Thyroid Disorders



Thyroid Disorders


Ari J. Wassner

Mandy Brown Belfort





I. THYROID PHYSIOLOGY IN PREGNANCY. Multiple changes occur in maternal thyroid physiology during normal pregnancy.

A. Increased iodine clearance. Starting early in pregnancy, increased renal blood flow and glomerular filtration lead to increased clearance of iodine from maternal plasma. Iodine is also transported across the placenta to enable iodothyronine synthesis by the fetal thyroid gland, which begins after the first trimester. These processes increase the maternal dietary requirement for iodine but have little impact on maternal plasma iodine concentration or on maternal or fetal thyroid function in iodine-sufficient regions such as the United States. In contrast, in regions with insufficient iodine intake, increased iodine clearance and transplacental transfer may lead to decreased thyroxine (T4), increased thyroid-stimulating hormone (TSH), and increased thyroid gland volume in both mother and fetus. To ensure adequate intake, supplementation with 150 µg of iodine per day is recommended for all pregnant and lactating women; of note, many prenatal vitamins lack iodine.

B. Human chorionic gonadotropin (hCG) has weak intrinsic TSH-like activity. The high circulating level of hCG in the first trimester leads to a slight, transient increase in free T4 accompanied by partial suppression of TSH that resolve by approximately the 14th week of gestation.

C. Increased thyroxine-binding globulin (TBG) levels occur early in pregnancy. TBG doubles by midgestation and then plateaus at a high level. This rise in TBG results largely from diminished hepatic clearance of TBG due to increased estrogen-stimulated sialylation of the TBG protein. Estrogen also stimulates TBG synthesis in the liver.


D. Increased total triiodothyronine (T3) and T4 levels occur early in gestation due to rapidly increasing TBG levels (see section I.C). Free T4 levels rise much less than total T4 in early pregnancy (see section I.B), then decline progressively in the second and third trimesters. This physiologic decline is minimal (<10%) in iodine-sufficient regions but may be more pronounced in regions with borderline or deficient iodine intake. Assays that directly measure free T4 may be affected by changes in TBG and should be used to monitor maternal thyroid function only if assay-specific and trimester-specific normal ranges are available; otherwise, an assay of total T4 should be used.

E. TSH levels decline in the first trimester in the setting of elevated levels of hCG (see section I.B) and may transiently fall below the normal range for nonpregnant women in approximately 20% of healthy pregnancies. After the first trimester, TSH levels return to the normal, nonpregnant range.

F. The negative feedback control mechanisms of the hypothalamic-pituitarythyroid (HPT) axis remain intact throughout pregnancy.

G. Placental metabolism and transplacental passage. Iodine and thyrotropinreleasing hormone (TRH) freely cross the placenta. The placenta is also permeable to antithyroid drugs and to TSH receptor-stimulating and -blocking immunoglobulin G (IgG) antibodies, but it is impermeable to TSH. T4 crosses the placenta in limited amounts due to inactivation by the placental enzyme type 3 deiodinase (D3), which converts T4 to inactive reverse T3. T3 is similarly inactivated by placental D3 and has minimal transplacental passage. In the setting of fetal hypothyroxinemia, maternal-fetal transfer of T4 is increased, particularly in the second and third trimesters, which helps protect the developing fetus from the effects of fetal hypothyroidism.

II. MATERNAL HYPERTHYROIDISM. Hyperthyroidism complicates 0.1% to 1% of pregnancies.

A. Graves’ disease accounts for ≥85% of clinical hyperthyroidism in pregnancy. Hyperemesis gravidarum is associated with transient subclinical or mild hyperthyroidism that may be due to the TSH-like effects of hCG and typically resolves without treatment.

B. Signs and symptoms of hyperthyroidism may include tachycardia, palpitations, increased appetite, tremor, anxiety, and fatigue. The presence of goiter, ophthalmopathy, or myxedema suggests Graves’ disease.

