Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency present at birth. CH must be diagnosed promptly because delay in treatment can lead to irreversible neurological deficits. Before the newborn screening program, CH was one of the most common preventable causes of intellectual disability. Newborn screening (NBS) programs have led to earlier diagnosis and treatment of CH, resulting in improved neurodevelopmental outcomes.
The thyroid hormone plays an essential role in energy metabolism, growth, and neurodevelopment. Specifically, the thyroid hormone acts on neuronal differentiation, synapsis development, and myelination in the prenatal and newborn periods, regulating central nervous system development. The thyroid hormones are derived from the amino acid tyrosine and produced by the thyroid gland in response to stimulation by the thyroid-stimulating hormone (TSH) produced by the anterior pituitary. TSH is regulated by the thyrotropin-releasing hormone (TRH), which is released from the hypothalamus. This regulation pathway is called the hypothalamic-pituitary-thyroid (HPT) axis. There are two active thyroid hormones, thyroxine (T4) and triiodothyronine (T3).
Both T3 and T4 are secreted by the thyroid gland, though the majority of circulating T3 is derived from peripheral tissue deiodination of T4. Deiodination of T4 to T3 is catalyzed by a group of enzymes known as iodothyronine deiodinases. T4 and T3 inhibit the secretion of TSH, both directly and indirectly, by inhibiting the secretion of TRH. Additional factors that inhibit TSH release are glucocorticoids, somatostatin, and dopamine. Both circulating T4 and T3 are bound tightly to serum proteins, including T4-binding globulin (TBG), and only the tiny fraction of T4 (0.02%) and T3 (0.3%) are unbound, so-called free T4 and free T3, which are biologically active.
Congenital hypothyroidism (CH) may be of thyroidal or central origin (primary and central CH, respectively). Primary CH can be caused by a defect in thyroid gland development (thyroid dysgenesis) or a defect of thyroid hormone biosynthesis (dyshormonogenesis). The majority of CH is due to thyroid dysgenesis (80%), which encompasses a variety of defects, including agenesis, ectopic, or hypoplastic gland. Thyroid dysgenesis is almost always sporadic or nonhereditary, although, in 2-5% of cases, mutations in genes responsible for thyroid gland development (the TSH receptor or the transcription factors PAX8, NKX2-1, or FOXE1) may be found.
While these defects cause permanent CH, the condition may also be transient, a result of transplacental passage of maternal anti-thyroid medications (methimazole or propylthiouracil), maternal thyroid blocking antibodies (in a mother with autoimmune thyroid disease), or iodine deficiency or excess. Iodine deficiency, still an important cause of CH worldwide, especially in iodine-poor regions. Newborns exposed to excess iodine (such as iodine-containing antiseptics, or radiographic contrast agents) may develop hypothyroidism as the synthesis of thyroid hormone is transiently inhibited via the Wolff-Chaikoff effect. Central CH is rare and results from a pituitary or hypothalamic abnormality (secondary/tertiary hypothyroidism).
The overall incidence of congenital hypothyroidism (CH) ranges from 1 in 3,000 to 1 in 4,000 live births, with variation worldwide among different ethnicity. The incidence is higher in Hispanics (1 in 1600) and Asian (1 in 2380) infants and lower in black (1:11,000) infants. The incidence is nearly 1.5 or 2 to 1 in females compared with males and is also higher in twin births, multiple births, older mothers, and preterm infants. Over the past few decades, several newborn screening programs in the United States and around the world reported a doubling of the incidence of CH to 1 in 2000. The reasons for this rise in the overall incidence of CH are thought to be multifactorial and related to the lowering of TSH screening cutoffs resulting in increased detection of milder cases, change in the ethnic demographics (increased births of Asians and Hispanic babies), increased screening of preterm or low-birthweight infants.
In infants with primary congenital hypothyroidism (CH), hypofunction of the thyroid gland typically causes low T4 and T3 levels, with elevated TSH and TRH levels due to feedback mechanism to the hypothalamus and pituitary gland. In compensated or subclinical hypothyroidism, serum T4 remains normal, while the TSH level is elevated. Infants with central hypothyroidism have low T4 or free T4, with low or low-normal TSH levels. TSH is the most sensitive indicator of thyroid dysfunction and the HPT axis. Additionally, patients with TBG deficiency present with a low total T4 and normal TSH. They are likely euthyroid. However, a free T4 and a TBG level should be added to confirm their thyroid status.
