Are you sure the pregnant or postpartum woman has thyrotoxicosis?

Symptoms

Graves’ disease is the most common cause of autoimmune hyperthyroidism in pregnancy. It may be diagnosed for the first time during pregnancy, but more frequently, affected women present with symptoms antedating pregnancy. Symptoms may include nervousness, heat intolerance, weight loss, palpitations, anxiety, insomnia, proximal muscle weakness, shortness of breath on exercise, irritability, frequent bowel movements, and excessive sweating.

However, not all of these are present in a given patient, and sometimes they are not recognized by the patient and only detected by a careful medical history. In addition, prior to pregnancy, irregular menstrual periods are not uncommon and fertility may be impaired. The severity of the symptoms depends on the duration of the disease, and they do not always correlate with the degree of hyperthyroxinemia.

Signs

The physical examination is of utmost importance in differentiating Graves’ hyperthyroidism from other non-autoimmune etiologies. Signs of Graves’ hyperthyroidism include: presence of diffuse goiter (non-tender, slightly irregular and firmer to palpation), a bruit that can be felt or heard, warm and moist skin, tremor of the outstretched fingers, persistent tachycardia (>90 beats/minute), various degrees of ophthalmopathy, proximal muscle weakness, localized pretibial myxedema (rarely), and other signs of autoimmunity, such as presence of vitiligo and premature graying of the scalp hair. The absence of goiter and eye findings indicates the need to search for other causes for hyperthyroidism.

Key laboratory findings

An elevation of serum free thyroxine (FT4) or free T4 index (FT4I) and a suppressed serum thyroid stimulating hormone (TSH) confirm the diagnosis of thyrotoxicosis. A positive serum thyroid peroxidase (TPO) antibody titer is present in the majority of patients, and a positive serum thyroid binding inhibiting immunoglobulin (TBII) or thyroid stimulating immunoglobulin (TSI) test is present in almost every pregnant woman with Graves’ disease.

What else could the patient have?

When hyperthyroidism is diagnosed in the first trimester of pregnancy, gestational hyperthyroidism (GH) or gestational thyrotoxicosis (GT), also known as “non-immune transient hyperthyroidism of pregnancy”, needs to be considered, since it is the most common cause of hyperthyroidism in the first trimester. The differential diagnosis between GT and Graves’ hyperthyroidism could be challenging for the physician, but a careful medical history and physical examination will be able to confirm the diagnosis in the majority of cases.

The causes of GT include hyperemesis gravidarum, multiple gestation pregnancies, and trophoblastic disease. In vitro fertilization may suggest the presence of multiple pregnancies and can be confirmed by abdominal ultrasound. Hyperemesis gravidarum is defined as persistent nausea and vomiting in the first trimester, 5% weight loss compared to the pre-pregnancy level, and presence of ketonuria (in the absence or other conditions, including acute pancreatitis and acute gallbladder disease). A significant percentage of women with hyperemesis gravidarum have laboratory evidence of hyperthyroidism; as such, the syndrome has been called “transient hyperthyroidism of hyperemesis gravidarum” (THHG).

Severe vomiting has being occasionally described as an initial manifestation of Graves’ hyperthyroidism. In contrast, the vast majority of women with GT give no history of hyperthyroid symptoms before conception, and frequently, there is a history of hyperemesis in previous pregnancies. In most women with GH, hyperthyroid symptoms are mild and include palpitations, tremor of the fingers, heat intolerance, and muscle weakness as the more frequent complaints. Serum FT4 or FT4I levels normalize to pregnancy levels with resolution of vomiting by 12-18 weeks gestation, although the serum TSH may remain suppressed for several weeks.

A patient in remission from Graves’ hyperthyroidism may present in early pregnancy with hyperemesis gravidarum. The differential diagnosis between relapse of hyperthyroidism (not unusual in women in remission from Graves’ hyperthyroidism) and isolated HG is difficult, and there are not any conclusive laboratory tests to separate both entities. A thyroid ultrasound by an experienced operator may show increased vascularity in Graves’ hyperthyroidism. Persistently abnormal thyroid function tests beyond the first trimester of pregnancy favors the diagnosis of Graves’ hyperthyroidism, as do the presence of elevated serum TSI or TBII titers.

Other unusual etiologies include an autonomous hyperfunctioning thyroid nodule diagnosed in the presence of a palpable dominant thyroid nodule and negative laboratory tests of autoimmunity, and subacute thyroiditis (silent or painless), a rare cause of hyperthyroidism in pregnancy.

Key laboratory and imaging tests

During pregnancy, the range of normal serum TSH levels is dependent on gestational age. In the first trimester of pregnancy, because of the thyroid stimulating effect of human chorionic gonadotropic (hCG), serum TSH levels may be as low as 0.01 uIU/L with the upper limit at 2.5 uIU/L. In the second and third trimesters, the upper TSH reference limit is 3.0 uIU/L. Therefore, crucial to the diagnosis of hyperthyroidism during pregnancy is an elevated serum free T4 or free T4 index levels, in addition to a suppressed serum TSH concentration, values more abnormal than normal pregnancy.