C. Poorly controlled maternal hyperthyroidism is associated with serious pregnancy complications including spontaneous abortion, preterm delivery, intrauterine growth restriction, fetal demise, preeclampsia, placental abruption, thyroid storm, and congestive heart failure.

D. Treatment of maternal hyperthyroidism substantially reduces the risk of associated maternal and fetal complications.

1. Antithyroid drugs are indicated for the treatment of moderate-tosevere hyperthyroidism. In the first trimester, propylthiouracil (PTU) rather than methimazole (MMI) is recommended due to possible teratogenic effects of MMI, which has been associated with aplasia cutis
congenita, tracheoesophageal fistula, and choanal atresia. Although PTU has also been associated with congenital malformations such as face/neck cysts and urinary tract abnormalities, these are less common and generally less severe than those caused by MMI, and PTU remains the drug of choice in the first trimester. However, because PTU can cause severe maternal liver dysfunction, in the second trimester, PTU should be switched to MMI. Both MMI and PTU cross the placenta, and the fetus is more sensitive than the mother to the effects of antithyroid drugs, so fetal hypothyroidism and goiter can occur even with doses in the therapeutic range for the mother. Clinicians should use the lowest possible dose and monitor closely, aiming to maintain T4 levels in the high-normal range and TSH levels in the low-normal or suppressed range. Mild hyperthyroidism can be monitored without treatment.

2. β-Adrenergic blocking agents such as propranolol may be useful in controlling hypermetabolic symptoms; however, long-term use should be avoided due to potential neonatal morbidities including hypotension, bradycardia, and impaired response to hypoglycemia.

3. Surgical thyroidectomy may be needed to control hyperthyroidism in women who cannot take antithyroid drugs due to allergy or agranulocytosis or in cases of maternal nonadherence to medical therapy. If thyroidectomy is necessary, it should be performed during the second trimester if possible, rather than in the first or third trimesters when risks to the fetus are higher.

4. Iodine given at a pharmacologic dose is generally contraindicated because prolonged administration can cause fetal hypothyroidism and goiter. However, a short course of iodine in preparation for thyroidectomy appears to be safe, and clinicians may also use iodine in selected cases in which antithyroid drugs cannot be used. Radioactive iodine (RAI) is contraindicated during pregnancy.

E. Fetal and neonatal hyperthyroidism occurs in approximately 1% to 2% of infants born to mothers with Graves’ disease. In these cases, hyperthyroidism results from transplacental passage of TSH receptor-stimulating antibodies. High levels of these antibodies in maternal serum during the third trimester are predictive of fetal and neonatal hyperthyroidism, as is a maternal history of having a prior child with the condition. All pregnant women with Graves’ disease should be monitored for fetal hyperthyroidism through serial measurement of fetal heart rate as well as prenatal ultrasound to assess for fetal goiter and to monitor fetal growth. Fetal hyperthyroidism can be treated by administration of antithyroid drugs to the mother, but excessive treatment can suppress the fetal thyroid gland and cause hypothyroidism.

F. Fetal and neonatal hypothyroidism in maternal Graves’ disease. Fetal exposure to MMI or PTU can cause transient hypothyroidism that resolves rapidly and usually does not require treatment (see section VI.A.2.a). In mothers with a history of Graves’ disease, transplacental passage of TSH receptor-blocking antibodies may cause fetal hypothyroidism (see section VI.A.2.e). A rare neonatal outcome of maternal Graves’ disease is transient central hypothyroidism, which may be due to pituitary suppression from prolonged intrauterine hyperthyroidism.


G. Infants of mothers with Graves’ disease can present with thyrotoxicosis or hypothyroidism in the newborn period and require close monitoring after birth (see section VII).

III. MATERNAL HYPOTHYROIDISM. Maternal hypothyroidism in pregnancy can be overt (0.3% to 0.5% of pregnancies) or subclinical (2% to 2.5% of pregnancies).

