Fig. 14.1
Thyrotropin-releasing hormone (TRH); thyroid-stimulating hormone (TSH); tetraiodothyronine (T4); triiodothyronine (T3)
Conditions that increase T3 and T4 production result in hyperthyroidism and those that decrease production result in hypothyroidism. Iodine is an essential element of thyroid hormone (i.e., tetraiodothyronine and triiodothyronine), and consumption of food or supplements rich in iodine content is critical for thyroid hormone production. Deficiency of iodine can result in hypothyroidism and goiter formation (i.e., enlargement of the thyroid gland). In general, primary disorders originate within the thyroid gland, and secondary disorders have an alternate source of pathology, such as the hypothalamus or pituitary gland. Disorders of function (i.e., hypothyroidism or hyperthyroidism) can result in overt or subclinical disease. Abnormal laboratory findings with minimal/no symptoms characterize subclinical disease. Growth of the thyroid gland can be diffuse or nodular (i.e., solitary or multinodular) in nature. Although nodules can be malignant, the majority of thyroid nodules are benign. Differentiated thyroid cancers (i.e., papillary and follicular thyroid cancers) are slow-growing tumors of the follicular epithelium with excellent prognosis. Other cancers of the thyroid include medullary and anaplastic.
Epidemiology
Women can present with a preexisting thyroid condition or develop a new thyroid problem during pregnancy and the postpartum period. An estimated 1–3 % of pregnancies experience gestational hyperthyroidism, 0.1–1 % are complicated by Graves’ disease (i.e., autoimmune hyperthyroidism), and another 4.1 % develop postpartum thyroiditis (PPT) [1–3]. The incidence of overt (OH) and subclinical hypothyroid (SCH) in women of childbearing age is 0.3–0.5 % and 2–2.5 %, respectively [4]. These rates are anticipated to be higher with iodine deficiency. In iodine-sufficient regions, autoimmune hypothyroidism is the leading etiology with 50 % of women with SCH and 80 % of women with OH presenting with detectable antibodies [4]. Although the prevalence of thyroid nodules in pregnancy can range between 3 and 21 % with mild to moderate iodine deficiency, thyroid cancer is relatively uncommon in pregnancy [5]. An estimated 14.4 thyroid cancers per 100,000 pregnancies are reported in the literature with papillary thyroid cancer being the most common type [6].
Normal Physiologic Changes
Fetal thyroid develops by 12 weeks of gestation and is fully functional by 18 weeks. The fetus is dependent on maternal thyroid hormone until 18 weeks and maternal iodine throughout pregnancy. In addition, thyroid physiology in pregnancy changes as a result of maternal factors. As estrogen levels rise in pregnancy, the liver production of thyroid-binding globulin (TBG) increases and the clearance of TBG is reduced. TBG binds thyroid hormone in the circulation and reduces the availability of free or bioavailable thyroid hormone. Further reductions in free thyroid hormone levels are precipitated by placental deiodinase, an enzyme that metabolizes maternal thyroid hormone. As a result, the production of T4 and T3 needs to increase by as much as 50 % during pregnancy [7]. The higher demand for thyroid hormone not only increases iodine requirements in pregnancy but also increases the size of the thyroid gland by as much as 10–20 % [7]. Increased renal clearance and fetal thyroid hormone production also contribute to higher iodine requirements in pregnancy.
B-human chorionic gonadotropins (B-hCG) can weakly bind TSH receptor and stimulate T4 and T3 production. B-hCG levels increase during the first trimester of pregnancy, peak by 8–12 weeks, and then decline. B-hCG stimulates the thyroid to produce thyroid hormone and subsequently lowers TSH levels during the first trimester of pregnancy. As a consequence of the above factors, thyroid function tests can be altered in pregnancy, and trimester-specific normal ranges for TSH and FT4 should be established by each laboratory. If it is not available, utilization of TSH reference range (refer to Table 14.1) and measurement of FT4 by equilibrium dialysis or liquid chromatography/tandem mass spectrometry should be considered. Typically, total T4 and T3 levels are elevated in pregnancy due to elevated TBG, but free levels (i.e., FT4) are within the normal range.
