Congenital Hypothyroidism

Congenital hypothyroidism (CH) is inadequate thyroid hormone production in newborn infants. It can occur because of an anatomic defect in the gland, an inborn error of thyroid metabolism, or iodine deficiency. CH is the most common neonatal endocrine disorder; thyroid dysgenesis is thought to account for approximately 80-95%& of cases.[13] Some infants identified as having primary congenital hypothyroidism may have transient disease and not permanent congenital hypothyroidism.[5] See the image below.

Congenital Hypothyroidism. An infant with cretinism. Note the hypotonic posture, coarse facial features, and umbilical hernia.

The term endemic cretinism is used to describe clusters of infants with goiter and hypothyroidism in a defined geographic area. Such areas were discovered to be low in iodine, and the cause of endemic cretinism was determined to be iodine deficiency. In the 1920s, adequate dietary intake of iodine was found to prevent endemic goiter and cretinism.[14] Endemic goiter and cretinism are still observed in some areas, such as regions of Bangladesh, Chad, China, Indonesia, Nepal, Peru, and Zaire.

The term sporadic cretinism was initially used to describe the random occurrence of cretinism in nonendemic areas. The cause of these abnormalities was identified as nonfunctioning or absent thyroid glands. This led to replacement of the descriptive term sporadic cretinism with the etiologic term congenital hypothyroidism. Treatment with thyroid replacement therapy was found to elicit some improvement in these infants (see the images below), although many remained impaired.

Congenital Hypothyroidism. An infant shown a few months after starting thyroid hormone replacement.

Congenital Hypothyroidism. Infant a few months after starting thyroid hormone replacement.

The morbidity from congenital hypothyroidism can be reduced to a minimum by early diagnosis and treatment.[15] Although initial preliminary studies were performed using thyroid-stimulating hormone (TSH) levels in cord blood,[16, 17] mass screening was made feasible by the development of radioimmunoassay for TSH and thyroxine (T4) from blood spots on filter paper, obtained for neonatal screening tests.[18, 19]

The thyroid gland develops from the buccopharyngeal cavity between 4 and 10 weeks' gestation. The thyroid arises from the fourth branchial pouches and ultimately ends up as a bilobed organ in the neck. Errors in the formation or migration of thyroid tissue can result in thyroid aplasia, dysplasia, or ectopy. By 10-11 weeks' gestation, the fetal thyroid is capable of producing thyroid hormone. By 18-20 weeks' gestation, blood levels of T4 have reached term levels. The fetal pituitary-thyroid axis is believed to function independently of the maternal pituitary-thyroid axis.

The thyroid gland uses tyrosine and iodine to manufacture T4 and triiodothyronine (T3). Iodide is taken into the thyroid follicular cells by an active transport system and then oxidized to iodine by thyroid peroxidase. Organification occurs when iodine is attached to tyrosine molecules attached to thyroglobulin, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). The coupling of two molecules of DIT forms tetraiodothyronine (ie, T4). The coupling of one molecule of MIT and one molecule of DIT forms T3. Thyroglobulin, with T4 and T3 attached, is stored in the follicular lumen. TSH activates the enzymes needed to cleave T4 and T3 from thyroglobulin. In most situations, T4 is the primary hormone produced by and released from the thyroid gland.

Inborn errors of thyroid metabolism can result in congenital hypothyroidism in children with anatomically normal thyroid glands.

T4 is the primary thyronine produced by the thyroid gland. Only 10-40% of circulating T3 is released from the thyroid gland. The remainder is produced by monodeiodination of T4 in peripheral tissues. T3 is the primary mediator of the biologic effects of thyroid hormone and does so by interacting with a specific nuclear receptor. Receptor abnormalities can result in thyroid hormone resistance.

The major carrier proteins for circulating thyroid hormones are thyroid-binding globulin (TBG), thyroid-binding prealbumin (TBPA), and albumin. Unbound, or free, T4 accounts for only about 0.03% of circulating T4 and is the portion that is metabolically active. Infants born with low levels of TBG, as in congenital TBG deficiency, have low total T4 levels but are physiologically normal. Familial congenital TBG deficiency can occur as an X-linked recessive or autosomal recessive condition.

The contributions of maternal thyroid hormone levels to the fetus are thought to be minimal, but maternal thyroid disease can have a substantial influence on fetal and neonatal thyroid function. Immunoglobulin G (IgG) autoantibodies, as observed in autoimmune thyroiditis, can cross the placenta and inhibit thyroid function. Thioamides used to treat maternal hyperthyroidism can also block fetal thyroid hormone synthesis. Most of these effects are transient. Radioactive iodine administered to a pregnant woman can ablate the fetus's thyroid gland permanently.