Other tests that may prove helpful diagnostically

Once the diagnosis of thyrotoxicosis is confirmed, a positive TPO antibody titer is diagnostic of autoimmune disease and a serum TSI or TBII is consistent with Graves’ hyperthyroidism. Determination of serum total T3 (TT3) is indicated only in the rare patient with a T3-producing autonomous functioning thyroid nodule, in which case, serum FT4 levels may be normal in the presence of a suppressed serum TSH and negative antibodies.

Management and treatment of the disease

Transient Hyperthyroidism of Hyperemesis Gravidarum (THHG)

This is a self-limited condition and although it requires multiple visits to the emergency room and sometimes hospitalizations, it resolves spontaneously by 13-18 weeks gestation. No anti-thyroidal drugs are indicated. THHG is managed by the obstetrical team with IV fluids and control of vomiting; occasionally, parenteral therapy may be required. Serum FT4 or FT4I levels normalize with resolution of the vomiting. However, serum TSH may remain suppressed for a few more weeks. Obstetrical outcomes are not affected in the vast majority of patients.

Graves’ hyperthyroidism during pregnancy

Anti-thyroidal drug therapy is required in the vast majority of patients for the treatment of thyrotoxicosis during pregnancy. Important issues that must be considered in its use include:

Choice of anti-thyroidal drug therapy: Both propylthiouracil and methimazole are equally effective in controlling hyperthyroidism. Both drugs, however, are associated with complications. Propylthiouracil is implicated in the development of liver toxicity and potential liver failure. Methimazole, when used in the first trimester of pregnancy and usually with only high doses may induce a specific embryopathy. In view of the above, it is recommended to avoid methimazole use during the first 13 weeks of gestation. Propylthiouracil is used instead, and the woman is switched to methimazole therapy after the first trimester for the rest of pregnancy. In those patients already on methimazole therapy and planning a pregnancy, propylthiouracil should be started before conception or as soon as the diagnosis of pregnancy is made. One caveat is the potential risk of allergic reactions to two, rather than one, antithyroid drug.
Anti-thyroidal drug dosage: The initial dose of propylthiouracil or methimazole is guided by the severity of hyperthyroid symptoms. An initial dose of 150-450 mg daily of propylthiouracil in three divided doses or 5-20 mg of methimazole, given as a single daily dose, is usually recommended. Both propylthiouracil and methimazole cross the placenta and in inappropriate doses may result in fetal hypothyroidism.
Thyroid function tests should be performed every 2-4 weeks or as clinically indicated. The target is to keep maternal serum FT4 or FT4I level in the upper limit of or slightly higher than the non-pregnant reference range. There is a progressive decrease in anti-thyroidal drug therapy requirements with the progression of pregnancy due to immunological changes (mainly a decrease in TSI titers). It is estimated that in the 20-30% of patients (those with short duration of hyperthyroidism, small goiter, low TSI or TBII titers, and those remaining euthyroid when maintained with very small doses of anti-thyroidal drug therapy), methimazole may be discontinued after 28-34 weeks gestation without a high chance of recurrence during the remaining of the pregnancy.
Interpretation of serum thyroid stimulating antibodies: Level of thyroid stimulating antibodies may be assessed by direct bioassay (TSI) or more commonly, by a radioreceptor assay, thyroid binding inhibitor immunoglobulin (TBII). This IgG immunoglobulin crosses the placenta, and in high titers, may stimulate fetal the TSH receptor to induce fetal hyperthyroidism. By 24-28 weeks gestation, a TBII value of >50% or a TSI value of >500%, is predictive of fetal hyperthyroidism. Conversely, lower values negatively predict fetal or neonatal hyperthyroidism. It is estimated than no more than 5% of Graves’ mothers are at risk.

Fetal hyperthyroidism is a rare disease, but if undiagnosed, may have potential long-lasting complications. Typical clinical findings include persistent fetal tachycardia (>180 beats/minute), intrauterine growth retardation, fetal goiter, and early bone ossification, as detected by fetal ultrasonography. In such cases, the dose of maternal anti-thyroidal drug therapy needs to be increased to control fetal thyroid hyperactivity, and the mother may need levothyroxine therapy to treat the possible occurrence of maternal hypothyroidism.

Transient neonatal hypothyroidism may rarely occur following delivery in women who remained hyperthyroid during pregnancy due to thyroid hormone suppression of fetal and pituitary TSH. Fetuses who are well-controlled are born euthyroid, but develop neonatal hyperthyroidism within 24-36 hours after birth, as the beneficial therapeutic effect of maternal anti-thyroidal drug therapy use lasts only 24-36 hours.

A special consideration is the mother with Graves’ disease who was treated with radioiodine ablation therapy prior to gestation. A minority of these women will have persistently high serum TSI titers, which is associated with the potential risk of fetal hyperthyroidism in a future pregnancy. Therefore, it is crucial that in women following radioiodine ablation and planning a pregnancy, a serum TSI titer should be assessed before 24-26 weeks gestation. If fetal hyperthyroidism is detected, maternal anti-thyroidal drug therapy should be started.