Most newborns with congenital hypothyroidism (CH) have no or few clinical manifestations at birth. This is due to partial maternal thyroxine hormone transfer (~25-50%). The classic clinical features of CH appear gradually over approximately six weeks, but early signs may appear within the first few weeks of life in more severe cases of CH. The early manifestations include lethargy, hypotonia, large anterior and posterior fontanels, feeding difficulty, prolonged jaundice, poor or hoarse cry, constipation, and hypothermia. The classic late manifestations of CH usually occur after about six weeks of life. These include coarse facies with depressed nasal bridge, puffy eyelids, large tongue, coarse hair, thick, dry and cold mottled skin, abdominal distension, umbilical hernia, hyporeflexia, bradycardia, hypotension, and anemia. The respiratory distress may develop due to myxedema of the airway and is characterized by noisy breathing, nasal stuffiness, and intermittent perioral cyanosis.
Neonates with CH are often asymptomatic at birth and detected by newborn screening (NBS). NBS is obtained via heel prick on a dried whole blood spot samples on filter paper cards. NBS for CH is routine in most countries worldwide. Methods for NBS detection and criteria for CH diagnosis vary throughout the United States and other countries. The priority of the NBS is the early detection of primary CH. The most specific test for detecting primary CH is a TSH measurement, while the T4 test is more sensitive as it includes babies with rare hypothalamic-pituitary-hypothyroidism.
Multiple factors may affect newborn thyroid screen results as thyroid physiology in neonates is dynamic. Interpretation of thyroid function test requires awareness of the newborn screening method, age at specimen collection, prematurity status, and clinical state of the newborn.
NBS for CH should ideally be performed between 2 and 4 days of life. If this is not possible, testing should be done before discharge from the hospital.
There are 3 screening Methods
1) Initial TSH with backup T4 measurement. Typically TSH cutoff is 20 to 50 U/L. This method is utilized by most programs in Europe, Japan, Canada, and the US. With this approach, central hypothyroidism, primary CH with delayed elevation of TSH, and hypothyroxinemia will be missed.
2) Initial T4 with backup TSH measurement. This method will miss mild cases of primary CH (subclinical hypothyroidism) where T4 is normal, but TSH is elevated. Initial T4 measurement can detect central hypothyroidism.
3) Simultaneous T4 and TSH measurements. This is an ideal screening method, however, more expensive.
Primary CH may be masked due to the suppression of TSH secretion caused by hypothalamic-pituitary immaturity, medication administration, and the effects of serious neonatal illness. Delayed TSH elevation (defined as elevated TSH in the second neonatal screening after normal TSH in the initial screening) is observed in one-half of preterm infants. A second screening is recommended by both the European and American Pediatric Societies for low-birth-weight (BW), preterm (<37 weeks gestational age), and ill neonates admitted to the neonatal intensive care unit (NICU) to identify those with delayed elevations in TSH concentration. Screening protocols for preterm infants (<32 weeks gestation) include measurement on days 3 to 5 and at 1 week, 2 weeks, 4 weeks, and term-corrected gestational age or the day of discharge home, whichever comes first. The TSH cutoff level of 10 mU/L or greater is considered to be positive for CH.
The second screening at 2 weeks of age or at discharge from the hospital is also recommended for infants with specimen collection within the first 24 hours, multiple births, particularly in cases of same-sex twins (concern for fetal blood mixing).
Infants exposed to iodine should be monitored for up to 1 month after exposure to identify iodine-induced hypothyroidism (with low T4 and elevated TSH) following exposure.
Criteria for diagnosis of primary CH and treatment initiation
When abnormal results on the NBS for CH are reported, a confirmatory venous sample for thyroid function test (free T4 and TSH) should be obtained immediately. Further evaluation of the etiology of CH should not delay treatment initiation.
Interpretation of Thyroid Function Tests
1. Low free T4 and high TSH: These results confirm the diagnosis of primary hypothyroidism.
2. Normal free T4 (or total T4) and high TSH: These results define compensated or subclinical hypothyroidism. If serum TSH is >20, mIU/L, treatment with levothyroxine should be initiated. If serum TSH is mildly elevated (e.g., 6 to 20 mIU/L), clinicians may observe the patient clinically and repeat TFT in 1 week. In many cases, the TSH will be normalized on the repeat TFT. However, if serum TSH remains elevated >10 mIU/L by 4 weeks of age, the infants should be treated.