The importance of thyroid hormone to brain growth and development is demonstrated by comparing treated and untreated children with congenital hypothyroidism. Thyroid hormone is necessary for normal brain growth and myelination and for normal neuronal connections. The most critical period for the effect of thyroid hormone on brain development is the first few months of life.[15]

Endemic cretinism is caused by iodine deficiency and is occasionally exacerbated by naturally occurring goitrogens.[20] Dysgenesis of the thyroid gland, including agenesis (ie, complete absence of thyroid gland) and ectopy (lingual or sublingual thyroid gland), may be a cause.

Inborn errors of thyroid hormone metabolism include dyshormonogenesis. Most cases are familial and inherited as autosomal recessive conditions. These may also include the following:

• Thyroid-stimulating hormone (TSH) unresponsiveness (ie, TSH receptor abnormalities)[21]

• Impaired ability to uptake iodide

• Peroxidase, or organification, defect (ie, inability to convert iodide to iodine)

• Pendred syndrome, a familial organification defect associated with congenital deafness

• Thyroglobulin defect (ie, inability to form or degrade thyroglobulin)

• Deiodinase defect

Thyroid hormone resistance (ie, thyroid hormone receptor abnormalities) may also be a cause.[21]

In maternal autoimmune disease, transplacental passage of antibodies cause transient or permanent hypothyroidism.[2, 22]

Radioactive iodine therapy of pregnant women may cause permanent congenital hypothyroidism. Iodine in contrast agents or skin disinfectants can cause hypothyroidism or hyperthyrotropinemia in premature neonates.[23]

TSH or thyrotropin-releasing hormone (TRH) deficiencies are also noted. Hypothyroidism can also occur in TSH or TRH deficiencies, either as an isolated problem or in conjunction with other pituitary deficiencies (eg, hypopituitarism). If present with these deficiencies, hypothyroidism is usually milder and is not associated with the significant neurologic morbidity observed in primary hypothyroidism.

Although the etiology of congenital hypothyroidism with thyroid gland-in-situ (GIS) is not completely understood, mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) have been identified.[24, 25]

Studies have reported a change in the epidemiology, with a doubling in incidence to around 1 in 1500 live newborns.[13, 26] This is thought to be due in part to an increase in congenital hypothyroidism with thyroid gland-in-situ (GIS).[24] Lower TSH screening cutoffs may also be driving this increase in diagnosis, although altered ethnicities of the screened population, increased multiple and premature births, and iodine status are contributing factors.[27]

Congenital hypothyroidism is more common in infants with birthweights less than 2,000 g or more than 4,500 g.[28, 29]

An increased incidence of congenital hypothyroidism is observed in twins.[30, 28, 31] Twin births are approximately 12 times as likely to have congenital hypothyroidism as singletons.[32] Usually, only one twin is hypothyroid, but a common in-utero exposure can cause hypothyroidism in both.[33]

Most studies of congenital hypothyroidism suggest a female-to-male ratio of a 2:1. Devos et al showed that much of the discrepancy is accounted for by infants with thyroid ectopy.[34]

In central Africa, where iodine deficiency occurs along with excess dietary cyanate from cassava (Manihot esculenta),[35] as many as 10% of newborns may have both low cord blood T4 concentration and TSH concentrations over 100 mU/L.[36]

Some of the highest incidences have been reported from various locations in the Middle East.[37, 38, 39, 40]

Congenital hypothyroidism does not affect the all-cause standardized mortality ratio in treated patients.[41] Profound mental retardation is the most serious effect of untreated congenital hypothyroidism. Severe impairment of linear growth and bone maturation also occurs. Affected infants whose treatment is delayed can have neurologic problems such as spasticity and gait abnormalities, dysarthria or mutism, and autistic behavior.

Early diagnosis and treatment of congenital hypothyroidism prevents severe mental retardation and other neurologic complications.[42] Even with early treatment, some children demonstrate mild delays in areas such as reading comprehension and arithmetic in third grade. Some of these delays improve by sixth grade. Despite treatment, individuals diagnosed by newborn screening as a group do not do as well as their euthyroid peers.[43]

Infants with delayed diagnosis or a longer time to normalize thyroid hormone levels have poorer outcomes. Although continued improvement in IQ has been documented in treated patients through adolescence, some cognitive problems may persist. These may include problems in visuospatial, language, and fine motor function. Defects in memory and attention may also be present.