Trimester | TSH (mIU/L) |
|---|---|
First | 0.1–2.5 |
Second | 0.2–3.0 |
Third | 0.3–3.0 |
Hyperthyroidism
Effect of Pregnancy on Hyperthyroidism
Gestational hyperthyroidism is the most common cause of thyrotoxicosis in pregnancy. It typically presents in the first trimester with the rise in human chorionic gonadotropin (hCG) and resolves by the second trimester. Approximately 10–20 % of normal women have suppressed TSH in the first trimester [9]. In conditions associated with exaggerated B-hCG production (i.e., molar pregnancy, hyperemesis gravidarum, multiple pregnancies), thyrotoxicosis (i.e., excess T3 and T4 levels) can ensue. Approximately 50 % of women with hyperemesis will have elevated FT4 and suppressed TSH [9].
Additionally, thyroid autoantibody titers can increase during the first trimester of pregnancy and postpartum period. Often antibody titers resolve by the second and third trimester. Under these circumstances, autoimmune-mediated disorders like Graves’ disease and PPT can manifest themselves according to the underlying autoantibody status. If thyrotoxicosis is not adequately treated, stress events like labor, infection, and trauma can precipitate a thyroid crisis called thyroid storm. Thyroid storm is an endocrine emergency presenting with mental status changes, hyperthermia, and cardiometabolic decompensation. Mortality rates as high as 50 % are noted in nonpregnant patients.
Effect of Hyperthyroidism on Pregnancy
Uncontrolled overt hyperthyroidism (e.g., Graves’ disease) can result in adverse pregnancy outcomes including low birth weight, prematurity, spontaneous abortion, preeclampsia, placental abruption, maternal congestive heart failure, pregnancy-induced hypertension, and thyroid storm. Subclinical hyperthyroidism (i.e., low TSH and normal FT4) has not been shown to cause adverse pregnancy outcomes. T4 can cross the placenta and cause fetal tachycardia, heart failure, and growth retardation. Treatment of thyrotoxicosis with antithyroid drugs needs close monitoring. Since these drugs can cross the placenta, fetal hypothyroidism and goiter formation are a potential complication.
Fetal thyroid is also affected by maternal T4 and thyroid autoantibodies. Excess T4 can interfere with the development of fetal hypothalamic-pituitary-thyroid axis and cause central congenital hypothyroidism in the infant. Patients with a history of Grave’s disease (even after treatment with thyroidectomy or radioiodine ablation) can continue to produce thyroid autoantibodies. TSH receptor antibodies (TRAbs) can cross the placenta and precipitate fetal Graves’ disease, which can manifest as fetal tachycardia, goiter, heart failure, hydrops, accelerated bone maturation, and growth retardation.
Diagnosis
Symptoms
Symptoms of hyperthyroidism include anxiety, heat intolerance, palpitations, hand tremors, and weight loss or failure of appropriate weight gain during pregnancy (refer to Table 14.2). Diffuse (e.g., Graves’ disease) or nodular goiter (e.g., toxic nodule or toxic multinodular goiter) can be palpated on exam. Graves’ disease can manifest unique clinical findings including ophthalmopathy (i.e., gritty feeling in eyes, diplopia, exophthalmos (proptosis), periorbital edema, limited eye movement), infiltrative dermopathy (i.e., orange peel-textured papules, pretibial nonpitting edema), and thyroid acropathy (i.e., clubbing, periosteal new bone formation in metacarpal bones). It is often associated with other autoimmune conditions such as vitiligo, alopecia, celiac disease, and pernicious anemia.
Table 14.2
Clinical features of hyperthyroid
General | Weight loss or failure of adequate weight gain despite increased appetite, rapid or pressured speech |
Eye | Stare, lid lag |
Neck | Diffuse or nodular goiter |
Cardiovascular | Palpitations, systolic hypertension, atrial fibrillation, heart failure, cardiomyopathy |
Respiratory | Shortness of breath, dyspnea on exertion, tracheal obstruction from large goiter |
GI | Hyperdefecation, malabsorption, dysphagia due to goiter, abnormal liver function tests |
Renal | Urinary frequency |
GU | Menstrual disorders, infertility, gynecomastia, erectile dysfunction |
Endocrine | Heat intolerance, glucose intolerance |
Skin | Increased perspiration, edema, skin moist and warm, thinning of hair, loosening of nails from nail bed (Plummer’s nails) |
Musculoskeletal | Proximal muscle weakness, myopathy, osteoporosis, hypercalcemia |
Neuro | Tremor, hyperreflexia |
Hematologic | Anemia |
Psych | Anxiety, emotional liability, psychosis, agitation, depression, insomnia |
Gestational hyperthyroidism is typically asymptomatic. It can be associated with hyperemesis gravidarum and present with severe nausea and vomiting symptoms that can result in a weight loss of more than 5 %, ketonuria, and dehydration. Hydatidiform moles and choriocarcinomas arise from trophoblastic epithelium of the placenta. Patients present with an enlarged uterus, vaginal bleeding, pelvic pain, and hyperthyroidism. Symptoms specific for thyroid conditions that can present in pregnancy are highlighted in Table 14.3.
