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Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.
CLINICAL RECOGNITION
Hyperthyroidism occurs in approximately 0.2-1.0% of all pregnancies. Most cases are due to Graves’ disease. The clinical recognition of Graves’ disease may prove challenging in pregnancy since the features of normal pregnancy overlap with symptoms of hyperthyroidism. Specific features which may point to Graves’ hyperthyroidism include the presence of a diffuse goiter, ophthalmopathy, or pre-tibial myxedema (Table 1).
Table 1.
Features of Graves’ Disease
| Past history of autoimmune thyroid disease |
| Family history of autoimmune thyroid disease |
| Features of hyperthyroidism such as weight loss and heat intolerance |
| Diffuse goiter |
| Ophthalmopathy |
| Pre-tibial myxedema |
| Proximal myopathy |
| Nail changes: onycholysis |
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
Hyperthyroidism is diagnosed on the basis of elevated trimester specific serum levels of free thyroxine (FT4) or free triiodothyronine (FT3) (or comparable measures of total thyroxine or FTI) and low thyroid stimulating hormone (TSH). In subclinical hyperthyroidism FT4 and FT3 are normal but TSH is low or suppressed to undetectable levels. Treatment is generally not required for subclinical hyperthyroidism in pregnancy. In fact, most instances of a low TSH in early pregnancy are not pathological and are due to TSH suppressive effects of β-human chorionic gonadotrophin (β-HCG). Detection of thyroid stimulating hormone receptor antibodies (TRAbs) in serum is diagnostically helpful in distinguishing Graves’ disease from other pathological and non-pathological causes of a low TSH. Most cases of hyperthyroidism in pregnancy are due to Graves’ disease. Other causes include single or multiple toxic nodules and thyroiditis (Table 2).
Table 2.
Causes of Hyperthyroidism in Pregnancy
| Graves’ disease |
| Gestational thyrotoxicosis |
| Single toxic nodule |
| Toxic multinodular goiter |
| Subacute thyroiditis |
| Silent thyroiditis |
| Thyrotoxicosis factitial |
It is important to distinguish hyperthyroidism in pregnancy from gestational transient thyrotoxicosis (GTT) which occurs as a result of the thyroid stimulatory actions of β–HCG. GTT is more common than Graves’ disease being diagnosed in about 1-3% of all pregnancies. It may be associated with hyperemesis gravidarum, choriocarcinoma, or hydatiform mole and in rare instances may result from functional mutations which increase TSH receptor hypersensitivity to β-HCG. GTT is typically mild in presentation, self-limiting and rarely requires specific treatment with antithyroid medications (Table 3). While GTT may be difficult to distinguish from Graves’ disease, features such as goiter, ophthalmopathy, or pretibial myxedema are suggestive of Graves’ disease.
Table 3.
Clinical Differences Between Graves’ Disease in Pregnancy and Gestational Transient Thyrotoxicosis
| Graves’ Disease | Gestational Thyrotoxicosis |
|---|---|
| Past history of thyroid autoimmunity Family history of thyroid autoimmunity May exhibit overt hyperthyroid features Goiter may be present Ophthalmopathy may be present TRAb positive TPOAb positive | No past history of thyroid autoimmunity No family history of thyroid autoimmunity May present with hyperemesis, dehydration and electrolyte imbalance No goiter No ophthalmopathy TRAb negative TPOAb negative |
Thyroid Stimulating Hormone Receptor Antibodies (TRAbs)
Measurement of TRAbs is useful for monitoring for the risk of fetal and neonatal hyperthyroidism (Table 4). The management of such patients can be considered in three categories.
Table 4.
Measurement of Thyroid Stimulating Hormone Receptor Antibodies (TRAbs)
| Patients with active hyperthyroidism Patients previously treated with radioiodine or surgery Patients with high TRAb levels require serial fetal monitoring with ultrasonography |
PATIENTS IN REMISSION FROM HYPERTHYROIDISM
Patients who have successfully completed treatment for hyperthyroidism who become pregnant while in remission require close monitoring since there is a risk of relapse in pregnancy. Such patients may continue to harbor TRAbs with the risk of transplacental transfer. This risk is lowest for patients who were treated with antithyroid drugs and it is recommended that TRAbs are checked in early pregnancy in patients who were treated with surgery or radioiodine. If TRAbs are positive in early pregnancy, then fetal monitoring is indicated with repeated measurement of TRAbs at 18-22 weeks, and again at 30-34 weeks if TRAbs continue to be positive. TRAb levels >5 IU/L or more than 3 times the upper limit of normal is an indication for close fetal or neonatal monitoring due to the high risk of fetal/neonatal hyperthyroidism from transplacental TRAb transfer.
PATIENTS CURRENTLY UNDERGOING TREATMENT FOR HYPERTHYROIDISM
Women who conceive while on antithyroid treatment should have TRAbs level checked in early pregnancy and again at 18-22 weeks, and at 30-34 weeks if TRAbs continue to be positive. Women of child bearing age with Graves’ disease should be counselled against becoming pregnant until a euthyroid state is achieved.
