INTRODUCTION — Overt hyperthyroidism (low thyroid-stimulating hormone [TSH], elevated free thyroxine [T4] and/or triiodothyronine [T3]) is relatively uncommon during pregnancy, occurring in 0.1 to 0.4 percent of all pregnancies [1,2]. The diagnosis of pregnant women with hyperthyroidism parallels that of nonpregnant individuals 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 and pregnancy".)
THYROID PHYSIOLOGY DURING NORMAL PREGNANCY — The diagnosis of thyroid disease during pregnancy requires an understanding of the changes in thyroid physiology and thyroid function tests that accompany normal pregnancy. These changes are reviewed briefly below and in more detail separately. (See "Overview of thyroid disease and pregnancy", section on 'Thyroid adaptation during normal pregnancy'.)
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:
●Thyroid hormone-binding globulin (TBG) excess results in high serum total T4 and total T3 concentrations but not high serum free T4 or free T3 concentrations.
●High serum human chorionic gonadotropin (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.
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
●Overt hyperthyroidism (low TSH, with free T4 and/or T3 levels that exceed trimester-specific normal reference ranges or total T4 and T3 that exceed 1.5 times the nonpregnant range) – Pregnancy complicated by poorly controlled overt hyperthyroidism (most often due to Graves' disease) is associated with increased rates of the following [3-7]:
•Spontaneous abortion
•Premature labor
•Low birth weight
•Stillbirth
•Preeclampsia
•Heart failure
A study of 180 pregnancies complicated by overt hyperthyroidism compared with 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 [8]. 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.
●Subclinical hyperthyroidism (low TSH, with normal free T4 and T3 using trimester-specific normal reference ranges or total T4 and T3 that are less than 1.5 times the nonpregnant range) – In contrast to the findings in women with overt hyperthyroidism, in one report of 433 women with subclinical hyperthyroidism, there was no evidence of adverse pregnancy outcomes [9]. In another report, women with subclinical hyperthyroidism during weeks 4 to 8 of pregnancy had a lower incidence of spontaneous abortion (1.7 versus 7.2 percent in the control group, odds ratio [OR] 0.21, 95% CI 0.05-0.84) and a higher risk of preeclampsia (OR 5.14, 95% CI 1.26-18.1) [10].
●Free T4 in the upper-normal quintile – A normal free T4 in the upper quintile with a normal TSH has been associated with lower birth weight [11,12] and maternal hypertension [13], but not adverse pregnancy outcomes [12].
Laboratory findings — Because of the changes in thyroid physiology during normal pregnancy, thyroid function tests may be difficult to interpret. 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 [14,15].
Transient subclinical hyperthyroidism (subnormal TSH with serum total or free T4 and T3 concentrations in the normal range for pregnancy) in the first trimester of pregnancy is considered a normal physiologic finding. True subclinical hyperthyroidism may occur, but it is not typically associated with adverse outcomes during pregnancy [9] and does not require therapy. (See "Hyperthyroidism during pregnancy: Treatment".)
During normal pregnancy, thyroid function tests should be interpreted using population based, trimester-specific TSH and T4 reference ranges for pregnant women [15]. In several population studies, the lower limit of the reference range for TSH in healthy pregnant women during the first trimester ranged from 0.03 to 0.1 mU/L [16-20]. 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 [16,19]. Total T4 and T3 levels during pregnancy are 1.5-fold higher than in nonpregnant women due to thyroid hormone-binding globulin (TBG) excess. Reference ranges for free T4 are assay method specific, and trimester-specific reference ranges should be provided with the assay kits. (See "Overview of thyroid disease and pregnancy", section on 'Trimester-specific reference ranges'.)
DIAGNOSIS — The diagnosis of true hyperthyroidism during pregnancy may be difficult because of the changes in thyroid function that occur during normal pregnancy.
The diagnosis of hyperthyroidism during pregnancy is based upon clinical manifestations and thyroid function tests. 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 or total T4 (or free T4 index) should be obtained. If the free or total T4 is in the normal range for pregnancy, a total T3 should also be measured.
The diagnosis of overt hyperthyroidism during pregnancy should be based primarily upon a suppressed (<0.1 mU/L) or undetectable (<0.01 mU/L) serum TSH value and a free T4 and/or free T3 (or total T4 and/or total T3) measurement that exceeds the normal range for pregnancy. (See 'Laboratory findings' above.)
ESTABLISHING THE CAUSE — Once the diagnosis of hyperthyroidism is established, the cause of hyperthyroidism should be determined (algorithm 1). Although hyperthyroidism from any cause can complicate pregnancy, Graves' disease (occurring in 0.1 to 1 percent of all pregnancies) and human chorionic gonadotropin (hCG)-mediated hyperthyroidism due to gestational transient thyrotoxicosis (1 to 3 percent of pregnancies) are the most common causes of hyperthyroidism [21]. Other causes of hyperthyroidism (including silent or subacute thyroiditis, toxic adenoma, toxic multinodular goiter, and factitious thyrotoxicosis) are less common during pregnancy. (See "Disorders that cause hyperthyroidism".)
