole. Antithyroid medications should preferentially be started before pregnancy; however, dosages will likely need to be adjusted throughout pregnancy to maintain the maternal free T4 level at or just above the normal nonpregnant limit.6 The goal of treatment is to balance the lowest possible dose of thionamide medications with the maintenance of free T4 levels just above or in the high-normal range, regardless of TSH levels; thus, free T4 levels, not TSH levels, are monitored every 2 to 4 weeks throughout treatment and medication dosage can be adjusted accordingly. The Endocrine Society recommends checking thyroid function tests 2 weeks after a medication change and every 2 to 4 weeks thereafter.6 While taking PTU, liver function tests should be monitored every 3 to 4 weeks throughout treatment, and patients should be encouraged to follow-up for any concerning symptoms.6
It is rare that a woman requires thyroidectomy in pregnancy. Indications for thyroidectomy in pregnancy include inability to tolerate antithyroid drugs due to contraindications or allergies, persistent hyperthyroidism despite maximum dose of antithyroid medication (>30 mg/day of methimazole or >450 mg/day of PTU), or noncompliance in the setting of uncontrolled hyperthyroidism.3,6 Thyroidectomy in pregnancy should be delayed until the second trimester, if possible.3 Radioactive iodine is contraindicated in pregnancy given the risk of complete destruction of the fetal thyroid.6
Thionamide medications are not without side effects. Drug reactions in patients taking thionamide drugs generally occur in 3% to 5% of patients; the most common reaction is allergic skin rash.26 Thionamide medications have been shown to cause leukopenia in up to 10% of women; however, this is a mild side effect and does not require drug cessation.4 More severe side effects of thionamide drugs are agranulocytosis and liver failure, which occur in 0.15% and less than 0.1% of patients, respectively.3 Although maternal side effects must be monitored, the greatest risk is to the fetus; methimazole has been associated with fetal aplasia cutis, choanal atresia, esophageal atresia, ventriculoseptal defects, abdominal wall defects, urinary system defects, and eye abnormalities. These complications can occur in 2% to 4% of fetuses exposed to methimazole in early pregnancy.3 If patients are on a low dose of antithyroid drugs and have normal thyroid hormone levels, physicians can consider discontinuing medication during early pregnancy due to teratogenic effects and follow thyroid hormone level every 2 weeks.
Pregnancy/Maternal Outcomes
Potential complications of hyperthyroidism in pregnancy include spontaneous pregnancy loss, maternal congestive heart failure, thyroid storm, preterm birth, preeclampsia, fetal growth restriction, stillbirth, fetal hydrops, fetal tachycardia, and associated perinatal morbidity and mortality.3,21 Some of the more common pregnancy-related morbidities include increased risk of hypertension and preeclampsia in pregnancies affected by maternal hyperthyroidism. The most concerning sequelae of hyperthyroidism in pregnancy are thyroid storm and maternal heart failure.
Although rare in pregnancy, thyroid storm may occur with untreated or inadequately treated hyperthyroidism during pregnancy.27 When thyroid storm occurs, maternal mortality can be as high as 10% to 30%.28 Thyroid storm is a hypermetabolic state caused by excess thyroid hormone and is diagnosed clinically by the presence of fever, tachycardia, cardiac dysrhythmia, agitation, confusion, and central nervous system dysfunction.4,20,27,28 Other potential etiologies must be evaluated and ruled out to expedite the clinical diagnosis and initiation of correct treatment. Treatment of thyroid storm in pregnancy does not differ from that outside of pregnancy and must be managed by a multidisciplinary team consisting of endocrinologists, maternal fetal medicine specialists, and an intensive care unit.