A. The most common cause of maternal hypothyroidism in iodine-sufficient regions is chronic autoimmune thyroiditis. Other causes include previous treatment of Graves’ disease or thyroid cancer with surgical thyroidectomy or radioiodine ablation, drug- or radiation-induced hypothyroidism, congenital hypothyroidism (CH), and pituitary dysfunction. Chronic autoimmune thyroiditis is more common in patients with type 1 diabetes mellitus. Occasionally, mothers with a prior history of Graves’ disease become hypothyroid due to the development of TSH receptor-blocking antibodies.

B. Signs and symptoms of hypothyroidism in pregnancy include weight gain, cold intolerance, dry skin, weakness, fatigue, and constipation. These may go unnoticed in the setting of pregnancy, particularly if hypothyroidism is mild.

C. Unrecognized or untreated hypothyroidism is associated with spontaneous abortion and maternal complications of pregnancy including anemia, preeclampsia, postpartum hemorrhage, placental abruption, and need for cesarean delivery. Associated adverse fetal and neonatal outcomes include preterm birth, intrauterine growth restriction, congenital anomalies, fetal distress in labor, and fetal and perinatal death. However, these complications are avoided with adequate treatment of hypothyroidism, ideally from early in pregnancy. Affected fetuses may experience neurodevelopmental impairments, particularly if both the fetus and the mother are hypothyroid during gestation (e.g., iodine deficiency, TSH receptor-blocking antibodies).

D. Women with preexisting hypothyroidism who are treated appropriately typically deliver healthy infants. Such patients should increase their usual L-thyroxine dose by 25% to 30% immediately upon missing a menstrual period or obtaining a positive result on a pregnancy test. Thyroid function tests should be measured as soon as pregnancy is confirmed, every 4 weeks during the first half of pregnancy, at least once between 26 and 32 weeks’ gestation, and 4 weeks after any L-thyroxine dose change. The TSH level should be maintained in trimester-specific normal ranges of 0.1 to 2.5 mU/L in the first trimester, 0.2 to 3 mU/L in the second trimester, and 0.3 to 3 mU/L in the third trimester. Achieving this goal often requires an L-thyroxine dose of 20% to 50% higher than in the nonpregnant state.

E. Routine thyroid function testing in pregnancy is currently recommended only for women at high risk for hypothyroidism, including those who are symptomatic; older than 30 years; live in an iodine-deficient area; have a family or personal history of thyroid disease; or have a history of thyroperoxidase (TPO) antibodies, type 1 diabetes, neck irradiation, morbid obesity, infertility, miscarriage, or preterm delivery. Because this strategy detects only two-thirds of women with hypothyroidism, many authors advocate
universal screening in early pregnancy, but this has not been shown to improve outcomes, and this topic remains controversial.

F. TSH receptor-blocking antibodies cross the placenta and may cause fetal and transient neonatal hypothyroidism (see section VI.A.2.e).

IV. FETAL AND NEONATAL GOITER

A. Fetal ultrasound by an experienced ultrasonographer is an excellent tool for intrauterine diagnosis and monitoring of fetal goiter.

B. Maternal Graves’ disease is the most common cause of fetal and neonatal goiter, which results most often from fetal hypothyroidism due to MMI or PTU even when given at relatively low doses. Fetal and neonatal goiter can also result from fetal hyperthyroidism due to TSH receptor-stimulating antibodies. TSH receptor antibodies can be present both in women with active Graves’ disease and in women previously treated for Graves’ disease with surgical thyroidectomy or RAI ablation. Maternal history and serum antibody testing is usually diagnostic. Rarely, cord blood sampling is necessary to determine where fetal goiter is due to MMI- or PTU-induced fetal hypothyroidism or to fetal hyperthyroidism induced by TSH receptorstimulating antibodies. After delivery, neonates exposed in utero to PTU or MMI eliminate the drug rapidly. Thyroid function tests usually normalize by 1 week of age, and treatment is not required.