Our approach — The primary objective is to differentiate Graves' disease from hCG-mediated hyperthyroidism. The two disorders typically can be distinguished based upon clinical findings and laboratory tests. In centers where expertise is available, ultrasound with measurement of thyroidal blood flow can aid in the diagnosis of Graves' disease (algorithm 1).
●Clinical findings – 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 (TRAb) concentrations or, rarely, mediated by a change in the activity of TRAbs from stimulatory to blocking [22,23]. 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.)
●Laboratory evaluation – In situations where the clinical diagnosis is uncertain, TRAbs, using either a third-generation thyrotropin-binding inhibitory immunoglobulin (TBII) assay or thyrotropin-stimulating immunoglobulin (TSI) assay, should be measured. TRAbs are positive in 96 to 97 percent of patients with Graves' disease, and therefore, the presence of TRAbs confirms the diagnosis of Graves' disease [15,24].
●Imaging – 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) [25]. However, its utility in diagnosing hCG-mediated hyperthyroidism is unknown. Thyroid radionuclide imaging is typically performed in nonpregnant patients to distinguish Graves' disease from thyroiditis. However, radionuclide imaging is contraindicated in pregnant women.
Graves' disease — Graves' disease is a syndrome that may consist of hyperthyroidism, goiter, thyroid eye disease (orbitopathy), and occasionally a dermopathy referred to as pretibial or localized myxedema. Hyperthyroidism is the most common feature of Graves' disease, affecting nearly all patients, and is caused by TRAbs 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 thyroid eye disease 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 'Autoantibodies to the TSH receptor' and "Pathogenesis of Graves' disease", section on 'The thyroid gland in Graves' disease'.)
The importance of measuring maternal serum TRAbs for prediction of fetal and neonatal Graves' disease is reviewed separately. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Fetal or neonatal hyperthyroidism' and "Evaluation and management of neonatal Graves disease", section on 'Prenatal testing'.)
hCG-mediated hyperthyroidism — Hyperthyroidism mediated by the effects of hCG include gestational transient thyrotoxicosis (GTT), hyperemesis gravidarum, and trophoblastic hyperthyroidism. Only the last (trophoblastic hyperthyroidism) requires treatment of the hyperthyroidism. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Indications for treatment'.)
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 and pregnancy", section on 'hCG and thyroid function'.)
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 [26]. This phenomenon is called 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 and 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 [27]; in addition, their hCG has more thyroid-stimulating activity [28-30]. 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) [27,29]. 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 may not be 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 [27]. 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 "Nausea and vomiting of pregnancy: Clinical findings and evaluation" and "Nausea and vomiting of pregnancy: Treatment and outcome".)
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 [31]. (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 United Kingdom treated for gestational trophoblastic disease between 2005 and 2010, biochemical hyperthyroidism was present in 7 percent and clinical hyperthyroidism in only 2 percent [32]. The difference in prevalence is likely related to earlier diagnosis of trophoblastic disease due to ultrasonography and monitoring of serum beta-hCG. (See "Hydatidiform mole: Epidemiology, clinical features, 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 for treatment'.)
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 [33,34].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism" and "Society guideline links: Thyroid disease and pregnancy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (The Basics)" and "Patient education: Hyperthyroidism (overactive thyroid) and pregnancy (The Basics)")
●Beyond the Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (Beyond the Basics)" and "Patient education: Antithyroid drugs (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●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 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".)
●Diagnosis – 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 thyroid-stimulating hormone (TSH) value and elevated thyroid hormone levels (serum free thyroxine [T4] and/or free triiodothyronine [T3] or total T4 and/or total T3) that exceed the normal range for pregnancy. (See 'Diagnosis' above.)
●Establishing the cause – Once the diagnosis of hyperthyroidism is established, the cause of hyperthyroidism should be determined (algorithm 1). Although hyperthyroidism from any cause can complicate pregnancy, Graves' (occurring in 0.1 to 1 percent of all pregnancies) and human chorionic gonadotropin (hCG)-mediated hyperthyroidism (1 to 3 percent of pregnancies) are the most common causes of hyperthyroidism. (See 'Our approach' above.)
Graves' disease and hCG-mediated hyperthyroidism typically can be distinguished based upon clinical findings and laboratory tests. hCG-mediated hyperthyroidism may occur transiently in the first half of gestation and is typically less severe than Graves' disease. Graves' disease usually becomes less severe during the later stages of pregnancy due to a reduction in TSH receptor antibody (TRAb) concentrations.
In situations where the clinical diagnosis is uncertain, we measure TSH receptor antibodies (TRAbs), using a third-generation thyrotropin-binding inhibitory immunoglobulin (TBII) assay or a thyrotropin-stimulating immunoglobulin (TSI) assay. TRAbs are positive in 95 percent of patients with Graves' disease, and therefore, the presence of TRAbs confirms the diagnosis of Graves' disease. If antibodies are negative, thyroid ultrasound with Doppler flow may be useful to distinguish Graves' disease (high blood flow) from painless or postpartum thyroiditis (low blood flow).
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