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Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes
Author
Douglas S Ross, MD
Section Editors
David S Cooper, MD
Charles J Lockwood, MD
Deputy Editor
Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2013. | This topic last updated: Oct 03, 2012.
INTRODUCTION — Overt hyperthyroidism (low TSH, elevated free T4 and/or T3) is relatively uncommon during pregnancy, occurring in 0.1 to 0.4 percent of all pregnancies [1]. The diagnosis of pregnant women with hyperthyroidism parallels that of nonpregnant women and men, but presents some unique problems. The clinical manifestations, diagnosis, and causes of hyperthyroidism during pregnancy are presented here. The treatment of hyperthyroidism during pregnancy and other aspects of thyroid disease during pregnancy are discussed separately. (See "Hyperthyroidism during pregnancy: Treatment" and "Overview of thyroid disease in pregnancy".)
CLINICAL FEATURES
Clinical manifestations — Many of the nonspecific symptoms associated with pregnancy are similar to those associated with hyperthyroidism, including tachycardia, heat intolerance, and increased perspiration. Additional symptoms include anxiety, hand tremor, and weight loss despite a normal or increased appetite. Specific findings such as goiter and ophthalmopathy suggest Graves' hyperthyroidism. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)
Pregnancy complications — Pregnancy complicated by poorly controlled overt hyperthyroidism (most often due to Graves’ disease) is associated with increased rates of the following [2-6]:
Spontaneous abortion
Premature labor
Low birth weight
Stillbirth
Preeclampsia
Heart failure
A study of 180 pregnancies complicated by hyperthyroidism compared to 360 controls found a higher rate of maternal hypertension and a 1.3 to 1.4-fold increased risk of fetal growth restriction, low birth weight, and preterm birth [7]. The risk of early pregnancy loss also appears to be increased in women with thyroid hormone resistance if the fetus does not carry the mutation, presumably due to the transplacental passage of high levels of thyroid hormone to the fetus. (See "Resistance to thyrotropin and thyrotropin-releasing hormone".)
Very rare cases of thyroid storm precipitated by labor, infection, preeclampsia, or cesarean section have been reported.
In contrast to these findings in women with overt hyperthyroidism, in one report of 433 women with subclinical hyperthyroidism (low TSH, normal free T4), there was no evidence of adverse pregnancy outcomes [8].
Laboratory findings — To meet the increased metabolic needs during a normal pregnancy, there are changes in thyroid physiology that are reflected in altered thyroid function tests. These changes include the following (see "Overview of thyroid disease in pregnancy", section on 'Thyroid adaptation during normal pregnancy'):
TBG excess results in high serum total T4 concentrations, but not high serum free T4 concentrations.
High serum hCG concentrations during early pregnancy and even higher concentrations in women with hyperemesis gravidarum or multiple pregnancies may result in transient subclinical or rarely overt hyperthyroidism.
Because of the changes in thyroid physiology during normal pregnancy, thyroid function tests should be interpreted using trimester-specific TSH and T4 reference ranges for pregnant women [9]. In several population studies, the lower limit of the reference range for healthy pregnant women during the first trimester ranged from 0.03 to 0.1 mU/L [10-14]. In one of the largest population-based studies (over 13,000 pregnant women), the reference range (2.5 to 97.5th percentile) for TSH in the first trimester was 0.08 to 2.99 mU/L [10,13]. Total T4 and T3 levels during pregnancy are 1.5-fold higher than in nonpregnant women due to TBG excess. Reference ranges for free T4 are method-specific and trimester-specific reference ranges should be provided with the assay kits. (See "Overview of thyroid disease in pregnancy", section on 'Trimester-specific reference ranges'.)
Most pregnant women with significant overt hyperthyroidism in the first trimester have a serum TSH below that which is seen in asymptomatic healthy pregnant women (ie, <0.01 mU/L) associated with an elevated free T4 and/or free T3 (or total T4 and/or total T3) measurement that exceeds the normal range during pregnancy [15].
DIAGNOSIS — The diagnosis of hyperthyroidism during pregnancy is based upon clinical manifestations and laboratory findings. Specific findings on physical examination such as goiter and ophthalmopathy suggest Graves' hyperthyroidism. (See 'Graves' disease' below.)
