OVERVIEW: What every practitioner needs to know

Hypothyroidism in the neonate can be divided into 3 forms:

1) Permanent

Ectopy (50%)

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Agenesis (30%)

Hypoplasia (5%)

10% caused by hereditary defects in thyroid hormone synthesis

<5% Central hypothyroidism

2) Transient

“Sick euthyroid” syndrome – abnormal thyroid function due to hypothalamic-pituitary-axis changes during critical illness, also known as low T4/T3 syndrome. Whether this condition requires treatment or not remains controversial.

Transplacental passage of maternal anti-thyroid medications

Maternal antithyroid autoantibodies

Iodine deficiency

3) False

Thyroid-binding globulin (TBG) deficiency

Physiologic, early thyroid-stimulating hormone (TSH) surge

How frequent is congenital hypothyroidism?

The frequency of congenital hypothyroidism is approximately 1:3000-4000 live births.

Are you sure your patient has hypothyroidism? What are the typical findings for this disease?

Clinical Presentation and Diagnosis

Most newborns have few or no clinical symptoms of thyroid hormone deficiency.

  • Two studies looking at a total of 38 newborns with documented congenital hypothyroidism found the following:

    prolonged jaundice (55%)

    large posterior fontanelle (42%)

    feeding problems (39%)

    hypothermia (24%)

    macroglossia (21%)

    umbilical hernia (18%)

    hypotonia (16%)

    lethargy (13%)

    edema (13%)

    constipation (5%)

These are non-specific signs and symptoms and cannot be relied upon to diagnose hypothyroidism. For this reason, newborn screening for congenital hypothyroidism is now the standard of care.

What caused this disease to develop at this time?

Maternal-Fetal Thyroid Physiology: What are the steps involved in thyroid embryonic development?

The fetal thyroid begins as a thickening of the pharyngeal floor, which forms a diverticulum that descends caudally to the resting position of the mature thyroid gland. The thyroglossal duct is the track that forms during this migration, connecting the pharyngeal floor to the thyroid bed, and normally involutes. By 7 weeks gestation, a bi-lobed thyroid gland is formed. By 11-12 weeks gestation, the fetal thyroid is capable of trapping iodine, synthesizing, and secreting thyroxine. Prior to this, during the first trimester, the fetus is dependent upon T4 of maternal origin.

Fetal serum T4 and TSH gradually rise from 12 weeks gestation until term. Birth is associated with transient, robust peaks in serum TSH (up to 60 to 80 mU/L), serum total T4 (up to 10-22 mcg/dL), and free T4 (up to 2-5 ng/dL). This normal neonatal thyroid surge typically lasts 1 to 2 days.

What maternal factors can affect fetal hypothalamic-pituitary-thyroid axis development by crossing the placenta?

Table I shows the components affecting fetal thyroid development that cross the placenta.

Table I.
Cross the placenta Do not cross the placenta
fT4, T4, T3 TRH
IgG antibodies TSH
Anti-thyroid medications

Abbreviations:TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone

What factors are involved in regulation of the thyroid axis?

The hypothalamus and pituitary stimulate thyroid secretion, primarily in the form of the prohormone T4, which is then converted in peripheral tissues to T3 by outer-ring deiodination. Both T4 and T3 exert negative feedback on the hypothalamus and pituitary. The hypothalamic-pituitary-thyroid (HPT) axis is shown in Figure 1.

Figure 1.

Hypothalamic-pituitary-thyroid (HPT) axis

What causes this disease and how frequent is it?

What are the underlying etiologies/genetic factors responsible for congenital hypothyroidism?
  • Genetic mutations have been described but are rarely found in a diagnosis of congenital hypothyroidism. Thyroid dysgenesis is found in 85% of congenital hypothyroidism cases. The underlying genetic abnormality for most of these cases remains unknown. Most cases appear to be sporadic.

    PAX8, TTF1, and TTF2 are transcription factors involved in thyroid gland development and differentiation. Rarely, mutations in these genes have been associated with thyroid dysgenesis.

    Inborn errors of thyroid hormone metabolism account for up to 10-15% of cases. Hereditary defects in each step of thyroid hormone synthesis have been described. The majority of these mutations are autosomal recessive. With the exception of TSH receptor defects, these commonly present with a goiter on exam. Examples include iodide transport defects, organification defects, THOX1 and 2 mutations affecting hydrogen peroxide generation and TPO activity, coupling defects, and thyroglobulin abnormalities.

  • Maternal antibody-mediated congenital hypothyroidism – Mothers with autoimmune thyroid disease may produce TSH receptor blocking IgG antibodies that cross the placenta during pregnancy. This form of hypothyroidism typically resolves by 3-4 months as the antibodies are cleared.

