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Preventing the potentially irreversible effects of congenital hypothyroidism requires early recognition, prompt treatment, and constant reassessment. A screening test for hypothyroidism on all newborns is just the beginning of your role.
|Jump to:||Choose article section... How the thyroid gland functions Causes of hypothyroidism at birth Screening varies by state Confirming the diagnosis Diagnostic complications Initiating therapy Look for other conditions Long-term management and outcome Support for families A clinical and economic payoff KEY POINTS Congenital hypothyroidism|
Preventing the potentially irreversible effects of congenital hypothyroidism requires early recognition, prompt treatment, and constant reassessment. Ensuring that a screening test for hypothyroidism is performed on all newborns is just the beginning of your role.
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Your office secretary hands you a fax from the health department at the end of a busy day. One of your patients, now 5 days old, had an abnormal newborn screening test for congenital hypothyroidism. You remember that she was born full term after an uncomplicated pregnancy and delivery to first-time parents. Her examination before hospital discharge was unremarkable.
What is the accuracy of the screening? What follow-up testing is needed, and how urgently? What is the prognosis if she has hypothyroidism? What sort of follow-up and treatment would she require?
Early detection of congenital hypothyroidism through newborn screening is one of the great successes of preventive medicine. Before the advent of screening in the 1970s, one third of children with congenital hypothyroidism were not detected until after their third month of life, at which point they had developed irreversible mental retardation.13 A five- or six-month delay in treatment for congenital hypothyroidism could result in an IQ of 70 in a child who probably otherwise would have had normal intelligence.4
General pediatricians play a vital role for children with congenital hypothyroidism. Most importantly, pediatricians must ensure that all their newborn patients are screened. Pediatricians are often the first point of contact between the state lab and the parents, and therefore must be able to initiate an appropriate diagnostic work-up and discuss the meaning of a positive screen. Because congenital hypothyroidism requires treatment for yearsoften for lifepediatricians can provide a medical home to coordinate treatment and to provide specific anticipatory guidance and preventive care.
To understand the causes of congenital hypothyroidism and its optimal management, it is helpful to first review the role of thyroid hormone and the development and early functioning of the thyroid gland.5,6 In the developing fetus, thyroid hormone is critical for brain development, including neuronal proliferation and nerve cell migration.7 Thyroid hormone also plays an important role in myelination,7 which continues through the first three years of life.
Thyroxine (T4) is the principal hormone released by the thyroid gland (Figure). To a lesser extent, the thyroid releases the more active hormone triiodothyronine (T3). These hormones are under control of the pituitary hormone thyroid-stimulating hormone (TSH), called also thyrotropin, through a negative feedback system. TSH is stimulated by thyrotropin- releasing hormone (TRH), which is secreted by the hypothalamus. T4 and T3 are bound to carrier proteins, including thyroxine-binding globulin (TBG), in circulation. More than 99% of thyroid hormone is bound to carrier proteins.8 At the tissue level, T4 is enzymatically converted to T3.
The thyroid first develops around the 17th day of gestation as a midline outpouching of the primitive pharynx.9 By the seventh week of gestation, the thyroid has migrated from an area at the base of the tongue to its final position at the neck. Until the 16th week of gestation, only small amounts of thyroid hormone are produced.9,10 By the 20th week of gestation, the hypothalamus releases TRH, which in turn stimulates pituitary release of thyrotropin, resulting in increased levels of both T4 and T3 from the thyroid.10
Circulating levels of T3 are relatively low until the 30th week of gestation. However, the enzymes (deiodinases) responsible for converting T4 to T3 are more active in the brain. Furthermore, although the placenta is impermeable to TSH, small amounts of maternal T4 and T3 can pass to the fetus. A compensatory increase in maternal thyroid hormone transfer and an increase in deiodinase activity can protect the fetus from hypothyroidism due to insufficient thyroid hormone production. This explains why babies with congenital hypothyroidism can appear normal in all respects. Without screening, even the most astute clinician will not be able to identify these children.