When there is a clinical suspicion of hyperthyroidism, serum TSH should be measured. If the TSH level is <0.1 mU/L, free T4 (or free T4 index) should be obtained. If the free T4 is in the normal range for pregnancy, a free T3 should also be measured. In the event that free thyroid hormone levels are discordant with serum TSH and clinical findings, total T4 should be measured. The diagnosis of hyperthyroidism during pregnancy should be based primarily upon a suppressed (<0.1 mU/L) or undetectable (<0.01 mU/L) serum TSH value and also a high serum free T4 and/or free T3 (or total T4 and/or total T3) measurement that exceeds the normal range for pregnancy.
ESTABLISHING THE CAUSE — Once the diagnosis of hyperthyroidism is established, the cause of hyperthyroidism should be determined. Although hyperthyroidism from any cause can complicate pregnancy, Graves' (occurring in 0.1 to 1 percent of all pregnancies) and hCG-mediated hyperthyroidism (1 to 3 percent of pregnancies) are the most common causes of hyperthyroidism [1,16]. Other causes of hyperthyroidism (including silent or subacute thyroiditis, toxic adenoma, toxic multinodular goiter, and factitious thyrotoxicosis) are rare during pregnancy. (See "Disorders that cause hyperthyroidism".)
Thus, the primary objective is to differentiate Graves’ disease from hCG-mediated hyperthyroidism. Although the clinical symptoms are similar, the presence of goiter or ophthalmopathy on physical examination favors the diagnosis of Graves’ disease. Goiter is not a classical clinical feature of hCG-mediated hyperthyroidism, but it may be present. Graves’ disease usually becomes less severe during the later stages of pregnancy due to a reduction in TSH receptor antibody concentrations or, rarely, mediated by a change in the activity of TSH receptor antibodies from stimulatory to blocking [17,18]. hCG-mediated hyperthyroidism may occur transiently in the first half of gestation and is typically less severe than Graves’ disease. (See 'Graves' disease' below and 'hCG-mediated hyperthyroidism' below.)
In situations where the clinical diagnosis is uncertain, thyrotropin (TSH) receptor antibodies (TRAb), using a second-generation thyrotropin-binding inhibitory immunoglobulin (TBII) assay, should be measured. TSH receptor antibodies are positive in 95 percent of patients with Graves' disease and, therefore, the presence of TSH receptor antibodies confirms the diagnosis of Graves' disease [19]. In addition, measurement of total T3 can sometimes help distinguish T3 toxicosis caused by Graves’ disease from hCG-mediated hyperthyroidism (both T4 and T3 elevated).
Thyroid radionuclide imaging is typically performed in nonpregnant patients to distinguish Graves’ disease from thyroiditis. However, radionuclide imaging is contraindicated in pregnant women. In experienced hands, thyroid ultrasound with Doppler flow may be useful to distinguish Graves’ disease (high blood flow) from painless or postpartum thyroiditis (low blood flow) [20]. However, its utility in diagnosing hCG-mediated hyperthyroidism is unknown.
Graves' disease — Graves' disease is a syndrome that may consist of hyperthyroidism, goiter, eye disease (orbitopathy), and occasionally a dermopathy referred to as pretibial or localized myxedema. The terms Graves' disease and hyperthyroidism are not synonymous because some patients may have orbitopathy but no hyperthyroidism, and there are many other causes of hyperthyroidism in addition to Graves' disease. Hyperthyroidism is the most common feature of Graves' disease, affecting nearly all patients, and is caused by autoantibodies to the thyrotropin (TSH) receptor (TRAb) that activate the receptor, thereby stimulating thyroid hormone synthesis and secretion as well as thyroid growth (causing a diffuse goiter). The presence of TRAbs in serum and orbitopathy on clinical examination distinguishes the disorder from other causes of hyperthyroidism. The thyroid gland is usually, but not always, diffusely enlarged. (See "Pathogenesis of Graves' disease", section on 'The thyroid gland in Graves' disease' and "Pathogenesis of Graves' disease", section on 'Autoantibodies to the TSH receptor'.)
The importance of measuring maternal serum TSH receptor antibodies (TRAb) for prediction of fetal and neonatal Graves’ disease is reviewed separately. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Fetal hyperthyroidism' and "Evaluation and management of neonatal Graves' disease", section on 'Measurement of antibodies'.)
hCG-mediated hyperthyroidism — During normal pregnancy, serum human chorionic gonadotropin (hCG) concentrations rise soon after fertilization and peak at 10 to 12 weeks gestation, after which time the levels decline. There is considerable homology between the beta-subunits of hCG and TSH. As a result, hCG has weak thyroid-stimulating activity and may cause hyperthyroidism during the period of highest serum hCG concentrations. (See "Overview of thyroid disease in pregnancy", section on 'hCG and thyroid function'.)