3. Low free T4 and low or normal TSH: These results suggest the possibility of central hypothyroidism that is usually accompanied by other pituitary hormone deficiencies, such as growth hormone or ACTH deficiency (infants may present with hypoglycemia due to these 2 hormone deficiencies) or diabetes insipidus. Besides neonatal hypoglycemia with cortisol and/or growth hormone deficiency, other clues for central hypothyroidism that should prompt clinicians to obtain serum free T4 and TSH are nystagmus, micropenis, midline defect such as cleft lip/cleft palate. Treatment with levothyroxine should be promptly initiated for central hypothyroidism. Other possibilities for this abnormal thyroid function test include primary hypothyroidism with delayed TSH elevation (rare), nonthyroidal illness, or transient hypothyroxinemia of prematurity (in premature infants). In sick neonates, low T4 can result from dopamine or high-dose glucocorticoids. Low total T4 and normal TSH may also be due to thyroid-binding globulin (TBG) deficiency, which does not require treatment.
Additional Laboratory Evaluation
1. Thyroid imaging studies
Imaging studies are not routinely recommended, as the results do not alter the treatment plan. The decision to start therapy is based solely on abnormal thyroid function tests. Imaging studies may be performed to determine an underlying etiology and occasionally help establish a cause of CH in a patient with a permanent form, as long as they do not interfere with medical therapy. Those circumstances include infants with a goiter, or infants with mildly elevated TSH (e.g., TSH 6-10 mIU/L), in whom thyroid dyshormogenesis is suspected.
1.1 Thyroid ultrasound— This imaging study is safe and can be performed after treatment initiation. Thyroid ultrasound can visualize the presence or absence, size, echogenic texture, and structure of a thyroid gland. However, it may not reliably detect the ectopic thyroid gland (lingual and sublingual).
1.2 Thyroid radio nuclear uptake scan: An iodine 123 uptake scan or sodium pertechnetate 99m, can be used to determine the size and location of the thyroid gland, and to diagnose ectopic thyroid, thyroid aplasia, or hypoplasia. A thyroid scan shows no uptake in patients with thyroid blocking antibodies, and patients with iodine trapping defects will have no uptake on the thyroid scan with a normal or enlarged thyroid on ultrasonography.
2. Thyroid autoantibodies— TSH-receptor blocking antibodies may be useful in diagnosing infants with transient CH due to maternal autoimmune thyroid disease, or infants with a sibling with a transient course of CH.
3. Serum thyroglobulin— A low or absent thyroglobulin level demonstrates a lack of any thyroid building architecture and suggests thyroid agenesis. However, intermediate levels may not differentiate the cause of CH.
4. Urine iodine concentration-- CH may be caused by iodine excess or deficiency (in infants born in an area of endemic goiter or iodine deficiency). Measurement of urine iodine can identify the excess or deficient state.
5. Radiographs of the knees may be obtained at diagnosis. The absence of a lower femoral epiphyseal center indicates severe CH and correlates with later intelligence and motor scores.
Treatment with levothyroxine (L-T4) must be started immediately after the diagnosis of congenital hypothyroidism (CH). NBS programs and early L-T4 treatment initiation (prior to 2 weeks of life) can prevent intellectual deficits and optimize neurodevelopmental outcomes. L-T4 alone is the treatment of choice. The initial dose depends upon the severity of CH. The higher initial L-T4 dose of 10 to 15 micrograms (ug)/kg/day (50 ug/day for full-term infants with severe CH) is recommended, especially for neonates with a very low pretreatment T4 level. A high initial L-T4 dose can normalize serum T4 in 3 days and TSH by two weeks of therapy. The majority of full-term infants with severe CH require a short-term high dose L-T4 (50 ug per day) with dose reduction to 37.5 ug per day after TSH is normalized to avoid overtreating.
L-T4 tablets crushed and mixed with a small amount (1 to 2 ml) of water or breast milk may be administered orally via a small spoon or syringe. L-T4 should be given at the same time each day and at a different time of the day from calcium, iron, and soy to avoid interference with the absorption of the L-T4.
The first repeat thyroid function test (TFT), which includes free T4 and TSH, is to be drawn at 1 to 2 weeks after the start of L-T4 therapy with follow up TFT every two weeks until a complete normalization of TSH. Repeat TFT is recommended every 1 to 3 months until 1 year of age. Children should have follow-up visits with TFT obtained every 2 to 4 months between the ages of 1 to 3 years, and every 3-12 months until growth is completed. More frequent visits and laboratory evaluations may be scheduled for patients with poor adherence or abnormal levels. Any L-T4 dose adjustment or formulation change requires a repeat TFT in 4-6 weeks. The goal of therapy is to maintain the total T4 in the upper half of the age-specific reference range and TSH level within the age-specific reference range.