  • Iatrogenic congenital hypothyroidism – Etiologies include maternal anti-thyroid drugs, iodine excess, or radioiodine exposure.

  • Chromosomal anomalies (ex. Trisomy 21) may also be associated with a higher incidence of congenital hypothyroidism.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Newborn Screening Program – Newborn screening for congenital hypothyroidism is universally mandated. In North America.

Two screening approaches are used:

1) Total T4 measurement with back-up TSH performed on infants with T4 levels below a specified cut-off, often the lowest 10% of the day’s values, or

2) TSH measurement only. Screening programs with a primary T4 approach will pick up infants with a delayed TSH surge and central hypothyroidism, and tend to have a higher recall rate than the primary TSH approach.

Interpretation of Screening for Congenital Hypothyroidism (First Screen):

Low Total T4; TSH >50 mU/L: Probable hypothyroidism. Infants with low T4 and elevated TSH should be considered to have congenital hypothyroidism until proven otherwise.

Normal Total T4; TSH = 20-49 mU/L: Probable Day 1 surge

Low Total T4; TSH <20 mU/L:

Thyroxine-binding globulin (TBG) deficiency – normal free T4 (1:4000 births)

Prematurity – low free T4

Sick euthyroid syndrome – low to normal free T4 with high reverse T3 (rT3)

Central hypothyroidism – low free T4 (1:100,000)

When congenital hypothyroidism is detected on newborn screen, send confirmatory serum TSH, T4, and fT4 but initiate treatment without waiting for results.

Pediatric Reference Intervals for TSH, T4, free T4, and T3

Table II shows the age-specific normal ranges for serum thyroid tests in children.

Table II.
Analyte Age Reference Range
TSH (mcIU/L) 0 – 2d 1.0 – 20.0
3d – 30d 0.5 – 8.0
31d – 4y 0.5 – 6.0
5y – 12y 0.5 – 5.5
13y + 0.5 – 5.0
T4 (mcg/dL) 0d – 3d 8.0-20.0
4d – 30d 5.0-15.0
31d – 1y 6.0-14.0
2y – 5y 4.5-11.0
6y – 18y 4.5-10.0
19y + 5.5-11.0
Free T4 (ng/dL) 0d – 3d 2.0-5.0
4d – 30d 0.9-2.2
31d – 19y 0.8-2.0
19y + 0.78-2.19
T3 (ng/dL) 0 – 3d 60-300
4d – 1y 90-260
2y – 6y 90-240
7y – 11y 90-230
12y – 18y 100-210
19y + 149-260

*Normal ranges as determined by assessment of laboratory data obtained from >2000 children at Children’s Hospital Colorado

Would imaging studies be helpful? If so, which ones?

Practice variations exist regarding the employment of thyroid imaging in congenital hypothyroidism. Modalities include nuclear medicine imaging (99mTc or 123I) and ultrasound. Scintigraphy is ideal for demonstrating thyroid aplasia (although some infants with normal thyroid glands may demonstrate absent uptake) and ectopic thyroid tissue. Increased uptake on nuclear medicine scan and a large gland are compatible with an inborn error of thyroxine biosynthesis beyond a defect of the TSH receptor. Ultrasound may diagnose absent or enlarged glands but is not accurate in showing ectopic tissue. Treatment of congenital hypothyroidism should not be delayed for imaging.

Arguments against imaging:

Imaging does not change the management course of replacing thyroid hormone and adjusting dosing based on an established monitoring schedule [see below].

Imaging modalities have low sensitivity and are operator dependent.

Arguments in favor of imaging:

Establishing a precise etiology may guide management (affect treatment dosing and monitoring schedule) and help determine disease severity and outcome, particularly early in life.

Imaging may aid in establishing a diagnosis of dyshormonogenesis, which has implications of a 25% recurrent risk in subsequent siblings.

Confirming the diagnosis

Figure 2 gives an algorithm for the diagnosis of congenital hypothyroidism.

Figure 2.

Congenital Hypothyroidism Algorithm

If you are able to confirm that the patient has hypothyroidism, what treatment should be initiated?

1) Permanent congenital hypothyroidism: Treat with replacement levothyroxine (LT4). Levothyroxine tablets should be crushed and mixed in a few drops of formula and applied directly in the mouth. Do not mix the tablet in a bottle of formula because settling may occur. Administration in the presence of soy formula may decrease absorption. Daily dosing is best, but if a dose is missed, a double dose may be given the next day. IV dosing: In the neonate requiring LT4 treatment with NPO orders, IV LT4 may be administered where the dose is equivalent to one-half the PO dose. IV administration is not the ideal route and results in greater inconsistency in serum levels compared with PO dosing.