There are a number of examples of hCG-mediated hyperthyroidism:
Gestational transient thyrotoxicosis — During the time of peak hCG concentrations (10 to 12 weeks), total serum T4 and T3 concentrations increase. Serum free T4 and T3 concentrations increase slightly, usually within the normal range, and serum TSH concentrations are appropriately reduced. Thus, in some women, the high serum concentration of hCG during early pregnancy can lead to subclinical or mild overt hyperthyroidism characterized by slightly low serum TSH concentrations and high-normal or mildly elevated serum free T4 concentrations [21]. This phenomenon is called gestational transient thyrotoxicosis (GTT). It occurs near the end of the first trimester and symptoms (if present) and thyroid hyperfunction subside as hCG production falls (typically 14 to 18 weeks gestation). (See "Overview of thyroid disease in pregnancy", section on 'hCG and thyroid function'.)
Hyperemesis gravidarum — Hyperemesis gravidarum is a syndrome of nausea and vomiting associated with weight loss of 5 percent or more during early pregnancy that occurs in 0.1 to 0.2 percent of pregnancies. Women who develop hyperemesis gravidarum have higher serum hCG and estradiol concentrations than normal pregnant women [22]; in addition, their hCG has more thyroid-stimulating activity [23-25]. Therefore, their serum TSH concentrations are often lower than those in normal pregnant women (60 versus 9 percent had a low serum TSH in one study) [22,24]. A few of these women have high serum free T4 concentrations and therefore have overt hyperthyroidism.
Features that distinguish the transient hyperthyroidism of hyperemesis gravidarum from hyperthyroidism of other causes (which in a pregnant woman is most likely due to Graves' disease) are the vomiting, absence of goiter and ophthalmopathy, and absence of the common symptoms and signs of hyperthyroidism (tachycardia greater than 100 beats/minute, hyperdefecation, muscle weakness, tremor). In addition, serum free T4 concentrations are only minimally elevated and serum T3 concentrations are frequently not elevated in women with hyperemesis gravidarum, whereas both are usually unequivocally elevated in pregnant women with true hyperthyroidism from Graves’ disease.
The thyroid hyperfunction in women with hyperemesis gravidarum usually does not require treatment because it is mild and subsides as hCG production falls (as does the vomiting). Like the thyroid hyperfunction, the vomiting is also proportional to the elevation in serum hCG and estradiol concentrations, and it is thought to be caused by estradiol [22]. If overt hyperthyroidism persists for more than several weeks or beyond the first trimester, it is probably not hCG-mediated.
The clinical presentation, diagnosis, and treatment of hyperemesis gravidarum are reviewed in detail elsewhere. (See "Clinical features and evaluation of nausea and vomiting of pregnancy" and "Treatment and outcome of nausea and vomiting of pregnancy".)
Trophoblastic hyperthyroidism — Hyperthyroidism can also occur with gestational trophoblastic disease. A hydatidiform mole (molar pregnancy) is benign, but may give rise to choriocarcinoma. Both are associated with high serum hCG concentrations and abnormal hCG isoforms [26]. (See "Gestational trophoblastic disease: Pathology".)
In the past, approximately 55 to 60 percent of women with trophoblastic disease had clinically evident hyperthyroidism at the time of diagnosis, which could be severe. However, in a review of 196 patients from the UK treated for gestational trophoblastic disease between 2005 and 2010, biochemical hyperthyroidism was present in 7 percent and clinical hyperthyroidism in only 2 percent [27]. The difference in prevalence is likely related to earlier diagnosis of trophoblastic disease due to ultrasonography and monitoring of serum beta-hCG. (See "Gestational trophoblastic disease: Epidemiology, clinical manifestations and diagnosis".)
Many patients with hyperthyroidism caused by trophoblastic disease have a normal thyroid gland and few symptoms of thyroid hormone excess. However, some patients have more typical clinical findings of hyperthyroidism and a diffuse goiter, but ophthalmopathy is not present. Nausea and vomiting may predominate, as in hyperemesis gravidarum.
The treatment of women with symptomatic moderate to severe hyperthyroidism due to trophoblastic hyperthyroidism is reviewed separately. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Indications'.)
Familial gestational hyperthyroidism — Recurrent gestational hyperthyroidism has been described in one family due to a mutant thyrotropin receptor that is hypersensitive to physiologic concentrations of hCG [28,29].