Early studies of outcome suggested that infants without a distal femoral epiphysis did less well than those with one, although both groups had results in the normal range.[44] The author of this study was later unable to demonstrate an effect of bone age at diagnosis on outcome.[45] Another study was unable to demonstrate any difference in outcome in infants with or without a distal femoral epiphysis.[46]

Parents should be educated regarding their child's disorder, the potential problems associated with no treatment or inadequate treatment, and the benefits of early and appropriate treatment. This should include instructions on the proper administration of the medication and how and when to follow up with the physician. Because learning problems are possible, even with early diagnosis and treatment, parents should be advised when to seek psychomotor and educational evaluations and interventions. Early childhood intervention programs, if available, should be encouraged.

When inborn errors of thyroid hormone production are suspected, genetic counseling should be provided.

Infants with congenital hypothyroidism are usually born at term or after term.

Symptoms and signs include the following:

• Decreased activity

• Large anterior fontanelle

• Poor feeding and weight gain

• Small stature or poor growth

• Jaundice

• Decreased stooling or constipation

• Hypotonia

• Hoarse cry

Often, they are described as "good babies" because they rarely cry and sleep most of the time.

Family history should be carefully reviewed for information about similarly affected infants or family members with unexplained mental retardation. In regions of iodide deficiency and a known prevalence of endemic cretinism, the diagnosis may be straightforward.

Maternal history of a thyroid disorder and mode of treatment, whether before or during pregnancy, can occasionally provide the etiology of the infant's problem.

The physical findings of hypothyroidism may or may not be present at birth (see the image below).

Congenital Hypothyroidism. An infant with cretinism. Note the hypotonic posture, coarse facial features, and umbilical hernia.

Signs include the following:

• Coarse facial features

• Macroglossia (See the image below.)

  Congenital Hypothyroidism. Note the macroglossia.

• Large fontanelles

• Umbilical hernia

• Mottled, cool, and dry skin

• Developmental delay

• Pallor

• Myxedema

• Goiter

A small but significant number (3-7%) of infants with congenital hypothyroidism have other birth defects, mainly atrial and ventricular septal defects.[1]

Newborn screening involves the following:

• Infants with congenital hypothyroidism are usually identified within the first 2-3 weeks of life.

• These infants should be carefully examined for signs of hypothyroidism, and the diagnosis should be confirmed by repeat testing.

• Infants with obvious findings of hypothyroidism (eg, macroglossia, enlarged fontanelle, hypotonia) at the time of diagnosis have intelligence quotients (IQs) 10-20 points lower than infants without such findings.

Anemia may occur, due to decreased oxygen carrying requirement.

Screening of neonates

Screening for congenital hypothyroidism is recommended when a baby is 3 days old. Testing should be performed before discharge or within 7 days of birth. False-positive TSH elevations may be found in specimens collected at 24-48 hours after birth, and false-negative results may be found in critically ill newborns or post-transfusion infants. Particular care should be taken not to miss screening in infants receiving emergency care.[58]

There are three screening strategies for the detection of congenital hypothyroidism[58] :

• Primary TSH measurement with backup thyroxine (T4) determination in infants with high TSH levels

• Primary T4 measurement with backup TSH assessment in infants with low T4 levels

• Simultaneous measurement of T4 and TSH levels (preferred)

Primary TSH measurement with backup T4 assessment misses delayed TSH elevation in infants with thyroxine-binding globulin (TBG) deficiency, central hypothyroidism, or hypothyroxinemia. In addition, the normal postnatal increase in TSH can be a problem when patients are discharged early. Primary T4 measurement with backup TSH misses hyperthyroxinemia in infants with delayed TSH increase and initial normal T4.

The European Society for Paediatric Endocrinology (ESPE) guidelines recommend performing a second screening for the following infants[59] :

• Preterm, low-birth weight (LBW) and very low-birth weight (VLBW) neonates

• Infants admitted to neonatal intensive care units (NICU)

• Infants originally tested within the first 24 hours of life

• Multiple births (particularly same-sex twins)

According to the American Academy of Pediatrics guidelines, any infant with a low T4 concentration and TSH concentration greater than 40 mU/L is considered to have primary hypothyroidism. Confirmatory serum testing should be performed to verify the diagnosis and treatment initiated immediately and before the results of the confirmatory tests are available.[58]

Infants with modestly elevated TSH levels between 17 and 19.9 mIU/L have a significant risk (24%) of having congenital hypothyroidism.[60] Testing should be repeated. It is important that age-appropriate normative values be used. The reference range for TSH for the most common time of TSH reevaluation (between 2 and 6 weeks of age) is 1.7 to 9.1 mU/L.[61]

Diagnosis of primary hypothyroidism is confirmed by demonstrating decreased levels of serum thyroid hormone (total or free T4) and elevated levels of thyroid-stimulating hormone (TSH).