PATIENTS WHO DEVELOP HYPERTHYROIDISM DURING PREGNANCY
Patients who develop hyperthyroidism for the first-time during pregnancy are at particular risk of adverse fetal and maternal adverse effects and should be controlled promptly and monitored carefully. TRAB levels should also be checked in late pregnancy to assess the risk of neonatal hyperthyroidism.
PATHOPHYSIOLOGY
Uncontrolled hyperthyroidism is associated with adverse feto-maternal effects including pre-eclampsia, maternal congestive cardiac failure, miscarriages, premature birth, still-birth, and low birth weight. Furthermore, neonates of hyperthyroid mothers with Graves’ disease are at risk of developing fetal hyperthyroidism and goiter due to the transplacental transfer of TRAbs. Fetal hypothyroidism may also develop due to transplacental transfer of maternal antithyroid drugs or in rare instances from transplacental transfer of maternal blocking TRAbs.
THERAPY
The natural course of Graves’ disease in pregnancy should be borne in mind during therapy. Due to the immune tolerant state of pregnancy there is a tendency for Graves’ disease to remit towards the latter stages of gestation.
Anti-Thyroid Drugs
Anti-thyroid drugs are the treatment of choice for hyperthyroidism in pregnancy (Table 5). The lowest effective dose should be used. Treatment should be monitored with FT4 and TSH. These should be measured every 2-4 weeks initially and then 4-6 weekly once thyroid hormone levels are stabilized. FT4 levels should be maintained at or just above the upper limit of the trimester specific reference range.
Dose reductions or even cessation of therapy with careful monitoring may be necessary in late pregnancy. The thionamides, propylthiouracil (PTU), methimazole (MMI), and its pro-drug derivative, carbimazole are the antithyroid drugs of choice. Both propylthiouracil and methimazole exhibit similar placental transfer kinetics, have similar effects on fetal and neonatal thyroid function, and are equally safe in lactation. Methimazole has greater efficacy than propylthiouracil and is associated with better compliance since it can be administered once daily whereas propylthiouracil needs to be taken twice or thrice daily. More so a growing number of reports have highlighted the association of propylthiouracil with fatal liver failure. However, methimazole is associated, rarely, with the occurrence of aplasia cutis and methimazole embryopathy in the neonate. Although this risk is slight it is most likely with methimazole administration in early pregnancy during embryogenesis. For the above reasons it is recommended that propylthiouracil is used in the first trimester and that consideration should be given to switching to methimazole in later pregnancy.
Table 5.
Guidelines for Anti-Thyroid Drugs (ATD) in Pregnancy
| PTU is recommended in first trimester Consider switching to MMI from second trimester Use lowest effective dose of ATD Consider reducing dose or stopping ATD in later pregnancy Monitor treatment with FT4 and TSH: Initially 2-4 weekly, later 4-6 weekly. Aim for FT4 at or just above the upper end reference range |
Beta-blocking agents such as propranolol may be used to control severe adrenergic symptoms but should be discontinued once symptoms begin to improve, usually within 2-4 weeks. The combination of thionamides with levothyroxine i.e. block and replace therapy is not recommended in pregnancy as this may lead to fetal hypothyroidism due to disproportionately greater transplacental transfer of antithyroid drugs than levothyroxine. Radioactive iodine is absolutely contraindicated in pregnancy. Adverse effects of radioiodine on fetal thyroid function include fetal hypothyroidism and this is more likely in later pregnancy since the fetal thyroid only starts to actively concentrate iodide from about 12 weeks gestation.
Surgery
Thyroidectomy is an option in patients with significant problems with compliance or severe adverse reactions to antithyroid medications. Surgery is best undertaken in the second trimester of pregnancy.
FOLLOW UP
Newborn
Following delivery, the infant of hyperthyroid mothers should be monitored for thyroid dysfunction. Transient neonatal hyperthyroidism due to transplacental transfer of maternal TRAbs is seen in 1-5% of neonates of mothers with Graves’ disease. The presentation may be more obvious after the first few days of life since TRAbs are cleared from the neonatal circulation at a slower rate than maternal antithyroid drugs.
Mothers
Mothers with a past history of hyperthyroidism require regular thyroid function tests after delivery since Graves’ disease may relapse in the postpartum period. Anti-thyroid drugs are safe in lactation and if indicated should be used at the lowest effective dose, preferably administered after breast feeds in divided doses. Women with risk factors for autoimmune thyroid dysfunction may develop postpartum thyroiditis (PPT). This occurs in 5-9% of pregnancies and is characterized by a transient hyperthyroid phase followed by a hypothyroid phase before return to euthyroidism. The hyperthyroid phase will usually not require treatment but levothyroxine may be given to symptomatic women in the hypothyroid phase. Long term follow-up is necessary due to the risk of permanent hypothyroidism.
GUIDELINES
- Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, Grobman WA.,
- Laurberg P, Lazarus JH, Mandel SJ, Peeters RP, Sullivan S. 2017 Guidelines of the.
- American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar;27(3):315–389. [PubMed: 28056690]
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- Hyperthyroidism in Pregnancy - EndotextHyperthyroidism in Pregnancy - Endotext
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