Congenital hypothyroidism is one of the most common preventable causes of intellectual disabilities worldwide, but newborn screening has not been established in all countries.
Additionally, screening alone is not enough to prevent adverse outcomes in children, write authors of a technical report published online in Pediatrics (Jan. 2023;151[1]:e2022060420).
Susan R. Rose, MD, with the division of endocrinology at Cincinnati Children’s Hospital Medical Center in Ohio, led the work group that updated guidance for screening and management of congenital hypothyroidism. The group worked in conjunction with the American Academy of Pediatrics 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 don’t always tell the full story with congenital hypothyroidism.
“Physicians need to consider hypothyroidism in the face of clinical symptoms, even if newborn screening thyroid test results are normal,” the authors write.
They add that newborn screening for congenital hypothyroidism followed by prompt levothyroxine therapy can prevent severe intellectual disability, psychomotor dysfunction, and impaired growth.
Incidence of congenital hypothyroidism ranges from approximately 1 in 2,000 to 1 in 4,000 newborn infants in countries that have newborn screening 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 write.
Multidisciplinary teams are best able to conduct comprehensive care 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 48-72 hours of age.
That timing may be difficult, the authors note, 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 [newborn screening] 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 note.
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 congenital hypothyroidism with similar accuracy,” the authors write.
Most newborn screening programs in the United States and worldwide use a primary TSH test strategy.
Multiple births, same-sex twins
The incidence of congenital hypothyroidism 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 congenital hypothyroidism in same-sex twins to be 1 in 593, compared with 1 in 3,060 in different-sex twins.
“Most twin pairs (> 95%) are discordant for congenital hypothyroidism,” the authors write. “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 congenital hypothyroidism, temporarily correcting the hypothyroidism and preventing its detection by newborn screening at 24-72 hours of life. Thus, all monozygotic twins, or same-sex twins for whom zygosity is unknown, should undergo repeat newborn screening 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 newborn screening results because of acute illness or excess iodine exposure,” the authors write.
Even infants with Down syndrome who don’t have congenital hypothyroidism are still at significant risk of developing primary hypothyroidism in their first year (approximately 7% in one prospective study).
“Therefore, in these infants, a second newborn screening should be performed at 2-4 weeks of life and serum TSH should be measured at 6 and 12 months of life,” the authors say.
Communication with primary care provider
Direct communication between the newborn screening program and the primary care physician 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 congenital hypothyroidism 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 say, 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 write.
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 congenital hypothyroidism affects cognitive development.
“[E]xpert opinion suggests that persistent TSH elevation > 10 mIU/L is an indication to initiate L-T4 treatment,” the authors write.
Normal TSH and low T4 is seen in patients with central hypothyroidism, prematurity, low birth weight, acute illness, or thyroxine-binding globulin deficiency.
“The concept that central hypothyroidism is usually mild appears unfounded: A study from the Netherlands found that mean pretreatment serum FT4 levels in central congenital hypothyroidism were similar to those of patients with moderately severe primary congenital hypothyroidism. Therefore, L-T4 treatment of central congenital hypothyroidism is indicated.”
Imaging
Routine thyroid imaging is controversial for patients with congenital hypothyroidism. In most cases, it won’t 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 congenital hypothyroidism diagnosis.
“Ultrasonography has lower sensitivity than scintigraphy for detecting ectopic thyroid tissue, the most common cause of congenital hypothyroidism, although its sensitivity is improved by the use of color Doppler,” the authors write.
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 10-15 mcg/kg per day, given once a day.
L-T4 tablets are the treatment of choice and generic tablets are fine for most children, the authors write, adding that a brand name formulation may be more consistent and better for children with severe congenital hypothyroidism.
An oral solution of L-T4 has been approved by the U.S. Food and Drug Administration for use in children.
“[H]owever, 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 4.1-4.8 mIU/L.
“[T]herefore, 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 write.
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 1-2 months in the first 6 months of life for children with congenital hypothyroidism, every 2-3 months in the second 6 months, and then every 3-4 months between 1 and 3 years of age.
In long-term follow-up, attention to behavioral and cognitive development is important, because children with congenital hypothyroidism may be at higher risk for neurocognitive and socioemotional dysfunction compared with their peers, even with adequate treatment of congenital hypothyroidism. Hearing deficits are reported in about 10% of children with congenital hypothyroidism.
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 congenital hypothyroidism.
In contrast, the neurodevelopmental prognosis is less certain when treatment starts late.
“[I]nfants with severe congenital hypothyroidism and intrauterine hypothyroidism (as indicated by retarded skeletal maturation at birth) may have low-to-normal intelligence,” the report states. “Similarly, although more than 80% of infants given L-T4 replacement therapy before 3 months of age have an intelligence [quotient] greater than 85, 77% of these infants show signs of cognitive impairment in arithmetic ability, speech, or fine motor coordination later in life.”
If a child is properly treated for congenital hypothyroidism but growth or development is abnormal, testing for other illness, hearing deficit, or other hormone deficiency is needed, the report states.
The authors report no relevant financial relationships.