If maternal antibody–mediated hypothyroidism is suspected, maternal and neonatal antithyroid antibodies may confirm the diagnosis.[2] Such antibodies are an uncommon cause of congenital hypothyroidism.[3]

Low or low-normal serum total T4 levels in the setting of a serum TSH within the reference range suggests TBG deficiency. This congenital disorder causes no pathologic consequence; however, it should be recognized to avoid unnecessary thyroid hormone administration. Thyroid-binding globulin (TBG) deficiency affects 1 individual per 3000 population; therefore, occurrence is nearly as frequent as that in congenital hypothyroidism. TBG deficiency results in low serum total T4 levels; however, serum TSH and serum-free T4 concentrations are normal. Assessment of the serum TBG concentration, preferably with simultaneous serum free and serum total T4 concentrations, confirms the diagnosis.

TBG levels can be measured in infants with suspected TBG deficiency. This condition does not require treatment, but appropriate diagnosis and parental counseling can avoid later confusion and misdiagnosis.

Routine laboratory testing in patients with TBG deficiency shows a low total T4 level and a TSH level within the reference range. Free T4 and T3 levels are within the reference range. Congenital nephrotic syndrome is a rare cause of TBG deficiency or congenital hypothyroidism.[62, 63]

Laboratory results similar to infants with TBG deficiency can be found in infants who have hypopituitarism or hypothalamic disease, but these children have normal TBG levels.

Ultrasonography and scintigraphy

Ultrasound and thyroid scintigraphy help determine the anatomy and function of the thyroid gland as well as the etiology of congenital hypothyroidism. Both the American Academy of Pediatrics (AAP) and the European Society for Paediatric Endocrinology (ESPE) recommend both ultrasound and scintigraphy be included in the initial workup but treatment should not be delayed.[58, 59] Ultrasound lacks sensitivity for detecting small ectopic glands but is the gold standard for measuring thyroid dimensions.[64] Scintigraphy (using technetium-99m or iodine-123) provides an etiologic diagnosis in most cases and can aid in distinguishing congenital hypothyroidism from transient hyperthyrotropinemia.[5, 65]

The absence of radionuclide uptake suggests sporadic athyreotic hypothyroidism but can also be seen when uptake is blocked by excess iodide or thyroid receptor–blocking antibodies. If no uptake is found on isotope scanning, thyroid ultrasonography may demonstrate thyroid tissue in these patients.[5, 66] One study of 210 scanned infants stated a preference for using iodine-123 over pertechnetate.[67]

Thyroid scans can also demonstrate the presence of an ectopic thyroid, such as a lingual or sublingual gland, which is also sporadic. The presence of a bilobed thyroid in the appropriate position or a goiter would suggest either an inborn error of thyroid hormone production or transient hypothyroidism or transient hyperthyrotropinemia.

Radiography

A lateral radiograph of the knee may be obtained to look for the distal femoral epiphysis. This ossification center appears at about 36 weeks' gestation. Its absence in a term or postterm infant indicates prenatal effects of hypothyroidism.[59]

Neonatal hypothyroidism screening, using TSH levels, has proven helpful in countries with mild to no iodine deficiency. It has not been found useful in countries with moderate-to-severe levels of iodine deficiency disorders (IDD), because resources are insufficient to deal with the problem, and efforts here should be made to supply sufficient iodine to the population as a whole.

In infants with suspected dyshormonogenesis, radioactive iodine uptake (iodine-123) and perchlorate flush testing (KCIO2) can be performed to determine the presence of an iodide uptake or organification defect.

The goal of treatment in congenital hypothyroidism is to correct hypothyroidism and ensure normal growth and neuropsychological development. The mainstay in the treatment of congenital hypothyroidism is early diagnosis and thyroid hormone replacement. Optimal care includes diagnosis before age 10-13 days and normalization of thyroid hormone blood levels by age 3 weeks.[8, 9, 68]

Only levothyroxine (L-T4) is recommended for treatment.[10] It has been established as safe, effective, inexpensive, easily administered, and easily monitored.