The management of thyroid storm includes a loading dose of PTU 1000 mg orally followed by 200 mg orally every 6 hours. Iodine administration must be given 1 to 2 hours after initiation of PTU to inhibit release of T3 and T4; this can be done by sodium iodide 500 to 1000 mg orally every 8 hours, potassium iodide 5 drops orally every 8 hours, Lugol's solution 10 drops orally every 8 hours, or lithium carbonate 300 mg orally every 6 hours.4,20,27 To further block the conversion of T4 to T3, IV dexamethasone 2 mg every 6 hours for a total of 4 doses or hydrocortisone 100 mg IV every 8 hours for a total of 3 doses can be administered.4,20,27 Beta-blockers can be given to control tachycardia; labetalol, propranolol, and esmolol have all been used successfully for this indication.4,20,27 Continuous monitoring of the fetus should be implemented as appropriate for gestational age; thyroid storm itself, however, is not an indication for immediate delivery and the fetus will generally recover when the mother is stabilized.28
Fetal Outcomes
Approximately 1% to 5% of neonates will have hyperthyroidism or neonatal Graves' disease caused by transplacental passage of maternal thyroid-stimulating immunoglobulin.4 Fetal thyroid examination by ultrasound should be completed between 18 to 22 weeks' gestation, if the mother has antithyroid antibodies. This ultrasound surveillance may be repeated every 4 to 6 weeks to evaluate for possible fetal abnormalities such as enlarged thyroid, growth restriction, hydrops, goiter, advanced bone age, tachycardia, and cardiac failure.6
Because thyroid receptor antibodies can cross the placenta, the Endocrine Society recommends that these antibodies be measured by 22 weeks of gestation in mothers with Graves' disease, a history of Graves' disease after treatment with radioactive iodine or thyroidectomy, a previous infant with Graves' disease, or previously elevated antithyroid antibodies.6 If a fetus is suspected to have fetal hyperthyroidism, antithyroid drugs should be initiated immediately; generally, fetal hyperthyroidism does not occur before 20 weeks' gestation.3,6 Both PTU and methimazole cross the placenta; thus, the lowest possible dose of antithyroid drugs should be used to prevent overtreatment of the fetus; maternal T4 should be kept at or just above the upper limit of normal for gestational age.3
Postpartum Thyroiditis
Postpartum thyroiditis (PPT) is an autoimmune inflammatory reaction diagnosed in 5% to 10% of women; it is characterized by thyroid dysfunction that occurs within 1 year of delivery in women who had normal thyroid function before pregnancy, and is distinct from Graves' disease.3,4,20 PPT may be caused by a rebound in immune activity during the postpartum period following the resolution of the immunosuppressed state of pregnancy.3 The largest risk factor for developing PPT is the presence of thyroid antibodies. Of women who are TPO antibody positive in the first trimester, 50% to 70% will develop PPT.29 Other risk factors include type 1 diabetes, a history of PPT, and a history of Graves' disease in remission.6 The Endocrine Society recommends that women at high risk for PPT should be screened with TSH levels at 3 to 6 months postpartum.6
The classic form of PPT generally presents as transient hyperthyroidism followed by a period of hypothyroidism, with return to normal thyroid function within a year postpartum. The presentation, however, may vary with some women having isolated hyperthyroidism or isolated hypothyroidism. PPT is often clinically missed because it can develop months after delivery, and signs and symptoms may be attributed to the stresses of early motherhood. The symptoms of the hyperthyroid phase are palpitations, fatigue, heat intolerance, irritability, and nervousness; these symptoms can be controlled with propanolol and do not require treatment with antithyroid medications.3,6 Women are more likely to be symptomatic during the hypothyroid phase, presenting with cold intolerance, dry skin, fatigue, impaired concentration, and/or parasthesias, which may require treatment with levothyroxine.3,5 Women in the hypothyroid phase of PPT do not require treatment if TSH level is between 4 and 10 mIU/L but should be treated with levothyroxine if TSH level is greater than 10 mIU/L; thyroid function testing should be completed every 4 to 8 weeks if no treatment is initiated.6
Women with PPT are at increased risk of developing chronic hypothyroidism in the 5 to 10 years postpartum and it is recommended that they have thyroid function testing annually.6 A prospective trial by Stagnaro-Green et al30 showed that 50% of women with PPT remained hypothyroid at 1 year postpartum. Women with PPT have a 70% chance of recurrence after subsequent pregnancies.3 Although a link between PPT and postpartum depression has been speculated, no consistent association has been found; however, all women with symptoms of depression should complete thyroid function testing, as many symptoms of depression and hypothyroidism overlap.6
Conclusion
Thyroid dysfunction is not uncommon in women of reproductive age. Although there are no recommendations for universal screening, maternal, fetal, and neonatal consequences of uncontrolled thyroid disease warrant surveillance in pregnancy for those at risk including women with a history of thyroid disease and women with positive thyroid antibodies. Table 1 provides a summary of recommendations regarding diagnosis and treatment of thyroid disease in pregnancy.
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