For issues related to acquired hypothyroidism, please see the separate chapter on page 16.
Basics
Description
Primary thyroid failure present at birth
Epidemiology
- Increasing trend in the United States
- Unclear etiology (definitional issues related to newborn screening vs. true increase from unidentified risk factors)
- Had been 1 in 3,000-4,000 births, United States and worldwide
- In 2007, U.S. incidence 1 in 2,370 births
- Male-to-female ratio is 1:2-1:3.
- 80% dysgenesis or agenesis; 20% dyshormonogenesis
- Racial differences: prevalence in African American infants ~1/3 that in whites
- Higher prevalence of congenital hypothyroidism in low-birth-weight (>2,000 g) and macrosomic (≥4,500 g) babies
Risk Factors
Genetics
- Dysgenesis is usually sporadic.
- Familial occurrence in 2%
- Mutations have been found in the TSH-receptor gene and in the transcription factors PAX-8, TTF-1, and TTF-2 (FOXE1).
- Dyshormonogenesis is inherited in an autosomal recessive pattern. Most commonly
- Chromosome 2p: Mutations in the thyroid peroxidase gene result in partial or complete loss of iodide organification.
- Chromosome 19p: Mutations in the sodium-iodide symporter gene result in an inability to maintain the normal thyroid-to-plasma iodine concentration difference.
- Pendred syndrome (chromosome 7q): Mutations in PDS gene cause the most common syndromal form of deafness; a mild organification defect leads to goiter, usually in childhood.
Etiology
- Thyroid gland malformation
- Agenesis: absent thyroid gland
- Dysgenesis: ectopic (e.g., sublingual) or incorrectly formed (e.g., hemigland) thyroid
- Dyshormonogenesis
- 15 known defects of thyroxine (T4) synthesis, including those in iodide transport and iodide organification
- Transient hypothyroidism
- Maternal ingestion of antithyroid drugs
- Transplacental transfer of maternal antithyroid antibodies (transient or permanent damage)
- Exposure to high levels of iodine-povidone, (i.e., Pyodine, Betadine) in neonatal period
Commonly Associated Conditions
- Down syndrome neonates have lower T4 (left-shifted normal distribution) and mildly elevated TSH, suggesting a mild hypothyroid state.
- Newborns with congenital hypothyroidism have an increased risk for congenital heart defects, and vice versa (common embryologic developmental program).
Diagnosis
History
- Symptoms that may relate to hypothyroidism:
- Prolonged jaundice
- Poor feeding
- Constipation
- Sedate or placid child
- Poor linear growth
- Family history of thyroid disorders
- Autoimmune thyroid disease
- Vague histories of "mild hypothyroidism" not requiring treatment are often found in families with thyroid-binding globulin deficiency.
- Maternal medications
- Birth history
- Results of the newborn screen
- Signs and symptoms:
- Most children are diagnosed by the neonatal screening program:
- 5-10% false-negative rate
- Neonatal screening protocols differ state to state (i.e., may screen TSH, T4, or both).
- In severely ill neonates transferred from 1 unit or hospital to another, be sure the state screen has been performed and not overlooked. If missed by the state screening procedure, the symptoms above are seen within the 1st 2 months of life.
Physical Exam
- Signs that may relate to hypothyroidism:
- Hypothermia
- Large fontanelles (especially posterior) with wide cranial sutures
- Coarse facial features, including macroglossia
- Hoarse cry
- Hypotonia
- Delayed deep tendon reflex release
- Distended abdomen
- Umbilical hernia
- Examine for possible goiter; helpful pearls
- Inspect the base of tongue for ectopic gland.
- While supporting the posterior neck and occiput, allow the infant's head to hang back over a parent's arm or exam table. This will extend the neck and allow better visualization of the anterior region.
Diagnostic Tests & Interpretation
Lab
- Neonatal screening program (filter card)
- Methods vary from state to state (screen for T4 or TSH); primary TSH screening plus serial testing for infants at risk for later rising TSH shown to outperform other strategies.
- Abnormal results on state screen should prompt immediate examination and confirmatory tests.
- Because of delayed TSH elevations, very low-birth-weight babies and those with congenital cardiac anomalies may need rescreening for diagnosis.
- Confirmatory tests:
- Serum T4 and TSH are preferable to a repeated filter screen, which may result in delayed diagnosis and treatment.
- If abnormalities in binding are suspected, also check thyroid-binding globulin level and free T4 concentration or triiodothyronine (T3) resin uptake.