The incidence of congenital hypothyroidism in the United States is approximately 1 in 3,500 live births.11 The incidence is lower among boys (1 in 7,700) than among girls (1 in 4,000), and among black children (1 in 10,000) than among non-Hispanic white children (1 in 4,400).11 For Hispanic children, the incidence varies by country of origin, ranging from approximately 1 in 1,500 in Mexico to 1 in 4,400 in Argentina.12 Children with Down syndrome have a 35-fold increase in the risk of congenital hypothyroidism.11
Worldwide, the most common cause of hypothyroidism is deficiency of iodine,9 a key element in both T4 and T3. Children born to profoundly iodine-deficient mothers may have uncompensated hypothyroidism due to decreased availability of thyroid hormone for transplacental passage, and may therefore have neurologic findings at birth. Iodine deficiency affects more than one third of the world's population and is the most prevalent cause of avoidable mental retardation.13 Fortunately, iodine deficiency does not occur in the US because iodine is widely present in the diet, chiefly as iodized salt.
We prefer to classify the causes of hypothyroidism by whether they are permanent or transient, because of the obvious impact on duration of treatment (Table 1). About 90% of cases of congenital hypothyroidism are permanent.
Thyroid dysplasia (agenesis or hypoplasia)
Secondary hypothyroidism (TSH deficiency or resistance, T4 resistance, T3 resistance)
Maternal or neonatal drug exposure, including iodine
Dyshormonogenesis (usually leads to permanent congenital hypothyroidism)
Sources: Fisher DA5; Brown RS6
The most common cause of congenital hypothyroidism in the US is failure of the thyroid to form (dysgenesis), which can span the spectrum from complete absence of thyroid tissue (agenesis) to partial formation of thyroid tissue (hypoplasia). Hypoplasia is often associated with failure of the normal migration of the thyroid (ectopic thyroid). Dysgenesis accounts for as many as 85% of cases of permanent congenital hypothyroidism. The causes of thyroid dysgenesis are unclear, but are believed to be multifactorial, including environmental and complex gene interactions.
Dyshormonogenesis, or failure of correct biosynthesis of thyroid hormone, accounts for as many as 15% of the cases of permanent congenital hypothyroidism. In contrast to dysgenesis, dyshormonogenesis usually follows an autosomal recessive inheritance pattern. Although sometimes transient, dyshormonogenesis usually leads to permanent congenital hypothyroidism.
Rare causes of permanent congenital hypothyroidism include TSH deficiency, sometimes associated with panhypopituitarism, resistance of the thyroid to TSH, and peripheral tissue resistance to T4 and T3. These other causes are classified as secondary hypothyroidism.
Transient hypothyroidism can be caused by maternal factors, such as TSH receptor-blocking antibodies that cross the placenta and drugs that interfere with production of thyroid hormone. The duration of transient hypothyroidism depends on the half-life of the offending agent. For maternal antibodies, the period of hypothyroidism can be as brief as a few weeks. Excess iodine can inhibit thyroid hormone synthesis (Wolff-Chaikoff effect).6 Iodine exposure could occur in utero, but is more likely to develop from skin absorption of povidone-iodine in a sick newborn undergoing multiple procedures. Other drugs associated with transient hypothyroidism include corticosteroids and dopamine.6
All states screen for congenital hypothyroidism on the blood spot collected for newborn screening. However, no national standard exists for the tests performed on the blood spot to identify hypothyroidism. Most states measure total T4; if the T4 is below a certain threshold, or less than a certain percentage of measures for that particular day (usually the tenth percentile), then TSH is also measured. The screen is positive if the T4 is below a critical value or the TSH is above a critical value. Some states have a similar algorithm, but begin with TSH testing. Other states screen both T4 and TSH on all specimens.
