Clinical Context

The incidence of congenital hypothyroidism (CH) has risen with increased application of newborn screening (NBS) and more accurate cutoff limits for abnormal values on screening. Congenital hypothyroidism affects between 1 in 2000 to 1 in 4000 births in countries in which NBS results are available. Most cases of CH are due to dysfunction of the thyroid gland or a defect in thyroid hormone synthesis.

The thyroid gland normally begins to form at 3 weeks of gestation and produces thyroid hormone at 10 to 12 weeks of gestation. Maternal thyroxine (T4) crosses the placenta in limited amounts and supports fetal metabolism. Untreated maternal hypothyroidism and maternal iodine deficiency are major risk factors for thyroid-related pathology among infants. However, the use of prenatal vitamins supplies the iodine necessary to support maternal and fetal thyroid function. Congenital hypothyroidism itself is more common among girls vs. boys and among children with trisomy 21.

The current recommendations from the American Academy of Pediatrics (AAP) describe best practices in screening for CH and its management.

Study Synopsis and Perspective

Congenital hypothyroidism is one of the most common preventable causes of intellectual disabilities worldwide, but newborn screening has not been established in all countries. However, screening alone is not enough to prevent adverse outcomes in children, wrote authors of a technical report published online in the January, 2023 issue of Pediatrics.^[1]

Susan R. Rose, MD, with the division of endocrinology at Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio, led the work group that updated guidance for screening and management of CH congenital hypothyroidism. The group worked in conjunction with the American Academy of Pediatrics (AAP) Section on Endocrinology, the AAP Council on Genetics, the Pediatric Endocrine Society, and the American Thyroid Association.

In addition to screening, timely diagnosis, effective treatment, and follow-up are important. Tests do not always tell the full story with CH.

"Physicians need to consider hypothyroidism in the face of clinical symptoms, even if [NBS] thyroid test results are normal," the authors wrote.

They added that NBS for CH followed by prompt levothyroxine (L-T4) therapy can prevent severe intellectual disability, psychomotor dysfunction, and impaired growth.

Incidence of CH ranges from approximately 1 in 2000 to 1 in 4000 newborn infants in countries that have NBS data, according to the report.

Following are highlights of the guidance:

Clinical Signs

Symptoms and signs include large posterior fontanelle, lethargy, large tongue, prolonged jaundice, umbilical hernia, constipation, and/or hypothermia. With these signs, measuring serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) is indicated, regardless of screening results.

Newborn Screening in First Days

Population screening is cost-effective when performed by state or other public health laboratories working with hospitals or birthing centers in their area, the authors wrote.

NBS conducted using a team-based approach promotes comprehensive care and facilitates communication across the care continuum when cases are detected.

The screening includes a dried blood spot from a heel stick on an approved paper card using appropriate collection methods. The blood spots are then sent to the laboratory. The preferred age for collecting the specimen is 48 to 72 hours of age.

That timing may be difficult, the authors noted, as 90% of infants in the United States and Europe are discharged before 48 hours, but taking the specimen before discharge is important to avoid missing the early diagnosis; "however, collection of the NBS specimen before 48 hours of age, and particularly before 24 hours of age, necessitates the use of age-specific TSH reference ranges or repeat screening, particularly to avoid false-positive results," the authors noted.

If a newborn infant is transferred to another hospital, communication about the screening is critical.

Testing Strategies

Three test strategies are used for screening: a primary TSH reflex T4 measurement; primary T4 reflex TSH measurement; and combined T4 and TSH measurement.

"All three test strategies detect moderate to severe primary [CH] with similar accuracy," the authors wrote.

Most newborn screening programs in the United States and worldwide use a primary TSH test strategy.

Multiple Births, Same-Sex Twins

The incidence of CH appears to be higher with multiple births (1:876 in twin births and 1:575 in higher-order multiple births in one study). Another study showed the incidence of CH in same-sex twins to be 1 in 593 compared with 1 in 3060 in different-sex twins.

"Most twin pairs (> 95%) are discordant for [CH]" the authors wrote, "however, in monozygotic twins who share placental circulation, blood from a euthyroid fetal twin with normal thyroid hormone levels may cross to a fetal twin with [CH], temporarily correcting the hypothyroidism and preventing its detection by [NBS] at 24-72 hours of life. Thus, all monozygotic twins, or same-sex twins for whom zygosity is unknown, should undergo repeat [NBS] around 2 weeks of age."

Down Syndrome

Congenital hypothyroidism incidence in infants with trisomy 21 (Down syndrome) is high and ranges from 1% to 12% in various reports. The infants tend to have lower T4 concentrations and higher TSH concentrations than do infants without trisomy. Down syndrome is associated with other comorbidities, including congenital heart disease, "that may further increase the risk of abnormal [NBS] results because of acute illness or excess iodine exposure," the authors wrote.

Even infants with Down syndrome who do not have CH are still at significant risk of developing primary hypothyroidism in their first year (≈ 7% in one prospective study).

"Therefore, in these infants, a second [NBS] should be performed at 2-4 weeks of life and serum TSH should be measured at 6 and 12 months of life," the authors said.