Neonates that were discharged from the hospital early, with NBS obtained within the initial 24 hours of life, may have elevated TSH levels due to post-delivery TSH surge in response to cold stress after birth. This causes false-positive results and requires a second screening test. The ideal time to obtain NBS for CH is between 2 and 4 days of life when TSH levels have deceased.
Special considerations for premature infants: Premature infants may have hypothyroxinemia of prematurity, characterized by low free T4 and normal TSH, due to an immature HPT axis. Interpretation of TFT in premature infants is often challenging, as this thyroid profile can also be secondary to central hypothyroidism or complicated by non-thyroidal illness. Repeating TFT is recommended, as mentioned above. Most patients will have a normal TFT by 6 to 10 weeks.
Current guidelines recommend treatment with L-T4 until at least 36 months of age. At that time, a trial off of L-T4 can be considered to determine the permanency of CH. Transient CH is more common in preterm or very low-birthweight infants. L-T4 dose < 2.8 mcg/kg/day in the third year of treatment is a predictor of transient CH. Thus, early discontinuation of L-T4 therapy at 2.5 years of age may be possible with careful monitoring of TFT. TFT should be repeated in 2 weeks after a trial time off the therapy. If repeat TFT is abnormal, L-T4 should be restarted. If repeat TFT is normal, TFT may be repeated again in 1 to 2 months to ensure normal thyroid hormone status.
In general, neurodevelopmental outcomes in congenital hypothyroidism (CH) are excellent. Early and adequate therapy initiation, prior to 2nd week of life, will result in an appropriate global intelligence. However, mild or subtle deficits in verbal skills, attention, memory, or motor development may be observed, particularly in those with severe CH. The severity of CH and pretreatment T4 level are important predictors of adverse cognitive and motor outcomes. Studies suggest that children with thyroid agenesis had a lower IQ than those with dysgenesis, which could be explained by the cerebral injury that may occur prenatally. In severe CH, high L-T4 starting doses (at 10-15 mcg/kg) rapidly normalize serum TSH concentrations and result in the attainment of normal global IQ at 4 years of age and young adults. Moreover, when children with CH and early L-T4 initiation are directly compared with their own siblings, they do exhibit a mild IQ loss. This loss can be minimized to a certain degree if a higher starting dosage is provided. Growth and bone age maturation are not affected by such a high dose.
There is an increased incidence of other congenital malformations in children with congenital hypothyroidism (CH), particularly cardiac malformations, including septal defects, renal abnormalities, and the risk of neurodevelopmental disorders. A thorough clinical examination, including a hearing screen, should be performed.
Sick neonates with congenital hypothyroidism (CH) in intensive care units, unable to receive medication via enteral route, or those under NPO status during pre or postoperative care will require intravenous (IV) L-T4 therapy, with IV dose generally 50% to 75% of the oral dose.
Parents need to be educated on the diagnosis of congenital hypothyroidism (CH), the importance of early and adequate treatment that will prevent poor neurodevelopmental outcomes. Clear and adequate instructions on the L-T4 administration should be provided for caretakers. The importance of close follow-up visits and thyroid laboratory monitoring needs to be emphasized. For excellent patient education resources, visit the Pediatric Endocrine Society website for educational materials.
Prompt diagnosis and treatment of congenital hypothyroidism (CH) is critical for the optimal neurodevelopmental outcome and requires interprofessional communication, and care coordination by newborn screen laboratory, primary care physicians, and pediatric endocrinologists are important. Abnormal NBS test results should be communicated immediately to the responsible physician, who will then contact the family so that follow-up testing and evaluation can be arranged, preferably on the day of results become available or on the next day at the latest.
Patient education on CH and the importance of treatment adherence and follow-up care needs must be emphasized to the family. Demonstration L-T4 administration to newborns should be provided by nurses. If follow-up thyroid testing after treatment initiation does not show normalized free T4 or decreased TSH level < 20 mIU/mL within 4 weeks, physicians and healthcare team (nurses) should evaluate compliance, dosage, and administration method. Moreover, ongoing counseling at each follow-up visit should be provided for the family.
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