Purpose and Goal: CNEP #2005

  • Learn about the symptoms of congenital hypothyroidism.
  • Understand the benefits of treating hypothyroidism in the NICU.

None of the planners, faculty or content specialists has any conflict of interest or will be presenting any off-label product use. This presentation has no commercial support or sponsorship, nor is it co-sponsored.

Requirements for successful completion:

  • Successfully complete the post-test.
  • Complete the evaluation form.

Date

  • April 2015 – April 2017

Learning Objectives

  • Describe the causes of congenital hypothyroidism.
  • Describe the clinical presentation of congenital hypothyroidism.
  • Identify at least two approaches to the treatment of congenital hypothyroidism in the NICU.

Introduction

  • Congenital hypothyroidism (CH) is present at birth
  • It is one of the most common causes of mental retardation
  • There are considerable regional and ethnic variations
  • It is difficult to predict which infants are at risk for CH
    • All infants should be screened for CH
    • All newborn screens should test for CH
  • Early recognition and treatment can prevent poor outcomes

Congenital Hypothyroidism

  • Congenital hypothyroidism (CH) is defined as decreased thyroid hormone production in the newborn
  • There are two types of congenital hypothyroidism
    • Transient hypothyroidism
    • Permanent hypothyroidism
  • CH occurs in ~1:2000 - 1:4000 newborns
  • CH is most frequently seen in geographical areas that lack iodine in food and/or water supplies
  • CH is seen less frequently in
    • African infants
    • African American infants
  • CH is seen more frequently in
    • Hispanic infants
    • Asian infants
    • Native American infants
  • Girls are affected twice as frequently as boys
  • There is an inverse relationship between the age at diagnosis and initiation of treatment and IQ scores later in life
  • Newborn screening programs developed in the 1970s were designed to detect CH as early as possible
  • Newborn screens test for either
    • Thyroxine (T4)
    • Thyroid Stimulating Hormone (TSH)
    • Some screens test for both T4 and TSH
      • This is ideal
      • Abnormal TSH levels can be easily missed if only T4 levels are tested

Causes of Hypothyroidism

  • Permanent hypothyroidism may be caused by:
    • An absent thyroid gland
    • An underdeveloped thyroid gland
    • An abnormal or defective thyroid gland
    • Abnormally placed (ectopic) thyroid tissue
    • Abnormal thyroid hormones (THs)
      • THs that are poorly formed
      • THs that do not work effectively
    • A genetically inherited error of thyroid function
    • An abnormally functioning hypothalamus
    • A abnormally functioning pituitary gland
  • An underdeveloped thyroid is the most common cause
  • Permanent hypothyroidism requires lifelong treatment
  • Transient hypothyroidism affects 10-20% of infants with CH
  • Transient hypothyroidism may be caused by:
    • A maternal iodine deficiency
      • The fetus is depends on maternal iodine
    • A maternal autoimmune thyroid disease
      • Graves’ disease
    • Maternal antithyroid medications
      • PTU (propylthiouracil)
      • Methimazole
    • Fetus or newborn exposure to iodine
      • Amiodarone (maternal or infant)
      • Iodine containing antiseptics (Betadine)

Genetic Transmission of Hypothyroidism

  • ~85-90% of CH occurs sporadically
    • Most of the time it is not inherited
  • ~ 10-15% of CH is hereditary
    • Most of the time it is autosomal recessive
    • It is caused by an inborn error of TH synthesis
    • It affects girls and boys equally
    • One pair of non-working genes is inherited
      • One gene from the mother
      • One gene from the father
    • Both parents are carriers, and are not affected
  • Rarely, CH occurs in other hereditary ways
    • By an X-linked recessive gene
    • By an autosomal dominant gene

The Thyroid Gland

  • The thyroid is one of the largest endocrine glands
    • It is a butterfly-shaped organ
    • It is located at the base of the neck
    • It consists of two lobes connected by an isthmus
  • The thyroid gland controls metabolism
    • Every cell in the body depends on the thyroid
    • It’s function is to produce thyroid hormones
  • THs are produced by the uptake of iodine by the thyroid
    • The thyroid gland is the only gland that uses iodine
    • Iodine is then combined with the amino acid tyrosine
    • This combination leads to the production of THs
      • Triiodothyronine (T3)
      • Thyroxine (T4)
  • The thyroid works on a negative feedback system
    • The feedback system involves:
      • The hypothalamus
      • The pituitary gland
      • The thyroid gland
    • This system is known as the HPT system
    • The hypothalamus secretes thyrotropin releasing hormone (TRH)
    • TRH stimulates the pituitary to produce TSH
    • TSH stimulates the thyroid to produce THs
    • TSH is the most important factor in TH regulation
  • Increased levels of THs “turn off” the feedback system
  • Decreased levels of THs “turn on” the system