Table III gives recommendations on age-specific dosing of levothyroxine.

Table III.
Age Daily dose of LT4 (mcg/kg) | (mcg/day) Monitoring (approximates well child visit schedule)
Newborn 10-15 | 25-50 at 1 month
0-5 months 8-10 | 37.5-50 q 2 months
6-12 months 6-7 | ~50 q 2-3 months
1-2 years 4-6 | 50-62.5 q 3 months
3-11 years 3-4 | 50-75 q 6-12 months
12+ years 2-3 | 75-150 q 12 months

*N.B. Great differences exist between individual patients. Some infants may require up to 75 mcg/day, while some teenagers only 25 mcg/day.

2) Transient hypothyroidism:

Sick Euthyroid Syndrome – see section on Management of Thyroid Dysfunction in the Preterm Infant

Hypothyroidism secondary to transplacental passage of maternal anti-thyroid drugs or maternal anti-thyroid antibodies: Anti-thyroid drugs are typically cleared within several days. Monitor thyroid function tests frequently and treat hypothyroidism with LT4 replacement if TSH starts to rise.

3) False hypothyroidism (ex. TBG deficiency, early TSH surge): Recognize that these conditions are normal physiologic states that do not require treatment. Individuals with TBG deficiency will have normal free T4 and TSH levels in the presence of low total T4, total T3, and decreased TBG.

What is the half-life of levothyroxine and how frequently should thyroid tests be obtained while on therapy?

Levothyroxine has a serum half-life of 5 to 7 days and permits the convenience of once daily dosing. Of note, if a dose is missed, administration may be doubled the following day. With adjustments in levothyroxine dosing, thyroid tests should be obtained again in 4 – 6 weeks. TSH is not helpful for monitoring early on, as levels may take months to normalize. The goal of treatment should be to maintain free T4 levels in the high-normal range. After normalization of TSH, subsequent elevations may be used to guide dose adjustments. Monitoring should otherwise be performed according to age-specific guidelines. Because thyroid hormone is critical to infant neurocognitive development within the first 3 years of life, more frequent monitoring is recommended during this time frame.

What is the evaluation and management of Central Hypothyroidism in the neonate?

The objective of newborn screening is to detect primary congenital hypothyroidism; however, evaluation may potentially detect infants with central, or congenital hypopituitary-hypothyroidism.

Laboratory findings in central hypothyroidism are low free T4 with normal or low TSH. Central hypothyroidism commonly occurs in association with other pituitary hormone deficiencies and rarely, as an isolated finding. Symptoms may be the same as those found in primary congenital hypothyroidism. Clinical clues for suspecting pituitary deficiencies include hypoglycemia, prolonged jaundice, micropenis and/or cryptorchidism, suggesting associated deficiencies in growth hormone, adrenocorticotropic hormone (ACTH), and luteinizing hormone (LH). Other midline defects that increase the likelihood of hypopituitarism include cleft lip and/or palate or nystagmus, suggestive of septo-optic dysplasia.

Additional work-up should include a brain MRI to assess for central nervous system disease. Findings may include an ectopic posterior pituitary, hypoplastic pituitary stalk, or anterior pituitary. Infants should also undergo an eye exam by a pediatric ophthalmologist for optic nerve assessment.

What is the management of Central Hypothryoidism?

Levothyroxine doses, in general, may be lower on a weight basis than for primary hypothyroidism. Serum free T4 or T4 should be followed at the same intervals as for primary hypothyroidism [see below]. Treatment goals are similar, aiming to keep free T4 or T4 in the upper range of normal for age. Serum TSH is not helpful for monitoring in central hypothyroidism.

What is the recommended Management of Thyroid Dysfunction in the Preterm Infant?

Thyroid dysfunction is relatively common in premature newborns for several reasons:

1) Preterm infants, especially VLBW infants, have immature hypothalamic-pituitary-thyroid systems.

2) High rates of associated morbidities, such as respiratory distress, cardiac and GI illness, CNS pathology, and sepsis, predispose premature infants to a state of thyroid dysfunction similar to that seen in sick euthyroid syndrome. This can be considered, in essence, a form of transient central hypothyroidism.

3) Preterm infants require higher iodine intake than term infants and, particularly in iodine-deficient regions of the world, there is increased risk for development of transient primary hypothyroidism in the first couple weeks to months of life.