- Free T4 is the most sensitive indicator of secondary or tertiary hypothyroidism (hypopituitarism).
- Antenatal tests
- Fetal goiter can be detected by prenatal ultrasound.
- Reference ranges for 3rd trimester amniotic fluid concentrations of TSH and total and free T4 are established for diagnosis of fetal hypothyroidism among those with goiters. Otherwise, cordocentesis is needed.
Imaging
- 123I or technetium thyroid scan to define gland anatomy (agenesis, dysgenesis, ectopic gland)
- 123I scan with perchlorate washout to help identify dyshormonogenesis
- 123I scan must be obtained before beginning thyroxine replacement therapy. If this delays treatment, defer scanning until brain growth is complete (2 years of age), when a period off medication is safer.
- Ultrasonography can also evaluate thyroid anatomy (but not dyshormonogenesis) and does not require deferral of treatment.
Differential Diagnosis
- Developmental
- Transient hypothyroxinemia in the 1st weeks of life in premature babies
- Metabolic
- Sick euthyroid syndrome in severely ill neonates
- Secondary or tertiary
- Panhypopituitarism
- Congenital isolated central hypothyroidism (a "hot spot" mutation in the TSH-β gene)
- Central congenital hypothyroidism due to maternal Graves disease during pregnancy (estimated incidence 1:35,000; thought to indicate impaired maturation of the fetal hypothalamic-pituitary-thyroid system from a hyperthyroid fetal environment)
- Genetic
- Thyroid-binding globulin deficiency (X-linked recessive)
- Environmental
- Iodine exposure (e.g., delivery by cesarean section, surgery in the neonatal period)
- Maternal iodine deficiency (American Thyroid Association recommends pregnant and lactating women to take prenatal vitamins containing 150 mcg of iodine daily.)
- Maternal use of antithyroid drugs or lithium
- Immunologic
- Transfer of maternal antithyroid and TSH receptor-blocking antibodies
Alert
False positives
- X-linked thyroid-binding globulin deficiency: low total T4, normal TSH, and normal free T4. Diagnose with low thyroid-binding globulin level or high T3 resin uptake. No treatment is necessary!
- Panhypopituitarism: low T4 and low or low-normal TSH (i.e., loss of the negative feedback loop). Screen with free T4. Treat with l-thyroxine as for primary hypothyroidism, and investigate for other pituitary hormone deficiencies.
- Blood specimens obtained before 48 hours of life may have "elevated" TSH as a result of the normal postnatal surge.
False negatives
- Normal newborn screening can be falsely reassuring in babies with congenital central hypothyroidism.
Treatment
Medication
Levothyroxine
- Start at 10-15 mcg/kg/24 hr PO once a day. Titer dose to keep T4 in the upper range of normal.
- TSH levels may not normalize for several weeks even with good T4 values.
- Starting dose of 50 mcg PO daily (12-17 mcg/kg/24 hr) may provide more rapid normalization (free T4 by 3 days and TSH by 2 weeks).
- A minority of infants have variable pituitary-thyroid hormone resistance, with relatively elevated serum levels of TSH for their free T4 that improves with age.
- Duration: lifelong
- If medication is started without imaging studies and diagnosis is not clear, can stop levothyroxine after completion of early brain growth (2-3 years of age). Reevaluate need for supplementation after a 6-week trial off therapy.
Ongoing Care
Follow-up Recommendations
- When to expect improvement:
- Most children are asymptomatic at diagnosis.
- Parents may note an increase in activity, improvement in feeding, and increase in urination and bowel movements soon after starting treatment.
- Signs to watch for: Poor growth and low T4 and elevated TSH values suggest poor compliance or undertreatment.
- Neuropsychological sequelae:
- IQ scores are predominantly in the normal range, but subtle impairments in language and motor skills and specific learning disabilities may occur despite early treatment.
- Neurocognitive evaluation and rehabilitation should be provided.
- Maternal hypothyroxinemia during early gestation can lead to neurodevelopmental delays if not corrected during pregnancy.
Diet
- No restrictions
- Soybean flour (as in some formulas) and iron can decrease gastrointestinal absorption of levothyroxine.
- Pharmacies in recent years have been recommending that levothyroxine be administered on an empty stomach. The Drugs and Therapeutics Committee of the Pediatric Endocrine Society recommended that consistency in administration, coupled with regular dose titration to thyroid function tests, is more important than improving absorption by restricting intake to only times of empty stomach.