Physiologic Effects of Thyroid Hormones

  • Cardiovascular
    • Increases heart rate
    • Increases force of contractions
    • Increases cardiac output
    • Promotes peripheral vasodilation
  • Central nervous system
    • Essential for normal brain development
      • Cerebellar growth
      • Nerve myelination
    • Essential for intellectual development
    • Essential for emotional stability
  • Gastrointestinal
    • Increases appetite
    • Increases gastric secretions
    • Increases gastric motility
  • Hematopoietic
    • Influences erythropoiesis
  • Metabolic
    • Profoundly effects oxidative metabolism
    • Increases oxygen consumption in all tissues
      • Except the brain, gonads and spleen
    • Promotes heat production
    • Influences synthesis and degradation
      • Carbohydrates, fats and protein
  • Respiratory
    • Influences lung development
    • Essential for surfactant production
    • Increases rate and depth of respirations
  • Skeletal
    • Indirectly promotes growth by pituitary stimulation
    • Acts synergistically with growth hormone
      • Promotes bone formation
    • Directly affects skeletal maturation
    • Essential for tooth development and eruption
  • Skin
    • Essential for growth and maturation
      • Epidermis and hair follicles

Thyroid Function in Infants

  • The thyroid system is altered at birth
    • Transiently
    • Permanently
  • Exposure to the cold extra-uterine environment
    • Leads to an acute surge in TSH release
    • TSH levels peak at 30 minutes of age
    • TSH levels rapidly decline over the next 24 hours
  • The surge in TSH stimulates the thyroid gland
    • The thyroid gland secretes T3 and T4
    • T3 and T4 levels peak at 24 hours
    • Levels then decrease over the next 4 weeks
  • TSH falls until permanent levels are reached
    • Permanent levels are lower than in-utero levels
    • Lower levels are thought to be due to:
      • Increased levels of T3 and T4
      • Maturation of the HPT system

Thyroid Function in Premature Infants

  • At birth, premature infants experience similar changes
  • However, their HPT system is immature
    • TSH surge and thyroid response is limited
    • The early TSH surge is dampened
    • Production of THs is decreased
    • T3 and T4 levels are lower than term infants
  • Permanent TH levels are not reached until 38-42 weeks
  • Therefore, premature infants have transient hypothyroidism
    • They have more abnormal newborn screen results
    • Infants born at 23-30 weeks have the lowest levels
    • Infants born at 31-36 weeks have slightly higher levels
    • Infants > 36 weeks should not have abnormal levels

Clinical Presentation

  • Most infants with CH have few or no clinical signs
  • This is because their thyroid hormone levels are low
    • They are protected by maternal hormones
    • Maternal hormones offer protection for 3-4 weeks
    • After that time, infants rely on their own production
  • Infants with severe CH often have a unique appearance:
    • Dull look
    • Puffy face
    • Thick protruding tongue
  • This appearance generally develops as CH progresses
  • Other clinical signs may include:
    • Choking episodes
    • Poor feeding
    • Jaundice
    • Hypothermia
    • Hypotonia
    • Constipation
    • Umbilical hernia
    • Enlarged fontanels
    • Dry brittle hair
    • Low hairline
    • Poor linear growth
    • Lethargy
    • Fatigue
  • If left untreated, further clinical signs develop:
    • Coarse swollen facial features
    • Breathing problems
    • Hoarse cry
    • Delayed milestones
      • Sitting
      • Crawling
      • Walking
      • Talking
    • Wide short hands
    • Poor weight gain
    • Poor height growth
    • Goiter
    • Anemia
    • Bradycardia
    • Hearing loss
  • If left untreated, significant intellectual disabilities develop
    • Speech delays
    • Behavioral problems
    • Mental retardation