C. Other causes of fetal and neonatal goiter include fetal disorders of thyroid hormonogenesis (usually inherited), excessive maternal iodine ingestion, and maternal iodine deficiency. All of these conditions are associated with fetal or neonatal hypothyroidism, and goiter resolves after normalization of the serum TSH concentration with L-thyroxine treatment.

D. Fetal goiter due to hypothyroidism is usually treated with maternal L-thyroxine administration. Rarely, treatment with intra-amniotic injections of L-thyroxine is used during the third trimester to reduce the size of a fetal goiter when needed to prevent complications of tracheal/esophageal compression including polyhydramnios, lung hypoplasia, and airway compromise at birth.

V. THYROID PHYSIOLOGY IN THE FETUS AND NEWBORN

A. The fetal HPT axis develops relatively independent of the mother due to the high placental expression of D3, which inactivates most of the T4 and T3 presented from the maternal circulation (see section I.G).

B. Thyroid embryogenesis is complete by 10 to 12 weeks’ gestation by which time the fetal thyroid gland starts to concentrate iodine and synthesize and to secrete T3 and T4. Concentrations of T4 and TBG increase gradually throughout gestation. Circulating T3 levels remains low, although T3 levels in the brain and pituitary are considerably higher due to local expression of type 2 deiodinase (D2), which converts T4 to the active thyroid hormone, T3. In the setting of fetal hypothyroidism, upregulation of D2 activity in the brain maintains the local T3 concentration, allowing normal development to proceed.


C. TSH from the fetal pituitary gland increases beginning in midgestation. The negative feedback mechanism of the HPT axis starts to mature by 26 weeks’ gestation. Circulating levels of TRH are high in the fetus relative to the mother, although the physiologic significance of this is unclear.

D. Exogenous iodine suppresses thyroid hormone synthesis, a property known as the Wolff-Chaikoff effect. However, the ability of the thyroid gland to escape from the suppressive effect of an iodine load does not mature until 36 to 40 weeks’ gestation. Thus, premature infants are more susceptible than term infants to iodine-induced hypothyroidism.

E. Neonatal physiology. Within 30 minutes after delivery, there is a dramatic surge in serum TSH, with peak levels as high as 80 mU/L at 6 hours of life. TSH then declines rapidly over 24 hours, then more slowly over the first week of life. The TSH surge causes marked stimulation of the neonatal thyroid gland, leading to sharp increases in serum T3 and T4 levels, which peak within 24 hours of life and then slowly decline.

F. In the preterm infant, the pattern of postnatal thyroid hormone changes is similar to that seen in the term infant, but the TSH surge is less marked and the resulting T4 and T3 increases are blunted. In very preterm infants (<31 weeks’ gestation), no TSH surge occurs, and circulating T4 may fall rather than rise over the first 7 to 10 days. Thyroid hormone levels in umbilical cord blood are related to gestational age and birth weight (Table 61.1).

VI. CONGENITAL HYPOTHYROIDISM

A. CH is one of the most common preventable causes of intellectual disability. The incidence of CH varies globally. In the United States, the incidence is approximately 1/2,500 and appears to be rising. CH is more common among Hispanic (1/1,600) and Asian Indian (1/1,757) infants but less common among non-Hispanic black infants (1/11,000). The femaleto-male ratio is 2:1. CH is also more common in infants with trisomy 21, congenital heart disease, and other congenital malformations including cleft palate and renal, skeletal, or gastrointestinal anomalies. CH may be permanent or transient. Hypothyroxinemia with delayed TSH rise can be caused by permanent or transient conditions.