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Basics topics (see "Patient information: Hyperthyroidism (overactive thyroid) (The Basics)" and "Patient information: Hyperthyroidism (overactive thyroid) and pregnancy (The Basics)")
Beyond the Basics topics (see "Patient information: Hyperthyroidism (overactive thyroid) (Beyond the Basics)" and "Patient information: Antithyroid drugs (Beyond the Basics)")
SUMMARY
Many of the nonspecific symptoms associated with pregnancy are similar to those associated with hyperthyroidism, including tachycardia, heat intolerance, and increased perspiration. Additional symptoms may include anxiety, hand tremor, and weight loss despite a normal or increased appetite. Specific findings such as goiter and ophthalmopathy suggest Graves' hyperthyroidism. (See 'Clinical features' above and "Overview of the clinical manifestations of hyperthyroidism in adults".)
The diagnosis of hyperthyroidism during pregnancy should be based primarily upon a finding of a suppressed (<0.1 mU/L) or undetectable (<0.01) serum TSH value and elevated thyroid hormone levels (serum free T4 and/or free T3 or total T4 and/or total T3) that exceed the normal range for pregnancy. (See 'Diagnosis' above.)
Although hyperthyroidism from any cause can complicate pregnancy, Graves' (occurring in 0.1 to 1 percent of all pregnancies) and hCG-mediated hyperthyroidism (1 to 3 percent of pregnancies) are the most common causes of hyperthyroidism. In situations where the clinical diagnosis is uncertain, thyrotropin (TSH) receptor antibodies, using a second-generation thyrotropin-binding inhibitory immunoglobulin (TBII) assay, should be measured. TSH receptor antibodies are positive in 95 percent of patients with Graves' disease and, therefore, the presence of TSH receptor antibodies confirms the diagnosis of Graves' disease. (See 'Establishing the cause' above and "Pathogenesis of Graves' disease".)
Hyperthyroidism mediated by the effects of hCG include gestational transient thyrotoxicosis, hyperemesis gravidarum, and trophoblastic hyperthyroidism. Only the latter requires treatment of the hyperthyroidism. (See 'hCG-mediated hyperthyroidism' above and "Hyperthyroidism during pregnancy: Treatment".)
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REFERENCES
1 Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev 2010; 31:702.
2 Davis LE, Lucas MJ, Hankins GD, et al. Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 1989; 160:63.
3 Sheffield JS, Cunningham FG. Thyrotoxicosis and heart failure that complicate pregnancy. Am J Obstet Gynecol 2004; 190:211.
4 Phoojaroenchanachai M, Sriussadaporn S, Peerapatdit T, et al. Effect of maternal hyperthyroidism during late pregnancy on the risk of neonatal low birth weight. Clin Endocrinol (Oxf) 2001; 54:365.
5 Millar LK, Wing DA, Leung AS, et al. Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 1994; 84:946.
6 Kriplani A, Buckshee K, Bhargava VL, et al. Maternal and perinatal outcome in thyrotoxicosis complicating pregnancy. Eur J Obstet Gynecol Reprod Biol 1994; 54:159.
7 Luewan S, Chakkabut P, Tongsong T. Outcomes of pregnancy complicated with hyperthyroidism: a cohort study. Arch Gynecol Obstet 2011; 283:243.
8 Casey BM, Dashe JS, Wells CE, et al. Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol 2006; 107:337.
9 Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011; 21:1081.
10 Dashe JS, Casey BM, Wells CE, et al. Thyroid-stimulating hormone in singleton and twin pregnancy: importance of gestational age-specific reference ranges. Obstet Gynecol 2005; 106:753.
11 Stricker R, Echenard M, Eberhart R, et al. Evaluation of maternal thyroid function during pregnancy: the importance of using gestational age-specific reference intervals. Eur J Endocrinol 2007; 157:509.
12 Gilbert RM, Hadlow NC, Walsh JP, et al. Assessment of thyroid function during pregnancy: first-trimester (weeks 9-13) reference intervals derived from Western Australian women. Med J Aust 2008; 189:250.
13 Fitzpatrick DL, Russell MA. Diagnosis and management of thyroid disease in pregnancy. Obstet Gynecol Clin North Am 2010; 37:173.
14 Lambert-Messerlian G, McClain M, Haddow JE, et al. First- and second-trimester thyroid hormone reference data in pregnant women: a FaSTER (First- and Second-Trimester Evaluation of Risk for aneuploidy) Research Consortium study. Am J Obstet Gynecol 2008; 199:62.e1.
15 American College of Obstetricians and Gynecologists.. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 37, August 2002. (Replaces Practice Bulletin Number 32, November 2001). Thyroid disease in pregnancy. Obstet Gynecol 2002; 100:387.