Patient Education
- Whether the child has learning disabilities related to hypothyroidism depends on when the diagnosis was made and how quickly treatment was started. There may be an increase in learning disabilities when compared with siblings, even in patients treated within the 1st 4 weeks of life.
- If a dose of levothyroxine is forgotten, it should be given as soon as it is remembered. If it is the next day, 2 doses should be given.
- Levothyroxine is available only in tablet form. The tablet should be crushed between 2 spoons and the powder dissolved in a small amount of formula or breast milk and offered to the baby at the start of a feeding to ensure complete ingestion.
- There are no side effects from the medication. The tablet contains only the hormone that the child's thyroid is not making. It is synthetically produced, so there are no infectious risks.
Prognosis
- Excellent, if treatment is started within the 1st 2 weeks of life
- Level of T4 at birth is an important indicator of long-term sequelae.
Complications
- If untreated:
- Severe mental retardation (cretinism)
- Poor motor development
- Poor growth
- Children with hypothyroidism as part of hypopituitarism do not seem to be as significantly affected by their low thyroid hormone levels as do those with primary hypothyroidism.
Additional Reading
- American Academy of Pediatrics, Rose SR, American Thyroid Association, Brown RS, et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics. 2006;117(6):2290-2303. [View Abstract]
- Delahunty C, Falconer S, Hume R, et al. Levels of neonatal thyroid hormone in preterm infants and neurodevelopmental outcome at 51/2 years: millennium cohort study. J Clin Endocrinol Metab. 2010;95(11):4898-4908. [View Abstract]
- Fu J, Jiang Y, Liang L, et al. Risk factors of primary thyroid dysfunction in early infants born to mothers with autoimmune thyroid disease. Acta Paediatr. 2005;94(8):1043-1048. [View Abstract]
- Gr ¼ters A, Krude H. Detection and treatment of congenital hypothyroidism. Nat Rev Endocrinol. 2011;8(2):104-113. [View Abstract]
- Kempers MJ, Ozgen HM, Vulsma T, et al. Morphological abnormalities in children with thyroidal congenital hypothyroidism. Am J Med Genet A. 2009;149A(5):943-951. [View Abstract]
- Korzeniewski SJ, Grigorescu V, Kleyn M, et al. Performance metrics after changes in screening protocol for congenital hypothyroidism. Pediatrics. 2012;130(5):e1252-e1260. [View Abstract]
- Larson C, Hermos R, Delaney A, et al. Risk factors associated with delayed thyrotropin elevations in congenital hypothyroidism. J Pediatr. 2003;143(5):587-591. [View Abstract]
- Leung AM, Pearce EN, Braverman LE. Iodine content of prenatal multivitamins in the United States. N Engl J Med. 2009;360(9):939-940. [View Abstract]
- Nebesio TD, McKenna MP, Nabhan ZM, et al. Newborn screening results in children with central hypothyroidism. J Pediatr. 2010;156(6):990-993. [View Abstract]
- Ng SM, Anand D, Weindling AM. High versus low dose of initial thyroid hormone replacement for congenital hypothyroidism. Cochrane Database Syst Rev. 2009;(1):CD006972. [View Abstract]
- Olney RS, Grosse SD, Vogt RF Jr. Prevalence of congenital hypothyroidism-current trends and future directions: workshop summary. Pediatrics. 2010;125(Suppl 2):S31-S36. [View Abstract]
- Passeri E, Frigerio M, De Filippis T, et al. Increased risk for non-autoimmune hypothyroidism in young patients with congenital heart defects. J Clin Endocrinol Metab. 2011;96(7):E1115-E1119. [View Abstract]
- Raymond J, LaFranchi SH. Fetal and neonatal thyroid function: review and summary of significant new findings. Curr Opin Endocrinol Diabetes Obes. 2010;17(1):1-7. [View Abstract]
Codes
ICD09
- 243 Congenital hypothyroidism
ICD10
- E03.1 Congenital hypothyroidism without goiter
- E03.0 Congenital hypothyroidism with diffuse goiter
SNOMED
- 190268003 Congenital hypothyroidism (disorder)
- 278503003 Congenital hypothyroidism with diffuse goiter (disorder)
- 237515009 Congenital hypothyroidism without goiter (disorder)
FAQ
- Q: What are some of the reasons that a normal newborn may have an abnormal thyroid screen?
- A: Blood tests obtained prior to 48 hours of age may have an elevated TSH from newborn surge; some states (for quality control) will ask to have a certain percentage of tests repeated, even though they are normal.