Chemistry
Thyroid related
Screening - neonatal hypothyroidism

Author: Andrey Bychkov, M.D., Ph.D. (see Authors page)

Revised: 16 August 2016, last major update August 2016

Copyright: (c) 2002-2016, PathologyOutlines.com, Inc.

PubMed Search: Screening [title] neonatal hypothyroidism

See also: Aplasia / hypoplasia, Congenital hypothyroidism, Dyshormonogenetic goiter

Definition / General
  • Congenital hypothyroidism is the most common congenital endocrine / metabolic disorder, with an estimated prevalence of 1 per 1,600 to 3,500 newborn infants (for TSH cutoffs of 10 and 20 mU/L, respectively)
  • Screening for neonatal hypothyroidism was established on a worldwide basis in the 1970s, now it is acclaimed as the most successful pediatric screening test, which approaches a cost to benefit ratio of 10:1 (J Clin Endocrinol Metab 1999;84:4332)
    • Screening for neonatal hypothyroidism is a part of a newborn screening blood test panel for congenital disorders including phenylketonuria, congenital adrenal hyperplasia, cystic fibrosis and others (from 2 to 40 conditions, depending on country / state)
    • Congenital hypothyroidism screening is most efficient in countries without iodine deficiency
    • Screening is not widely adopted in countries with moderate to severe iodine deficiency, where efforts should be made to supply sufficient iodine to the population
    • Only 25% of babies are born in countries with newborn screening programs in place; for the other 75%, diagnosis is made when development of clinical features prompts thyroid function testing (Orphanet J Rare Dis 2010;5:17)
  • The major effect of screening for congenital hypothyroidism is that it allows treatment to be started much earlier than in infants diagnosed on the basis of clinical findings, preventing severe intellectual disability (Braverman, Cooper: Werner & Ingbar's The Thyroid, Tenth Edition, 2012)
  • Clinical guidelines on screening were issued in the USA (Pediatrics 2006;117:2290) and Europe (J Clin Endocrinol Metab 2014;99:363)
Terminology
  • Congenital hypothyroidism = neonatal or fetal hypothyroidism
  • Congenital hypothyroidism is permanent if the absent, ectopic or dyshormonogenetic thyroid gland is confirmed by thyroid imaging and ancillary studies, or if at any time during the first year of life serum TSH rises above 20 mU/L presumably due to insufficient T4 replacement (Pediatrics 2006;117:2290, Orphanet J Rare Dis 2010;5:17)
Epidemiology
Pathophysiology / Etiology
  • Thyroid dysgenesis and dyshormonogenesis (prevalence ratio 5:1) are the two main causes of congenital hypothyroidism
  • See details on mechanism in aplasia and dyshormonogenetic goiter topics
  • Less frequent causes, usually of transient hypothyroidism, are transplacental passage of maternal antithyroid drugs, maternal blocking antibodies, iodine deficiency or excess and germline mutations in the TSH receptor
  • Central congenital hypothyroidism (pituitary or hypothalamic) is much rarer, incidence is 1:25,000 to 1:100,000 births
Diagrams / Tables

Images hosted on other servers:

Diagnostic algorithm full

Diagnostic algorithm simplified

Classification of congenital hypothyroidism

Thyroid imaging and serum Tg in congenital hypothyroidism



Reference ranges

Genetic screening

Genetic diagnosis

Pregnancy and fetal hypothyroidism

Heel stick diagram

Clinical Features
If no laboratory screening:
  • Signs of clinically evident congenital hypothyroidism: jaundice, lethargy, hypothermia, constipation, macroglossia, poor feeding, hoarse cry, wide posterior fontanel
  • However, in > 95% of infants, signs are often subtle and not present at birth, because newborn continues to be protected by maternal hormones for 3 - 4 weeks
  • Growth and developmental delay are usually apparent by 4 - 6 months
  • Extrathyroidal congenital abnormalities (heart malformations and facial dysmorphism) can be a part of syndromic congenital hypothyroididsm
Laboratory
Methodology
  • Routinely performed on all newborns
    • Every infant should be tested before discharge from the nursery, optimally by 2 to 4 days of age
    • Specimens collected in the first 24 to 48 hours of life may lead to false positive TSH elevations when using any screening test approach
  • Use dry blood spots to measure both T4 and TSH
    • TSH alone screening is common in Europe and Japan due to higher cost effectiveness
    • Cord blood is rarely used because of mixing with maternal blood and logistics (J Clin Endocrinol Metab 2002;87:4072)
  • If measure only TSH (checking for values of 10 mU/L or higher), have false positives from premature or severely stressed infants and miss infants with hypothalamic or pituitary disease (J Clin Res Pediatr Endocrinol 2013;5:8)
  • If measure only T4 (checking for low values), have high false positive rate due to prematurity or congenital absence of thyroid binding globulin, and miss patients with elevated TSH but normal T4
  • It is recommended that screening should be conducted in centralized laboratories under external quality control programs, covering 50,000 - 100,000 newborns per year (Paediatric Thyroidology Endocr Dev 2014;26:44)

Algorithm
  • TSH less than 10 mU/L: no further action for newborns
  • TSH 10 - 20 mU/L: retest at 2 - 6 weeks
  • TSH > 20 mU/L: endocrine workup needed
  • Preterm and low birth weight infants (J Med Screen 2005;12:166), twins (An Pediatr (Barc) 2006;65:129), and all neonates admitted to an intensive care unit should be retested at 2 weeks

Actions if TSH is high
  • Immediate recall for further workup, usually via family doctor or direct contact with further referral to pediatric endocrinology center
    • Many screening programs achieve recall in 8 to 14 days, which allows median treatment age of 14 days
  • Rapid TSH and free T4 measurement in a new venous blood sample
    • Serum free T4 is used to stratify hypothyroidism as biochemically severe, moderate and mild (< 5, 5 to < 10, and 10 to 15 pmol/l, respectively)
  • Immediate hormone replacement therapy
  • Thyroid imaging studies including scintiscan, sonography and knee Xray
  • After initiation of therapy, the usual recommendation is to monitor TSH and T4 levels at weekly intervals for 1 month, at monthly intervals for 3 months, followed by a continuous followup every 3 months during the first 2 years of life and later every 6 months (Nat Rev Endocrinol 2011;8:104)
  • Genetic workup is optional
Radiology Description
Prognostic Factors
  • Early diagnosis and treatment (not later than 3 months of age, optimally within 2 weeks) of hypothyroidism are critical to prevent intellectual disability / mental retardation
  • Mean IQ of children with congenital hypothyroidism before neonatal screening was 86, which has been improved to 95 - 105 (control IQ = 110) in the current screening era (Arch Dis Child 2011;96:374)
Case Reports
Treatment
  • T4 treatment should be started immediately if the results of screening are frankly abnormal (TSH > 30 - 40 mU/L), and any delay in obtaining results of the confirmatory serum or scintigraphy tests should not delay treatment (Braverman, Cooper: Werner & Ingbar's The Thyroid, Tenth Edition, 2012)
  • Use single, daily dose (10 to 15 μg / kg) of oral levothyroxine; avoid mixing with soy (Arch Dis Child 2004;89:37, Endocr Pract 2001;7:193) or iron (South Med J 1997;90:637)
  • The goal of therapy is to normalize T4 within 2 weeks and TSH within 1 month
  • May be discontinued after 3 years of age if hypothyroidism was proven to be transient
    • If no permanent cause of hypothyroidism was found by scan (aplasia / ectopia) or there was no TSH increase after the newborn period, then T4 administration should be discontinued for 30 days at some point after the child is 3 years of age
    • If the FT4 and TSH concentrations remain in the reference range, euthyroidism is assumed and a diagnosis of transient hypothyroidism recorded
Molecular / Cytogenetics Description