Some authors suggest that generic forms may be just as effective as branded medications,[69] but others disagree.[70] The American Thyroid Association guidelines note that switches between levothyroxine products could potentially result in variations in the administered dose; prescription of either a brand name or generic preparation of levothyroxine is advised. Because use of different levothyroxine products may sometimes be associated with altered serum TSH values, a change in an identifiable formulation of levothyroxine (brand name or generic) should be followed by re-evaluation of serum TSH at steady state.[71]

Optimum dosage regimens and follow-up laboratory monitoring have not yet been determined.[72, 73, 74] Initial dosages of 10-15 mcg/kg/day, equivalent to a starting dose of 50 mcg in many newborns, have been recommended.[59, 71] However, in up to 43% of infants and 10% of older children with congenital hypothyroidism, TSH elevation fails to normalize despite appropriate L-T4 treatment.[75]

The treatment of hypothyroidism is straightforward. However, because of the potential for serious morbidity with inadequate treatment or overtreatment, primary physicians should consult a pediatric endocrinologist. Appropriate psychological, developmental, and educational evaluations should also be considered.[75]

Dietary iodide supplementation in iodine-deficient areas can prevent endemic cretinism but does not have a major effect on sporadic congenital hypothyroidism. Dietary iodine deficiency is the most common preventable cause of brain damage worldwide.[76]

Soy-based formulas may decrease the absorption of levothyroxine.[77] This is not a contraindication to their use, even in infants with congenital hypothyroidism. Switching an infant from a milk-based formula to a soy-based formula may increase the dose of thyroid hormone needed to maintain a euthyroid status.[78]

Dietary iodide supplementation can prevent endemic goiter and cretinism, but not sporadic congenital hypothyroidism. Iodization of salt is the usual method, but cooking oil, flour, and drinking water have also been iodinated for this purpose. Long-acting intramuscular injections of iodized oil (Lipiodol) have been used in some areas, and oral lipiodol[79, 80] can also be effective.

Properly administered newborn screening programs have made diagnosis of infants with congenital hypothyroidism possible within the first 3 weeks of life. With early and adequate treatment, the sequelae can be eliminated in most and minimized in the rest.

Methods of prenatal diagnosis and treatment are being evaluated.

Children with congenital hypothyroidism should be monitored clinically and biochemically. Clinical parameters should include linear growth, weight gain, developmental progression, and overall well-being.

Laboratory measurements of T4 (total or free T4) and TSH should be repeated 4-6 weeks after initiation of therapy, then every 1-3 months during the first year of life and every 2-4 months during the second and third years. In children aged 3 years and older, the time interval between measurements may be increased, depending on the reliability of the patient's caretakers. As dosage changes are made, testing should be more frequent.

Formal developmental and psychoneurological evaluations should be considered in all infants with congenital hypothyroidism. Such evaluations are especially important in children whose treatment was delayed or inadequate. As mentioned above, infants diagnosed early who have detectable signs of hypothyroidism at the time of diagnosis are also at increased risk of developmental problems. As with any child, school progression should be monitored and parents encouraged to seek early evaluations and interventions as soon as problems are recognized.[81]

Unless an anatomic defect of the thyroid was found at diagnosis, reevaluation after withdrawing treatment should be considered at about age 3 years.[82] If the child remains hypothyroid at age 3 years, thyroid hormone replacement and medical monitoring are usually required for life.

Screening of Newborns

Congenital hypothyroidism is included in the RUSP (Recommended Uniform Screening Panel) list of disorders to be screened at birth recommended by the Department of Health and Human Services.[83] The American Academy of Pediatrics (AAP) guidelines include an algorithm for screening and interpreting results.[58]

The European Society for Paediatric Endocrinology (ESPE) guidelines recommend performing a second screening for the following infants[59] :

• Preterm, low-birth weight (LBW) and very low-birth weight (VLBW) neonates

• Infants admitted to neonatal intensive care units (NICU)

• Infants originally tested within the first 24 hours of life

• Multiple births (particularly same-sex twins)

Treatment

The AAP, ESPE, and American Thyroid Association (ATA) guidelines all agree that levothyroxine replacement at a dose of 10–15 μg/kg/day should be initiated once newborn screening is positive. Additional key recommendations from ESPE include the following[59] :

• Levothyroxine treatment should be initiated as soon as possible and no later than 2 weeks after birth or immediately after confirmatory serum test results in infants with congenital hypothyroidism detected by a second screening test.
• Infants with severe disease, as defined by a very low pretreatment TT4 or FT4 concentration, should be treated with the highest initial dose
• L-T4 should be administered orally; if intravenous treatment is necessary, the dose should be no more than 80% of the oral dose, The dose should then be adjusted according to TSH and FT4 determinations.

Class Summary

These agents are administered to supplement thyroid hormone in patients with hypothyroidism. Levothyroxine is the preferred form of thyroid hormone replacement in all patients with hypothyroidism.[84] Desiccated thyroid is an obsolete medication made from pooled animal tissue. Desiccated thyroid should not be used.

Levothyroxine (Levothroid, Levoxyl, Synthroid)

Also known as L-thyroxine, T4, and thyroxine. A thyroid hormone with proven record of safety, efficacy, and ease of use. In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development.