1. Causes of permanent CH (see Table 61.2)

a. Thyroid dysgenesis. Abnormal thyroid gland development is the cause of permanent CH in about 70% of cases. Thyroid dysgenesis includes agenesis, hypoplasia, and ectopy (failure to descend normally into the neck). It is almost always sporadic with no increased risk to subsequent siblings. Rarely, thyroid dysgenesis is associated with a mutation in one of the transcription factors necessary for thyroid gland development (PAX8, FOXE1, NKX2.1, NKX2.5). Clinically, infants with thyroid dysgenesis have no goiter, low total and free T4 levels, elevated TSH, and normal TBG. The serum concentration of thyroglobulin (TG) reflects the amount of thyroid tissue present and is low in cases of thyroid agenesis or hypoplasia. Ultrasound confirms the presence or absence of a normally located thyroid gland, whereas scintigraphy with RAI or pertechnetate (99mTc) can locate a normally placed or ectopic gland that is able to concentrate iodine.









Table 61.1. Thyroid Hormone Reference Ranges (M ± SD) for Full-Term and Preterm Neonates























































































































































































Gestational Age (Weeks)


Age


Birth


7 Days


14 Days


28 Days


Total T4 (µg/dL)







23-27


5.4 ± 2.0


4.0 ± 1.8


4.7 ± 2.6


6.1 ± 2.3



28-30


6.3 ± 2.0


6.3 ± 2.1


6.6 ± 2.3


7.5 ± 2.3



31-34


7.6 ± 2.3


9.4 ± 3.4


9.1 ± 3.6


8.9 ± 3.0



≥37


9.2 ± 1.9


12.7 ± 2.9


10.7 ± 1.4


9.7 ± 2.2


Free T4 (ng/dL)







23-27


1.3 ± 0.4


1.5 ± 0.6


1.4 ± 0.5


1.5 ± 0.4



28-30


1.4 ± 0.4


1.8 ± 0.7


1.6 ± 0.4


1.7 ± 0.4



31-34


1.5 ± 0.3


2.1 ± 0.6


2.0 ± 0.4


1.9 ± 0.5



≥37


1.4 ± 0.4


2.7 ± 0.6


2.0 ± 0.3


1.6 ± 0.3


Total T3 (ng/dL)







23-27


19.5 ± 14.9


32.6 ± 20.2


41.0 ± 24.7


63.1 ± 27.3



28-30


28.6 ± 20.8


56.0 ± 24.1


72.3 ± 28.0


87.2 ± 31.2



31-34


35.2 ± 23.4


91.8 ± 35.8


109.4 ± 41.0


119.8 ± 40.1



≥37


59.9 ± 34.5


147.8 ± 50.1


167.3 ± 31.2


175.8 ± 31.9


TSH (mU/L)







23-27


6.8 ± 2.9


3.5 ± 2.6


3.9 ± 2.7


3.8 ± 4.7



28-30


7.0 ± 3.7


3.6 ± 2.5


4.9 ± 11.2


3.6 ± 2.5



31-34


7.9 ± 5.2


3.6 ± 4.8


3.8 ± 9.3


3.5 ± 3.4



≥37


6.7 ± 4.8


2.6 ± 1.8


2.5 ± 2.0


1.8 ± 0.9


TBG (mg/dL)







23-27


0.19 ± 0.06


0.17 ± 0.04


0.19 ± 0.05


0.23 ± 0.06



28-30


0.20 ± 0.05


0.20 ± 0.05


0.21 ± 0.05


0.22 ± 0.06



31-34


0.24 ± 0.08


0.24 ± 0.08


0.23 ± 0.08


0.23 ± 0.08



≥37


0.29 ± 0.06


0.34 ± 0.11


0.28 ± 0.04


0.27 ± 0.07


TSH, thyroid-stimulating hormone; TBG, thyroxine-binding globulin.


Source: Adapted from Williams FL, Simpson J, Delahunty C, et al. Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. J Clin Endocrinol Metab 2004;89(11):5314-5320.

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Oct 27, 2018 | Posted by in PEDIATRICS | Comments Off on Thyroid Disorders
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