16 Patil-Sisodia K, Mestman JH. Graves hyperthyroidism and pregnancy: a clinical update. Endocr Pract 2010; 16:118.
17 Salvi M, How J. Pregnancy and autoimmune thyroid disease. Endocrinol Metab Clin North Am 1987; 16:431.
18 Kung AW, Lau KS, Kohn LD. Epitope mapping of tsh receptor-blocking antibodies in Graves' disease that appear during pregnancy. J Clin Endocrinol Metab 2001; 86:3647.
19 Vos XG, Smit N, Endert E, et al. Frequency and characteristics of TBII-seronegative patients in a population with untreated Graves' hyperthyroidism: a prospective study. Clin Endocrinol (Oxf) 2008; 69:311.
20 Ota H, Amino N, Morita S, et al. Quantitative measurement of thyroid blood flow for differentiation of painless thyroiditis from Graves' disease. Clin Endocrinol (Oxf) 2007; 67:41.
21 Glinoer D, de Nayer P, Bourdoux P, et al. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 1990; 71:276.
22 Goodwin TM, Montoro M, Mestman JH, et al. The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum. J Clin Endocrinol Metab 1992; 75:1333.
23 Yamazaki K, Sato K, Shizume K, et al. Potent thyrotropic activity of human chorionic gonadotropin variants in terms of 125I incorporation and de novo synthesized thyroid hormone release in human thyroid follicles. J Clin Endocrinol Metab 1995; 80:473.
24 Kimura M, Amino N, Tamaki H, et al. Gestational thyrotoxicosis and hyperemesis gravidarum: possible role of hCG with higher stimulating activity. Clin Endocrinol (Oxf) 1993; 38:345.
25 Hershman JM. Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and trophoblastic tumors. Thyroid 1999; 9:653.
26 Yoshimura M, Pekary AE, Pang XP, et al. Thyrotropic activity of basic isoelectric forms of human chorionic gonadotropin extracted from hydatidiform mole tissues. J Clin Endocrinol Metab 1994; 78:862.
27 Walkington L, Webster J, Hancock BW, et al. Hyperthyroidism and human chorionic gonadotrophin production in gestational trophoblastic disease. Br J Cancer 2011; 104:1665.
28 Rodien P, Brémont C, Sanson ML, et al. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 1998; 339:1823.
29 Smits G, Govaerts C, Nubourgh I, et al. Lysine 183 and glutamic acid 157 of the TSH receptor: two interacting residues with a key role in determining specificity toward TSH and human CG. Mol Endocrinol 2002; 16:722.
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Official Topic from UpToDate®, the clinical decision support resource accessed by 700,000+ clinicians worldwide. Available via the web and mobile devices, subscribe to UpToDate® at www.uptodate.com/store.
Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes
Author
Douglas S Ross, MD
Section Editors
David S Cooper, MD
Charles J Lockwood, MD
Deputy Editor
Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2013. | This topic last updated: Oct 03, 2012.
INTRODUCTION — Overt hyperthyroidism (low TSH, elevated free T4 and/or T3) is relatively uncommon during pregnancy, occurring in 0.1 to 0.4 percent of all pregnancies [1]. The diagnosis of pregnant women with hyperthyroidism parallels that of nonpregnant women and men, but presents some unique problems. The clinical manifestations, diagnosis, and causes of hyperthyroidism during pregnancy are presented here. The treatment of hyperthyroidism during pregnancy and other aspects of thyroid disease during pregnancy are discussed separately. (See "Hyperthyroidism during pregnancy: Treatment" and "Overview of thyroid disease in pregnancy".)
CLINICAL FEATURES
Clinical manifestations — Many of the nonspecific symptoms associated with pregnancy are similar to those associated with hyperthyroidism, including tachycardia, heat intolerance, and increased perspiration. Additional symptoms include anxiety, hand tremor, and weight loss despite a normal or increased appetite. Specific findings such as goiter and ophthalmopathy suggest Graves' hyperthyroidism. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)
Pregnancy complications — Pregnancy complicated by poorly controlled overt hyperthyroidism (most often due to Graves’ disease) is associated with increased rates of the following [2-6]:
Spontaneous abortion
Premature labor
Low birth weight
Stillbirth
Preeclampsia
Heart failure
A study of 180 pregnancies complicated by hyperthyroidism compared to 360 controls found a higher rate of maternal hypertension and a 1.3 to 1.4-fold increased risk of fetal growth restriction, low birth weight, and preterm birth [7]. The risk of early pregnancy loss also appears to be increased in women with thyroid hormone resistance if the fetus does not carry the mutation, presumably due to the transplacental passage of high levels of thyroid hormone to the fetus. (See "Resistance to thyrotropin and thyrotropin-releasing hormone".)