Table 14.3
Differential diagnosis for thyrotoxicosis
Differential diagnosis | Predisposition to a particular trimester | History and exam | TSH | T3 and T4 | Ultrasound | Other studies | Treatment in pregnancy |
|---|---|---|---|---|---|---|---|
hCG-mediated hyperthyroidism (i.e., gestational hyperthyroidism, hyperemesis gravidarum, trophoblastic disease) | Gestational hyperthyroidism presents in first trimester and resolves by second trimester | Nausea, vomiting, weight loss, dehydration, ketonuria with hyperemesis gravidarum; trophoblastic disease can present with enlarged uterus, vaginal bleeding, and pelvic pain | Low | Normal or high | Evaluate for trophoblastic disease (i.e., molar pregnancy and choriocarcinoma) | Exaggerated hCG levels | IV fluids in severe cases as well as antiemetics; surgical excision recommended for trophoblastic disease |
Graves’ disease | Activates in first trimester and postpartum period. Typically improves in second and third trimester | Ophthalmopathy, infiltrative dermopathy, thyroid acropathy, features of other autoimmune conditions | Low | Normal or high | Diffuse goiter | TRAb positive; fetal ultrasound if high TRAb titers (>3× normal) | ATDs; thyroidectomy if intolerant to ATDs |
Thyroiditis (i.e., postpartum, lymphocytic, subacute thyroiditis) | Up to 12 months postpartum | Painless thyroid exam with postpartum thyroiditis (pain with subacute thyroiditis) | Low | Normal or high | – | – | Self-limiting |
Multinodular goiter | – | Nodular goiter on exam | Low | Normal or high | Multiple nodules | – | ATDs; thyroidectomy if intolerant to ATDs |
Solitary nodule | – | Single nodule on exam | Low | Normal or high | Single nodule | – | ATDs; thyroidectomy if intolerant to ATDs |
Struma ovarii (i.e., ovarian tumor with thyroid tissue) | – | Abdominal mass, pelvic pain, ascites | Low | Normal or high | Ovarian teratoma | – | ATDs followed by surgical removal of ovarian tumor |
Exogenous intake of T3 or T4 | – | Access to thyroid hormone or diet medications | Low | Normal or high | – | Thyroglobulin suppressed | Stop exogenous intake |
Pituitary tumor | – | Headache, visual field defect, signs and symptoms of other pituitary hormone defects | Normal or high | High | – | MRI of pituitary | ATDs; surgical excision in high-risk patients (i.e., vision loss) |
Differential Diagnosis
A range of medical conditions associated with thyrotoxicosis can manifest in pregnancy. Although hCG-mediated hyperthyroidism (i.e., gestational hyperthyroidism, hyperemesis gravidarum, and trophoblastic disease), autoimmune Graves’ disease, and postpartum thyroiditis are associated with pregnancy, other etiologies should also be considered (refer to Table 14.3).
Thyroiditis is an inflammatory process that results in the release of stored thyroid hormone and thyrotoxicosis initially (refer to Table 14.2). This results in the suppression of TSH and endogenous thyroid hormone production, which can manifest as hypothyroidism after a few weeks to months (refer to Table 14.4). Eventually, the thyroid restarts thyroid hormone production and euthyroid status is established. This self-limiting condition can last 6–12 months. Other conditions in the differential diagnosis include TSH-secreting pituitary tumor, ovarian teratoma with thyroid tissue (i.e., struma ovarii), exogenous intake of thyroid hormone, toxic nodule, and toxic multinodular goiter.
Table 14.4
Clinical features of hypothyroidism
General | Fatigue, weakness, weight gain, slow speech |
HEET | Hoarseness, decreased hearing, enlarged tongue, periorbital edema, loss of lateral eyebrow |
Neck | Diffuse or nodular goiter |
Cardiovascular | Bradycardia, diastolic hypertension, pericardial effusion |
Respiratory | Shortness of breath, dyspnea on exertion, heart failure, pleural effusion, tracheal obstruction from large goiter, sleep apnea |
GI | Constipation, decreased taste, dysphagia due to goiter, abnormal liver function tests, ascites |
Renal | Decreased GFR |
GU
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