In an effort to ensure that no true cases are missed, a few states mandate that repeat newborn screening be performed on all children after the first weeks of life. Usually, between 0.05% and 0.3% of infants will have an initial abnormal screening test.14 Of those who do, 10% or fewer will be diagnosed with hypothyroidism.14
Newborn screening strategies change frequently. Pediatricians need to understand and keep abreast of the newborn screening policy in their state. Two excellent resources are the National Newborn Screening and Genetics Resource Center ( http://genes-r-us.uthscsa.edu ), administered by the Maternal and Child Health Bureau of the U.S. Department of Health and Human Services and the University of Texas, and Save Babies Through Screening ( http://www.savebabies.org ), a screening advocacy organization.
Newborn screening for congenital hypothyroidism is particularly challenging because of the unique changes in serum TSH and T4 concentrations in newborns. In the first hour after birth, there is a surge in TSH release, believed to be caused by a drop in the baby's temperature.9,10 This leads to a rise in both T3 and T4, which lasts four to six weeks.10 TSH peaks at 30 minutes of life and then declines over about five days. In contrast, T4 does not peak until 24 to 36 hours of life and then slowly declines over weeks.15 Because of these dynamic changes, it is difficult to set a threshold that does not miss any cases of congenital hypothyroidism without inflating the rate of false positive results.15,16 Newborns who are screened to facilitate early discharge may have physiologically high TSH. Preterm infants tend to have low total T4 and may be disproportionately reflected in states where a primary T4 screen is utilized. Many state programs accept a high proportion of false positive screening results to decrease the chance of missing infants who really do have congenital hypothyroidism.
In the 1980s, it was estimated that two cases were missed for every 1 million infants screened.17 Most missed cases were the result of errors in collection of the blood spot or lost follow-up; only a minority was due to biologic variability. Because of the potential for missed cases, it makes sense to consider signs and symptoms of hypothyroidism during well-child visits (Table 2).
Large anterior or posterior fontanelle
Cold hands or feet
Poor weight gain
Respiratory distress in an infant weighing >2.5 kg
Delayed passage of stools
Prolonged unconjugated hyperbilirubinemia
Source: Brown RS6
Because early intervention maximizes long-term developmental outcome for children with congenital hypothyroidism, the diagnostic evaluation should occur as soon as possible. The goal should be to begin therapy for children with congenital hypothyroidism by 14 days of life.
Evaluation should include a review of the mother's medical history. Since the transmission of maternal thyroid-blocking antibodies may produce transient hypothyroidism in infants,13 antithyroid-blocking antibodies should be measured in mothers of children with suspected congenital hypothyroidism if the mother has hypothyroidism.13 Assessment should also be made of whether the infant was exposed in the perinatal period to iodine or drugs that interfere with thyroid function.
Laboratory evaluation is key to the diagnosis of congenital hypothyroidism. Because there can be significant variations between laboratories, all studies should be sent to a reference laboratory recommended by the state laboratory or an endocrinologist. At a minimum, serum TSH and free T4 should be measured. In congenital hypothyroidism, usually TSH is high and free T4 is low. Sometimes, however, only one of these measures is abnormal.
An abnormally low total T4 concentration is seen in infants with thyroxine-binding globulin (TBG) deficiency, an inherited variant that does not produce disease or retardation. Children with TBG deficiency have normal free T4 and TSH. Some laboratories report indirect measures (for example, the free T4 index); however, direct measurement is more accurate and useful. Ranges of normal hormone levels for full-term children are listed in Table 3. Because of laboratory variation and the importance of early detection and treatment, review of thyroid test results with an endocrinologist is useful.
|Age||TSH (mU/L)||Free T|
Imaging studies of the thyroid can help determine whether congenital hypothyroidism will be permanent. Thyroid scintigraphy, nuclear imaging with 99mTC or 123I, can identify whether the gland has limited function (hypoplastic or ectopic, for example) or whether there is a defect of hormone production (dyshormonogenesis).1821 These imaging studies should be performed only before initiation of thyroid hormone supplementation. Also, if an infant has TSH receptor-blocking antibodies, the uptake of radionuclide material in the thyroid may be blocked as well, making it appear as if the child has thyroid dysgenesis on scintigraphy. Although thyroid hormone replacement prevents accurate nuclear imaging, treatment should not be delayed for scintigraphy. The accuracy of thyroid ultrasonography is variable,22 and it is not recommended for routine assessment.