Relative to term infants at birth, the neonatal TSH surge is blunted in preterm infants. Total T4, T3 and TBG concentrations are lower and rT3 levels are higher. fT4 levels are variable within the first 2-4 weeks of life, reach a nadir at 1-2 weeks postnatally, and return to near cord blood values by 3-4 weeks of life. Transient hypothyroxinemia of prematurity (THOP) may be protective from a metabolic standpoint but may have potentially adverse consequences for the developing neonatal brain.

Current trials are underway to determine the long-term benefits, harms, and neurocognitive outcomes of levothyroxine replacement as well as optimal replacement doses. We recommend consideration of levothyroxine replacement, particularly in VLBW infants <28 wks gestational age with persistent hypothyroxinemia lasting >2-3 weeks. Preliminary trials suggest clinical benefit with low dose replacement starting at 4 mcg/kg/day. Concurrent illnesses that may be impacted by a change in the infant’s metabolic state (for example, cardiac dysfunction) should be taken into consideration before starting treatment, and thyroid function studies should be monitored closely to avoid overtreatment.

What are the possible outcomes / prognosis of congenital hypothyroidism?

Congenital hypothyroidism is one of the most common preventable causes of mental retardation in the world, and, when treated, ideally within the first 3 weeks of life, cognitive outcome is excellent. Untreated hypothyroidism is associated with irreversible mental retardation, growth retardation, and the condition known as cretinism. Studies assessing cognitive outcome in pre-school aged children with congenital hypothyroidism have found IQ levels that are inversely proportional to the delay in treatment start.

Are additional laboratory studies available; even some that are not widely available?

  • Direct or Equilibrium Dialysis free T4

    Pros: the most accurate and reliable method currently available for directly measuring free T4.

    Cons: more costly and less widely available than the routine free T4 assay.

  • T3 resin uptake – helps to estimate the availability of thyroid-binding globulin (TBG) and binding proteins in the blood

  • Reverse T3 – levels are elevated at birth and during the first few days of life. Values decrease rapidly to adult range by 1 week of life (10-50 ng/dL). Levels are high in sick euthyroid syndrome.

How can congenital hypothyroidism be prevented?

Worldwide, particularly in India, China, Southeast Asia, and Africa, maternal iodine deficiency remains the most common cause of congenital hypothyroidism and preventable mental retardation. An estimated population of 2.2 billion worldwide are at risk for mental impairment as a result of iodine deficiency. Global organizations are working to address and eliminate this public health problem by increasing the availability and consumption of iodized salt. In the United States, overall iodine intake appears to be sufficient; however, some concerns have been reported about mild deficiencies in pregnant and lactating women. The American Thyroid Association recommends that all pregnant women receive 150 mcg iodine supplements daily while pregnant and lactating.

What is the evidence?

“Update of newborn screening and therapy for congenital hypothyroidism”. Pediatrics. vol. 117. 2006. pp. 2290-303. A review of newborn screening practices for congenital hypothyroidism published by the American Academy of Pediatrics and co-authored by an expert panel on thyroid and pediatric endocrine diseases. This publication contains a detailed algorithm for screening and management, as well as discussion on follow-up and clinical outcomes in children diagnosed with congenital hypothyroidism.

Huang, SA, Kappy, MS, Allen, DB, Geffner, ME. “Thyroid”. Pediatric practice: Endocrinology. 2010. pp. 107-29.. This chapter provides an overview of thyroid disease with a concise summary of the topic of discussion. The chapter is easily readable and tailored to the practicing pediatrician or fellow in training.

LaFranchi, SH, Hanna, CE, Kappy, MS, Allen, DB, Geffner, ME. “The thyroid gland and its disorders”. Principles and practice of pediatric endocrinology. 2005. pp. 284-303. A detailed, comprehensive chapter on thyroid gland development, physiology, thyroid hormone metabolism, and thyroid gland disorders.

La Gamma, EF, van Wassenaer, AG, Ares, S. “Phase 1 trial of 4 thyroid hormone regimens for transient hypothyroxinemia in neonates of <28 weeks' gestation”. Pediatrics.. vol. 124. 2009. pp. e258-68. There is limited evidence to support use of thyroid hormone replacement in preterm infants, with inconclusive data on neonatal mortality, morbidity, and neurodevelopmental outcomes. This preliminary trial sets the grounds for data collection on the safety, potential benefits, and/or detrimental effects of varying thyroid hormone regimens in very low birth weight infants.

Marks, SD. “Nonthyroidal Illness syndrome in children”. Endocrine.. vol. 36. 2009. pp. 355-67. A review examining adult and pediatric literature on nonthyroidal illness syndrome with discussion on pathophysiology and treatment. This article cites evidence for both sides of the argument, debating whether nonthyroidal illness is an adaptive or maladaptive process.

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