Communication With Primary Care Provider

Direct communication between the [NBS] program and the primary care clinician is important for appropriate follow-up. Consulting a pediatric endocrinologist can speed diagnosis and management.

Serum Confirmation After Abnormal Screening

The next step if any child's screening results suggest CH is to perform a physical exam (for goiter, lingual thyroid gland, and/or physical signs of hypothyroidism) and to measure the concentrations of TSH and FT4 (or total T4) in the blood.

For confirmation of abnormal screening results, the authors said, measurement of FT4 is preferred over measuring total T4.

Interpreting Serum Confirmation

Some interpretations are clear cut: "Elevated TSH with low FT4 on the confirmatory serum testing indicates overt primary hypothyroidism," the authors wrote, but there are various other outcomes with more controversy.

Elevated TSH and normal FT4, for instance, is known as hyperthyrotropinemia, or subclinical hypothyroidism, and represents a mild primary thyroid abnormality.

In this scenario, there is controversy regarding the need for L-T4 therapy because there are few and conflicting studies regarding how mild CH affects cognitive development.

"[E]xpert opinion suggests that persistent TSH elevation > 10 mIU/L is an indication to initiate L-T4 treatment," the authors wrote.

Normal TSH and low T4 is seen in patients with central hypothyroidism, prematurity, low birth weight, acute illness, or thyroxine-binding globulin deficiency.

Imaging

Routine thyroid imaging is controversial for patients with CH. In most cases, it will not alter clinical management before age 3 years.

Thyroid ultrasonography can find thyroid tissue without radiation exposure and can be performed at any time after a CH diagnosis.

"Ultrasonography has lower sensitivity than scintigraphy for detecting ectopic thyroid tissue, the most common cause of [CH], although its sensitivity is improved by the use of color Doppler," the authors wrote.

Infants with normal thyroid imaging at birth may have transient hypothyroidism. In these patients, reevaluation of thyroid hormone therapy after 3 years of age to assess for persistent hypothyroidism may be beneficial.

Treatment

Congenital hypothyroidism is treated with enteral L-T4 at a starting dose of 10 to 15 µg/kg/d, given once a day.

L-T4 tablets are the treatment of choice, and generic tablets are fine for most children, the authors wrote, adding that use of a brand name formulation may be superior to provide a consistent formulation for children with severe CH.

The FDA has approved an oral solution of L-T4 for use in children; "however, limited experience with its use showed that dosing may not be equivalent to dosing with tablet formulations," the guidance states.

The goal of initial L-T4 therapy is to normalize serum FT4 and TSH levels as quickly as possible. The outlook is poorer for infants whose hypothyroidism is detected later in life, who receive inadequate doses of L-T4, or who have more severe forms.

Age-specific TSH reference ranges vary by laboratory, but recent studies indicate the top limit of normal TSH in infants in the first 3 months of life is 4.1 to 4.8 mIU/L; "therefore, TSH values above 5 mIU/L generally are abnormal if observed after 3 months of age. Whether overtreatment (defined by elevated serum FT4) is harmful remains unclear and evidence is conflicting," the authors wrote.

Monitoring

In the near-term follow-up, close laboratory monitoring is necessary during L-T4 treatment to maintain blood TSH and FT4 in the target ranges. Studies support measuring those levels every 1 to 2 months in the first 6 months of life for children with CH, every 2 to 3 months in the second 6 months, and then every 3 to 4 months between the ages of 1 and 3 years.

In long-term follow-up, attention to behavioral and cognitive development is important, because children with CH may be at higher risk for neurocognitive and socioemotional dysfunction compared with their peers, even with adequate treatment of CH. Hearing deficits are reported in about 10% of children with CH.

Developmental Outcomes

When L-T4 therapy is maintained and TSH and FT4 are within target range, growth and adult height are generally normal in children with CH.

In contrast, the neurodevelopmental prognosis is less certain when treatment starts late.

"[I]nfants with severe [CH] and intrauterine hypothyroidism (as indicated by retarded skeletal maturation at birth) may have low-to-normal intelligence," the report stated.

If a child is properly treated for CH but growth or development is abnormal, testing for other illness, hearing deficit, or other hormone deficiency is needed, the report stated.

The authors report no relevant financial relationships.

Pediatrics. 2023;151:e2022060420.^[1]

Clinical Implications

• NBS for CH may include both TSH and FT4 or one test followed by the other in case of an abnormal result. Ideally, NBS should occur at 48 to 72 hours after delivery, but a sample should still be taken among infants discharged earlier. Abnormal NBS should prompt evaluation with a serum TSH and FT4.
• The preferred treatment for CH is enteral L-T4 starting at a dose of 10 to 15 µg/kg once daily. Generally, TSH and FT4 should be measured every 1 to 2 months during the first 6 months of life, then every 2 to 3 months during the second 6 months of life, and then every 3 to 4 months between ages 1 and 3 years. Most children with CH can undergo a trial without L-T4 at age 3 years, with re-initiation of treatment if thyroid levels remain abnormal.
• Implications for the healthcare team: The healthcare team should work together to ensure the broad application of NBS for CH as well as appropriate follow-up for children with CH to prevent complications of disease.

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