Clinicians must be aware of TBG deficiency to avoid misdiagnosis and overtreatment.23 TBG deficiency is a recessive X-linked disease and is more common among boys (1 in 2,400) than true congenital hypothyroidism is.8,14
It is unclear what to do for infants who have a slightly elevated TSH but a normal free T4. Because these infants are at much higher risk of hypothyroidism in early childhood and may benefit from treatment,24 such cases should be reviewed with an endocrinologist.
Another potential pitfall lies in determining whether premature infants have hypothyroidism. Children born at 32 weeks of gestation or earlier often have low T4 without elevated TSH, referred to as "hypothyroxinemia of prematurity."10 Determining the state of thyroid function is complicated by the fact that many of these infants are sick and require treatment with drugs such as dopamine that can lead to transient hypothyroidism. Although premature infants have a higher rate of transient hypothyroidism, they do not have a greater risk of permanent congenital hypothyroidism.25 The benefit of treating premature infants with hypothyroxinemia of prematurity is controversial. One report suggests there is potential harm in treating those children born after 26 weeks' gestation.25
Primary care pediatricians are especially well-suited to following up abnormal screening results. Parents have easier access to their pediatrician than to a previously unknown endocrinologist. Pediatricians can build on their knowledge of the family and their newborn child to minimize family stress over the positive screening result. Pediatricians should, however, consult by telephone with a pediatric endocrinologist in the event of any abnormal or questionable finding to help guide treatment or further testing that may be required. The directors of state newborn screening programs can help identify a pediatric endocrinologist interested in congenital hypothyroidism if one is not known locally.
The treatment for hypothyroidism is hormone replacement with l-thyroxine (Levothroid, Levoxyl, Synthroid, Unithyroid), starting at 10 to 15 µg/kg/day as a single daily dose. Aggressive treatment with relatively high dosage l-thyroxine is safe and may lead to a better neurologic outcome.2628
The goal of treatment is to keep T4 in the upper half of the normal range and the TSH around 1 mU/L. Delay of normalization of TSH has been reported and is believed to be due to alterations in the normal feedback mechanisms associated with the previous hypothyroid state.4 Normalization of TSH by 1 to 2 months of age is associated with improved neurologic outcome.29
Few data are available regarding the optimal frequency for measuring TSH and T4.30 Frequent follow-up is critical to ensure the success of treatment. The American Academy of Pediatrics recommendations for follow-up are shown in Table 4.30,31 Frequent visits in infancy are important to maintain appropriate T4 concentrations to facilitate normal brain development. As with the diagnostic studies, follow-up testing should be sent to an appropriate reference laboratory. Frequent visits also emphasize to the family the importance of therapy.
Measure TSH and free T4
Source: American Academy of Pediatrics31
Adjustments to the dosage of l-thyroxine will be necessary as the child grows. If T4 cannot be raised to an appropriate level, one of four things may be to blame: The child has TBG deficiency and not true hypothyroidism; the preparation of l-thyroxine is not appropriately active; the absorption of l-thyroxine is incomplete; or the child is not receiving the medication.
Soy formulas can interfere with the absorption of l-thyroxine.32 Some drugs also interfere with absorption, including ferrous sulfate, sucralfate, aluminum hydroxide antacids, bile acid sequestrants, and calcium carbonate.33 Soy formula and drugs that interfere with l-thyroxine absorption should not be given within an hour of the l-thyroxine dose, and are best avoided altogether.
Although there has been some concern about the equivalence of generic to non-generic l-thyroxine, l-thyroxine is regulated to maintain drug potency.34 It is, however, best to continue the same preparation after initiating therapy.