Very rare cases of thyroid storm precipitated by labor, infection, preeclampsia, or cesarean section have been reported.
In contrast to these findings in women with overt hyperthyroidism, in one report of 433 women with subclinical hyperthyroidism (low TSH, normal free T4), there was no evidence of adverse pregnancy outcomes [8].
Laboratory findings — To meet the increased metabolic needs during a normal pregnancy, there are changes in thyroid physiology that are reflected in altered thyroid function tests. These changes include the following (see "Overview of thyroid disease in pregnancy", section on 'Thyroid adaptation during normal pregnancy'):
TBG excess results in high serum total T4 concentrations, but not high serum free T4 concentrations.
High serum hCG concentrations during early pregnancy and even higher concentrations in women with hyperemesis gravidarum or multiple pregnancies may result in transient subclinical or rarely overt hyperthyroidism.
Because of the changes in thyroid physiology during normal pregnancy, thyroid function tests should be interpreted using trimester-specific TSH and T4 reference ranges for pregnant women [9]. In several population studies, the lower limit of the reference range for healthy pregnant women during the first trimester ranged from 0.03 to 0.1 mU/L [10-14]. In one of the largest population-based studies (over 13,000 pregnant women), the reference range (2.5 to 97.5th percentile) for TSH in the first trimester was 0.08 to 2.99 mU/L [10,13]. Total T4 and T3 levels during pregnancy are 1.5-fold higher than in nonpregnant women due to TBG excess. Reference ranges for free T4 are method-specific and trimester-specific reference ranges should be provided with the assay kits. (See "Overview of thyroid disease in pregnancy", section on 'Trimester-specific reference ranges'.)
Most pregnant women with significant overt hyperthyroidism in the first trimester have a serum TSH below that which is seen in asymptomatic healthy pregnant women (ie, <0.01 mU/L) associated with an elevated free T4 and/or free T3 (or total T4 and/or total T3) measurement that exceeds the normal range during pregnancy [15].
DIAGNOSIS — The diagnosis of hyperthyroidism during pregnancy is based upon clinical manifestations and laboratory findings. Specific findings on physical examination such as goiter and ophthalmopathy suggest Graves' hyperthyroidism. (See 'Graves' disease' below.)
When there is a clinical suspicion of hyperthyroidism, serum TSH should be measured. If the TSH level is <0.1 mU/L, free T4 (or free T4 index) should be obtained. If the free T4 is in the normal range for pregnancy, a free T3 should also be measured. In the event that free thyroid hormone levels are discordant with serum TSH and clinical findings, total T4 should be measured. The diagnosis of hyperthyroidism during pregnancy should be based primarily upon a suppressed (<0.1 mU/L) or undetectable (<0.01 mU/L) serum TSH value and also a high serum free T4 and/or free T3 (or total T4 and/or total T3) measurement that exceeds the normal range for pregnancy.
ESTABLISHING THE CAUSE — Once the diagnosis of hyperthyroidism is established, the cause of hyperthyroidism should be determined. Although hyperthyroidism from any cause can complicate pregnancy, Graves' (occurring in 0.1 to 1 percent of all pregnancies) and hCG-mediated hyperthyroidism (1 to 3 percent of pregnancies) are the most common causes of hyperthyroidism [1,16]. Other causes of hyperthyroidism (including silent or subacute thyroiditis, toxic adenoma, toxic multinodular goiter, and factitious thyrotoxicosis) are rare during pregnancy. (See "Disorders that cause hyperthyroidism".)
Thus, the primary objective is to differentiate Graves’ disease from hCG-mediated hyperthyroidism. Although the clinical symptoms are similar, the presence of goiter or ophthalmopathy on physical examination favors the diagnosis of Graves’ disease. Goiter is not a classical clinical feature of hCG-mediated hyperthyroidism, but it may be present. Graves’ disease usually becomes less severe during the later stages of pregnancy due to a reduction in TSH receptor antibody concentrations or, rarely, mediated by a change in the activity of TSH receptor antibodies from stimulatory to blocking [17,18]. hCG-mediated hyperthyroidism may occur transiently in the first half of gestation and is typically less severe than Graves’ disease. (See 'Graves' disease' below and 'hCG-mediated hyperthyroidism' below.)
