Congenital Hypothyroidism

Background

• Congenital hypothyroidism is a hypometabolic state due to deficiency of, reduced activity of, or resistance to thyroid hormone.
• Congenital disease may be caused by dysgenesis of the thyroid gland, dyshormonogenesis, hypothalamic-pituitary dysfunction, or transitory causes such as illness, prematurity, iodine deficiency or excess, or maternal antibodies.
• Congenital disease may be associated with other congenital abnormalities, especially cardiac and hypothalamic-pituitary abnormalities.
• Most neonates present with no clinical manifestations at birth, but they usually have abnormal findings on their neonatal thyroid screening test.
• Symptomatic neonates or infants may present with jaundice, umbilical hernia, wide anterior fontanelle, noisy respirations, hypotonia, decreased deep tendon reflexes, lethargy, poor feeding, poor weight gain, or a hoarse cry.
• Children may present with dry skin, growth failure, fatigue, cold intolerance, constipation, developmental delay or learning difficulties, weight gain, or goiter.

Evaluation

• All infants should be screened for congenital hypothyroidism.
  • The American Academy of Pediatrics recommends screening:
    • within 2-4 days of a normal hospital delivery
    • within 7 days of a neonatal intensive care unit (NICU) or preterm home delivery
    • immediately from umbilical cord blood if either a maternal thyroid disorder or drug exposure is present, or there is a family history of congenital hypothyroidism
  • Combination screening with both thyroid-stimulating hormone (TSH) and thyroxine (T4) is ideal, but it is not universally done; T4 with TSH back-up or initial TSH testing as an alternative is performed by some clinicians.
  • The European Reference Network on Rare Endocrine Conditions (ENDO-ERN) recommends:
    • TSH screening for detection of primary congenital hypothyroidism (Strong recommendation)
    • considering adding total or free T4 for detection of central congenital hypothyroidism (Weak recommendation)
• If the screening shows low T4 (< 10 mcg/dL [128.7 nmol/L]) or serum TSH > 10 milliunits/L, check the back-up screening test if it was not done previously, since these results are consistent with primary congenital hypothyroidism.
  • Perform serum free T4 and TSH as soon as possible in newborns with low T4 and TSH > 40 milliunits/L.
  • Repeat capillary screening in newborns with low T4 and TSH 11-40 milliunits/L and perform serum free T4 and TSH testing as soon as possible if abnormal or at age 2-6 weeks if normal.
• In newborns with low T4 and TSH ≤ 10 milliunits/L:
  • These results are concerning for central hypothyroidism, but can also be seen in hypothyroxinemia of prematurity or nonthyroidal illness syndrome (sick thyroid syndrome).
  • Perform serum free T4 and TSH as soon as possible in symptomatic newborns.
  • Perform serum free T4 and TSH in 1-2 weeks if otherwise normal or in 2 weeks if there is low birth weight, very low birth weight, prematurity, or illness present.
  • If neonate is symptomatic or abnormal results present on serum testing:
    • perform pituitary screening with growth hormone (GH), adrenocorticotrophic hormone (ACTH) and cortisol, and antidiuretic hormone (ADH) to test hypothalamic-pituitary function if TSH and T4 remain abnormally low
• In newborns with low T4 and normal TSH:
  • check serum free T4
  • consider checking thyroxine-binding globulin (TBG) to rule out TBG deficiency
• In newborns with normal T4 and elevated TSH:
  • these results may suggest transient hypothyroidism, mild congenital hypothyroidism, delayed maturation of hypothalamic pituitary axis, prolonged birth surge of TSH and T4, or thyroid hormone resistance
  • check serum TSH and free T4 at 2-4 weeks
• Screen for thyrotropin receptor-blocking antibodies in the neonate and birthing parent if there is infant hypothyroidism with a history of maternal autoimmune thyroid disorder or a previously affected infant.
• Imaging with thyroid ultrasound and thyroid radionuclide uptake scan may be done.
  • European Reference Network on Rare Endocrine Conditions (ENDO-ERN) recommendations:
    • perform either or both to assess severity and cause of congenital hypothyroidism (Strong recommendation)
    • obtain both in newborns with low T4 or high TSH (Strong recommendation)
    • consider in newborns ≥ 21 days old with normal T4 and TSH 6-20 milliunits/L and no symptoms or risk factors
  • The American Academy of Pediatrics considers imaging optional.
  • The results of imaging are sometimes helpful in establishing the etiology of congenital hypothyroidism and can aid in long-term management.

Management

• Prescribe levothyroxine for treatment of all causes of hypothyroidism.
  • Consider avoiding switches between levothyroxine products.
  • Consider using a brand name, especially in infants and/or severe cases.
  • Begin levothyroxine 10-15 mcg/kg/day orally:
    • immediately if screening tests show T4 < 10 mcg/dL and TSH > 40 milliunits/L, even before repeat confirmatory testing returns
    • when follow-up testing or clinical symptoms confirm hypothyroidism, including for transient and subclinical hypothyroidism
  • Check thyroid function tests 1-4 weeks after initiating the treatment and continue to monitor at intervals based on age.
  • Adjust dose as needed to maintain free T4 in the upper half of an age-appropriate reference range and TSH between 0.5 and 2 milliunits/L for 3 years, after which T4 and TSH can be maintained at age-appropriate norms.
• Reassess thyroid function around age 3 years if no clear cause for congenital hypothyroidism was found and/or levothyroxine dose has not increased since infancy.