Beta blocking therapy may be indicated to control hyperthyroid symptoms for a short period of time. Propranolol 10-20 mg every 4 to 6 hours is very effective.

Thyroid surgery during pregnancy for Graves’ hyperthyroidism is rarely indicated, unless the mother has an allergy to both anti-thyroidal drugs, she has a large goiter which requires a large dose of the anti-thyroidal drug; or she is non-compliant with taking the anti-thyroidal drug. In the rare case in which surgery is indicated, it should be performed during the second trimester by an experienced surgeon.

Graves’ disease in the postpartum period

Breastfeeding: This is not contraindicated. If the woman still requires anti-thyroidal drug therapy, doses of methimazole (up to 20 mg a day) or PTU (up to 450 mg a day) have been shown to be safe for the infant and do not affect neonatal thyroid function. Some authors recommend checking thyroid function tests in the infant periodically.

Graves’ hyperthyroidism in remission following delivery

Follow-up during the first post-partum year is highly recommended. Graves’ hyperthyroidism may recur in the first three months after delivery or at the end of the first year, each with different clinical implications. Recurrence in the first 3 months post-partum could be due to an episode of postpartum thyroiditis or recurrence of Graves’ hyperthyroidism. The most practical diagnostic tool to differentiate between these is a I-123 thyroid nuclear uptake, which is low in postpartum thyroiditis and elevated in Graves’ recurrence. However, in lactating women, this test is contraindicated.

Determination of serum total T3 and total T4 levels might be of clinical utility; a ratio of T3/T4 over 20 favors the diagnosis of Graves’ hyperthyroidism. A high incidence of recurrence of Graves’ hyperthyroidism at the end of the first postpartum year has been reported, in which usual recommendations for therapy should be followed. Interestingly, it has been shown that there is a high incidence of newly diagnosed Graves’ hyperthyroidism 8-12 months postpartum.

It is strongly recommended that in women with active Graves’ disease during the reproductive years, pregnancy should be avoided until the hyperthyroidism is under control. A plan of therapy during these years needs to be agreed upon between the patient and her physician.

What’s the Evidence?/References

Abalovich, M, Amino, N, Barbour, LA. “Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab. vol. 92. 2007. pp. S1(Recent guidelines by the Endocrine Society.)

Stagnaro-Green, A. “Guidelines of the American thyroid Association for the diagnosis and management of thyroid disease during pregnancy”. Thyroid. vol. 19. 2011. pp. 1081-125. (Recommendations for the diagnosis and management of hyperthyroidism in pregnancy recently published.)

Laurberg, P, Bournaud, C, Karmisholt, J. “Management of Graves’ hyperthyroidism in pregnancy: focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy”. Eur J Endocrinol. vol. 160. 2009. pp. 1(This article discusses potential fetal and neonatal complications of unrecognized elevated maternal TSI titers in pregnant women post-ablation therapy and in those undergoing thyroidectomy for Graves’ during pregnancy.)

Patil-Sisodia, K, Mestman, JH. “Graves’ hyperthyroidism and pregnancy: A clinical update”. Endocr Pract. vol. 16. 2010. pp. 118(Update in the diagnosis of and management of the disease.)

Goodwin, TM, Hershman, JM. “Hyperthyroidism due to inappropriate production of human chorionic gonadotropin”. Clin Obstet Gynecol. vol. 40. 1997. pp. 32(Extensive review of the pathophysiology of gestational thyrotoxicosis and management transient non-immune hyperthyroidism of early pregnancy.)

Goldman, AG, Mestman, JH. Journal of Thyroid Research. 2011. pp. 142413(Discussion of the causes, differential diagnosis, and management of non-autoimmune hyperthyroidism diagnosed in early pregnancy.)

Tagami, T, Hagiwara, H, Kimura, T. “The incidence of gestational hyperthyroidism and postpartum thyroiditis in treated patients with Graves’ disease”. Thyroid. vol. 17. 2007. pp. 767(Discussion of the incidence and differential diagnosis of hyperthyroidism in early pregnancy and in the postpartum period in women with Graves’ hyperthyroidism treated before conception.)

Mortimer, RH, Tyack, SA, Galligan, JP. “Graves’ disease in pregnancy: TSH receptor binding inhibiting immunoglobulins and Maternal and neonatal thyroid function”. Clin Endocrinol (Oxf). vol. 32. 1990. pp. 141(Discussion of neonatal outcomes according to TSI titers and rationale of anti-thyroid drug dosage.)

Luton, D, LeGac, I, Vuillard, E. “Management of Graves’ disease during pregnancy: the key role of fetal thyroid gland monitoring”. J Clin Endocrinol Metab. vol. 90. 2005. pp. 6093(Discussion of the diagnosis and management of the fetus at risk of thyroid dysfunction in maternal Graves’ disease and the role of fetal ultrasonography and TSI titers.)

Bahn, RS, Burch, HS, Cooper, DS. “The role of propylthiouracil in the management of Graves’ disease in adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration”. Thyroid. vol. 19. 2009. pp. 673-4. (Extensive discussion of potential propylthiouracil hepatotoxicity and recommendations for its limited use in pregnancy.)

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