In situations where the clinical diagnosis is uncertain, thyrotropin (TSH) receptor antibodies (TRAb), using a second-generation thyrotropin-binding inhibitory immunoglobulin (TBII) assay, should be measured. TSH receptor antibodies are positive in 95 percent of patients with Graves' disease and, therefore, the presence of TSH receptor antibodies confirms the diagnosis of Graves' disease [19]. In addition, measurement of total T3 can sometimes help distinguish T3 toxicosis caused by Graves’ disease from hCG-mediated hyperthyroidism (both T4 and T3 elevated).
Thyroid radionuclide imaging is typically performed in nonpregnant patients to distinguish Graves’ disease from thyroiditis. However, radionuclide imaging is contraindicated in pregnant women. In experienced hands, thyroid ultrasound with Doppler flow may be useful to distinguish Graves’ disease (high blood flow) from painless or postpartum thyroiditis (low blood flow) [20]. However, its utility in diagnosing hCG-mediated hyperthyroidism is unknown.
Graves' disease — Graves' disease is a syndrome that may consist of hyperthyroidism, goiter, eye disease (orbitopathy), and occasionally a dermopathy referred to as pretibial or localized myxedema. The terms Graves' disease and hyperthyroidism are not synonymous because some patients may have orbitopathy but no hyperthyroidism, and there are many other causes of hyperthyroidism in addition to Graves' disease. Hyperthyroidism is the most common feature of Graves' disease, affecting nearly all patients, and is caused by autoantibodies to the thyrotropin (TSH) receptor (TRAb) that activate the receptor, thereby stimulating thyroid hormone synthesis and secretion as well as thyroid growth (causing a diffuse goiter). The presence of TRAbs in serum and orbitopathy on clinical examination distinguishes the disorder from other causes of hyperthyroidism. The thyroid gland is usually, but not always, diffusely enlarged. (See "Pathogenesis of Graves' disease", section on 'The thyroid gland in Graves' disease' and "Pathogenesis of Graves' disease", section on 'Autoantibodies to the TSH receptor'.)
The importance of measuring maternal serum TSH receptor antibodies (TRAb) for prediction of fetal and neonatal Graves’ disease is reviewed separately. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Fetal hyperthyroidism' and "Evaluation and management of neonatal Graves' disease", section on 'Measurement of antibodies'.)
hCG-mediated hyperthyroidism — During normal pregnancy, serum human chorionic gonadotropin (hCG) concentrations rise soon after fertilization and peak at 10 to 12 weeks gestation, after which time the levels decline. There is considerable homology between the beta-subunits of hCG and TSH. As a result, hCG has weak thyroid-stimulating activity and may cause hyperthyroidism during the period of highest serum hCG concentrations. (See "Overview of thyroid disease in pregnancy", section on 'hCG and thyroid function'.)
There are a number of examples of hCG-mediated hyperthyroidism:
Gestational transient thyrotoxicosis — During the time of peak hCG concentrations (10 to 12 weeks), total serum T4 and T3 concentrations increase. Serum free T4 and T3 concentrations increase slightly, usually within the normal range, and serum TSH concentrations are appropriately reduced. Thus, in some women, the high serum concentration of hCG during early pregnancy can lead to subclinical or mild overt hyperthyroidism characterized by slightly low serum TSH concentrations and high-normal or mildly elevated serum free T4 concentrations [21]. This phenomenon is called gestational transient thyrotoxicosis (GTT). It occurs near the end of the first trimester and symptoms (if present) and thyroid hyperfunction subside as hCG production falls (typically 14 to 18 weeks gestation). (See "Overview of thyroid disease in pregnancy", section on 'hCG and thyroid function'.)
Hyperemesis gravidarum — Hyperemesis gravidarum is a syndrome of nausea and vomiting associated with weight loss of 5 percent or more during early pregnancy that occurs in 0.1 to 0.2 percent of pregnancies. Women who develop hyperemesis gravidarum have higher serum hCG and estradiol concentrations than normal pregnant women [22]; in addition, their hCG has more thyroid-stimulating activity [23-25]. Therefore, their serum TSH concentrations are often lower than those in normal pregnant women (60 versus 9 percent had a low serum TSH in one study) [22,24]. A few of these women have high serum free T4 concentrations and therefore have overt hyperthyroidism.