Diagnosis of Hypothyroidism

  • Diagnosing hypothyroidism requires
    • A thorough prenatal history
    • A thorough neonatal history
    • A thorough physical examination
    • Diagnostic laboratory evaluation
  • The primary diagnostic method is newborn screening
    • Timing of the newborn screen should be noted
    • False positive results can occur in the first 24-48 hours
    • Immediate repeat screens may be helpful
  • Laboratory evaluation
    • Thyroid function tests
      • Free T4
      • TSH levels
    • Serum thyroglobulin
    • Urine iodine
  • Radiographic evaluation
    • Long bone and skull x-rays may be helpful
    • To assess bone growth and development
    • To assess duration and severity of hypothyroidism
  • Ultrasound evaluation
    • To identify thyroid presence and function
    • To identify the absence of a thyroid
  • Radioisotope evaluation
    • Radioisotope scanning is the most reliable method
    • Scanning identifies thyroid development and function

Treatment of Hypothyroidism

  • The goal of CH treatment is to prevent poor growth and poor neurodevelopmental outcomes
    • Rapid restoration and maintenance of THs is critical
    • An Endocrinology consult should be obtained
  • The primary treatment is TH replacement
    • If replacement is started early
      • Mental and physical development is good
      • Poor outcomes may be prevented
    • If replacement is started late
      • Neurological damage is permanent
      • Poor outcomes cannot be reversed
  • The treatment of choice is oral levothyroxine (T4)
  • Levothyroxine should be started immediately
    • As soon as newborn screening is reported as abnormal
    • As soon as TSH and T4 levels have been obtained
    • While the TSH and T4 results are pending
    • If the newborn screen results are borderline, treatment may be delayed until TSH and T4 results are available
    • The AAP recommends starting with 10-15 mcg/kg/day
  • Levothyroxine should be given in a systematic manner
    • At the same time every day
    • Prepared in the same way every day
  • Only levothyroxine tablets should be used
    • There are currently no approved liquid formulations
    • Tablets should be crushed and mixed with small amounts of breastmilk, formula or water and fed to the infant
    • They should not be mixed with soy or fortified formulas
      • Soy formula decreases absorption rates
      • High iron formula decreases absorption rates
      • High calcium formula decreases absorption rates
    • They should not be mixed with
      • Antacids
      • Iron supplements
      • Simethicone (Mylicon) drops
  • Follow up is critical to ensure adequate T4 levels
    • The goal is to maintain T4 levels in the upper half of normal
    • In the first year of life, the goal is 10-16 mcg/dL
    • TSH levels should be maintained at < 5 mU/L
      • Ideally TSH levels should be 0.5-5 mU/L
  • T4 and TSH levels should be obtained every few months
    • The AAP recommends the following schedule:
      • At 2 weeks following the start of treatment
      • Every 1-3 months during the first 12 months
      • Every 2-4 months between 1 and 3 years
      • Every 6-12 months until growth is complete
      • 2 weeks after any change in dosing occurs
      • At more frequent levels if compliance is questioned or abnormal results are obtained
  • If permanent hypothyroidism has not been established
    • At age 3, treatment can be stopped for one month
    • Thyroid function tests should be obtained
    • If levels are normal, treatment can be discontinued
    • Periodic thyroid levels are still recommended
  • Close developmental follow up should always be provided

Summary

  • CH is one of the most common causes of mental retardation
  • It is generally caused by an underdeveloped thyroid gland
  • It is not possible to predict which infants are at risk
    • All infant should be tested for CH
    • At least 2 newborn screens should be obtained
  • CH is treatable and early recognition is critical
    • To ensure normal growth
    • To ensure normal cognitive development
  • Cognitive damage from hypothyroidism is permanent

References

  1. LaFranchi, S. 2015. Clinical Features and Detection of Congenital Hypothyroidism. Up-To-Date.
  2. LaFranchi, S. 2014. Treatment and Prognosis of Congenital Hypothyroidism. Up-To-Date.
  3. Rubin, D.I. 2014. Neurologic Manifestations of Hypothyroidism. Up-To-Date.
  4. LaFranchi, S. 2014. Thyroid Physiology and Screening in Preterm Infants. Up-To-Date.
  5. Schmaltz, C. 2012. Thyroid Hormone in the Neonate. Advances in Neonatal Care, 12 (4), p. 217-222.
  6. Kirsten, D. 2000. The Thyroid Gland: Physiology and Pathophysiology. Neonatal Network, 19 (8), p. 11-26.

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