All caregivers must understand the importance of thyroid hormone replacement. Inability to achieve an appropriate T4 can have serious long-term consequences and should be aggressively evaluated. Children with permanent congenital hypothyroidism should be taught the importance of their medicine. To help ensure compliance, children and their families benefit from support groups.
Historically, radiographs of the wrist and knee to assess bone age were used as a test of congenital hypothyroidism and to determine the effectiveness of treatment.35 With the ability to follow TSH and T4 directly, routine radiographs are unnecessary.
Nearly 12% of children with congenital hypothyroidism have another congenital abnormality as well.11,36 Cardiac defects, including sick sinus syndrome, patent ductus arteriosus (PDA), atrial septal defect (ASD), pulmonic stenosis (PS), and tricuspid atresia (TA), account for many of these other congenital abnormalities.11,36,37 Congenital hypothyroidism due to impaired hormone synthesis is associated with deafness (Pendred syndrome).35 It is important to ensure that all newborns with congenital hypothyroidism receive hearing screening. Not every newborn with congenital hypothyroidism needs a formal cardiology evaluation, but primary care providers should obtain a complete history for any signs of congestive heart failure (such as slow feeding) and perform a thorough cardiac examination. Any concern should prompt further investigation or referral.
When beginning therapy for congenital hypothyroidism, it is often unclear whether the condition is permanent or transient. When appropriately dosed, l-thyroxine has minimal side effects,26 and initiation of treatment should not be delayed for a work-up. It often becomes clear while the child is on therapy that he or she has permanent congenital hypoplasiaTSH rises when medication is missed, for example, or TSH remains persistently elevated despite appropriate supplementation. By the child's third birthday, the brain is sufficiently developed to permit a trial off thyroid supplementation if the hypothyroidism is believed to be transient. Because of the long half-life of T4, therapy must be discontinued for at least one month before assessing free T4 and TSH.
Long-term outcome of congenital hypothyroidism is determined by the cause of the hypothyroidism, the degree of hypothyroidism at birth, the age that treatment was initiated, and the aggressiveness of treatment. In terms of physical development, children who receive appropriate treatment will obtain their normal predicted height.38 Head circumference may be slightly enlarged in children who initially had more severe hypothyroidism.39
Neurologic outcome is clearly improved with appropriate treatment. It is important to consider subtle problems that may develop, however. Some children have delays in sensorimotor skills.7 Some children benefit from physical or occupational therapy.
Mild problems with reading comprehension and arithmetic have been reported in the third grade, with catch-up and normal functioning by the sixth grade.40 Primarily, problems with memory and attention have been reported.7,41 Impulsiveness and hyperactivity, however, are not associated with congenital hypothyroidism.7 Pediatricians should ensure that families are aware of these potential complications so that appropriate steps can be taken with schools in the event that problems do develop. Any alteration in memory or attention, or any other neurologic change, should prompt measurement of TSH and T4.29
Congenital hypothyroidism can be a serious financial burden to many families because of the need for daily medication, frequent physician visits, and laboratory tests. Fortunately, many of these children are eligible for services through each state's Title V (Children with Special Health Care Needs) program.
Families and patients need appropriate counseling about the benefits of treatment of congenital hypothyroidism.42 The Magic Foundation ( www.magicfoundation.org ; 800-3-MAGIC-3 or 708-383-0808) is a nonprofit organization that offers support to families facing certain chronic conditions, including congenital hypothyroidism. Among other services, they network families for peer support. Of course, many other resources are available at the local level. The state directors of the newborn screening programs can be invaluable in identifying these other resources.
The benefits of hormone replacement for children with congenital hypothyroidism can be profound. In fact, screening for congenital hypothyroidism is one of the few public health interventions that is cost-saving.43 The success of treatment for congenital hypothyroidism hinges on early treatment and constant reassessment. By providing a medical home for children with congenital hypothyroidism, general pediatricians play a pivotal role in the management of these patients and have the satisfaction of seeing children who might otherwise be significantly impaired experience normal long-term development.
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Alex Kemper, Carol Foster. Congenital hypothyroidism: A guide for the general pediatrician.