Features that distinguish the transient hyperthyroidism of hyperemesis gravidarum from hyperthyroidism of other causes (which in a pregnant woman is most likely due to Graves' disease) are the vomiting, absence of goiter and ophthalmopathy, and absence of the common symptoms and signs of hyperthyroidism (tachycardia greater than 100 beats/minute, hyperdefecation, muscle weakness, tremor). In addition, serum free T4 concentrations are only minimally elevated and serum T3 concentrations are frequently not elevated in women with hyperemesis gravidarum, whereas both are usually unequivocally elevated in pregnant women with true hyperthyroidism from Graves’ disease.
The thyroid hyperfunction in women with hyperemesis gravidarum usually does not require treatment because it is mild and subsides as hCG production falls (as does the vomiting). Like the thyroid hyperfunction, the vomiting is also proportional to the elevation in serum hCG and estradiol concentrations, and it is thought to be caused by estradiol [22]. If overt hyperthyroidism persists for more than several weeks or beyond the first trimester, it is probably not hCG-mediated.
The clinical presentation, diagnosis, and treatment of hyperemesis gravidarum are reviewed in detail elsewhere. (See "Clinical features and evaluation of nausea and vomiting of pregnancy" and "Treatment and outcome of nausea and vomiting of pregnancy".)
Trophoblastic hyperthyroidism — Hyperthyroidism can also occur with gestational trophoblastic disease. A hydatidiform mole (molar pregnancy) is benign, but may give rise to choriocarcinoma. Both are associated with high serum hCG concentrations and abnormal hCG isoforms [26]. (See "Gestational trophoblastic disease: Pathology".)
In the past, approximately 55 to 60 percent of women with trophoblastic disease had clinically evident hyperthyroidism at the time of diagnosis, which could be severe. However, in a review of 196 patients from the UK treated for gestational trophoblastic disease between 2005 and 2010, biochemical hyperthyroidism was present in 7 percent and clinical hyperthyroidism in only 2 percent [27]. The difference in prevalence is likely related to earlier diagnosis of trophoblastic disease due to ultrasonography and monitoring of serum beta-hCG. (See "Gestational trophoblastic disease: Epidemiology, clinical manifestations and diagnosis".)
Many patients with hyperthyroidism caused by trophoblastic disease have a normal thyroid gland and few symptoms of thyroid hormone excess. However, some patients have more typical clinical findings of hyperthyroidism and a diffuse goiter, but ophthalmopathy is not present. Nausea and vomiting may predominate, as in hyperemesis gravidarum.
The treatment of women with symptomatic moderate to severe hyperthyroidism due to trophoblastic hyperthyroidism is reviewed separately. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Indications'.)
Familial gestational hyperthyroidism — Recurrent gestational hyperthyroidism has been described in one family due to a mutant thyrotropin receptor that is hypersensitive to physiologic concentrations of hCG [28,29].
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SUMMARY
Many of the nonspecific symptoms associated with pregnancy are similar to those associated with hyperthyroidism, including tachycardia, heat intolerance, and increased perspiration. Additional symptoms may include anxiety, hand tremor, and weight loss despite a normal or increased appetite. Specific findings such as goiter and ophthalmopathy suggest Graves' hyperthyroidism. (See 'Clinical features' above and "Overview of the clinical manifestations of hyperthyroidism in adults".)
The diagnosis of hyperthyroidism during pregnancy should be based primarily upon a finding of a suppressed (<0.1 mU/L) or undetectable (<0.01) serum TSH value and elevated thyroid hormone levels (serum free T4 and/or free T3 or total T4 and/or total T3) that exceed the normal range for pregnancy. (See 'Diagnosis' above.)
Although hyperthyroidism from any cause can complicate pregnancy, Graves' (occurring in 0.1 to 1 percent of all pregnancies) and hCG-mediated hyperthyroidism (1 to 3 percent of pregnancies) are the most common causes of hyperthyroidism. In situations where the clinical diagnosis is uncertain, thyrotropin (TSH) receptor antibodies, using a second-generation thyrotropin-binding inhibitory immunoglobulin (TBII) assay, should be measured. TSH receptor antibodies are positive in 95 percent of patients with Graves' disease and, therefore, the presence of TSH receptor antibodies confirms the diagnosis of Graves' disease. (See 'Establishing the cause' above and "Pathogenesis of Graves' disease".)
Hyperthyroidism mediated by the effects of hCG include gestational transient thyrotoxicosis, hyperemesis gravidarum, and trophoblastic hyperthyroidism. Only the latter requires treatment of the hyperthyroidism. (See 'hCG-mediated hyperthyroidism' above and "Hyperthyroidism during pregnancy: Treatment".)
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