Management of raised neonatal bloodspot TSH and initial management of congenital hypothyroidism
Flowchart
Introduction

Untreated severe congenital hypothyroidism can lead to neurological and psychiatric deficits including intellectual disability, spasticity, and disturbances of gait and co-ordination. 

Congenital hypothyroidism is one of the most common preventable causes of mental/intellectual disabilities. Newborn screening programmes have been successful in the early detection of infants with congenital hypothyroidism. Early institution of levothyroxine treatment can eliminate the severe neurodevelopmental deficits which will occur if there is a late diagnosis or delayed treatment with levothyroxine.
Scope

Paediatricians working in DGHs across Wessex, and consultants covering when the designated lead for paediatric endocrinology at each DGH is on leave.

Each DGH across the Wessex Paediatric Endocrine Network has a designated lead for the management of babies with congenital hypothyroidism (please see Wessex Paediatric Endocrine Network) and to whom the newborn screening laboratory will ring positive results.  If this individual is away, there will be alternative local arrangements in place to enable prompt action of a newborn screening positive result (usually consultant of the week).
Purpose

The aim of the guideline is to improve patient experience, clinical outcomes, provide an agreed clinical approach to managing these babies, enable prompt institution of levothyroxine with no delay and optimise communication with parents.
Definitions

Newborn screening of blood TSH can detect primary congenital hypothyroidism. This condition causes an elevated blood TSH with a low or normal FT4 and results from either thyroid agenesis (thyroid gland absent or ectopically sited) or from dyshormonogenesis (thyroid gland present but an enzymatic defect leads to abnormally low thyroid hormone synthesis).

Secondary hypothyroidism (which may occur from congenital abnormalities of the hypothalamic-pituitary axis) will result in a normal or low TSH with a low FT4 and will not be detected by the newborn TSH screen. 

​CHT - Congenital Hypothyroidism
FT4 - Free T4
TFT - Thyroid Function Tests
TSH - Thyroid Stimulating Hormone
Important points to guide the history and examination

Important points to guide the history
Enquire about:
  • Family history of thyroid disease
  • Maternal history of thyroid disease (including past history of thyroidectomy)
  • Medication taken during pregnancy (including anti-thyroid drugs-carbimazole, propylthiouracil)
  • Baby
    • reduced/slow feeding,
    • sleepiness, not waking for feeds,
    • jaundice
    • any supplements containing biotin (vitamin B7) given to baby

Important points to guide the examination
  • goitre or posterior lingual swelling
  • check for congenital abnormalities (especially cardiac)
  • underlying dysmorphic syndromes
  • jaundice
  • hypotonia
  • umbilical hernia
  • dry skin
  • document head circumference
Investigations required following an elevated TSH result confirmed by newborn screening 
​
Baby
  • TSH.
  • FT4.
  • FT3
  • Thyroglobulin (a marker of the presence of thyroid tissue).

Mother
  • TSH.
  • Free T4. 
  • Thyroid TPO antibodies .​
Clinical Practice Points
​Twins
  • Repeat screening (TFT) of a same sex twin should be considered, as the initial screen in affected twin may be normal. The non-affected sibling of twins should be followed up for possible TSH elevation later in life
Down’s syndrome
  • Measure TSH at the end of the neonatal period
Other groups requiring special considerationSome groups of children may have a false-negative neonatal screening result or have a high risk of mild CHT not detected by neonatal screening.  This is more likely in the following groups:
  • sick babies
  • premature babies
  • low birthweight babies and:
For these groups, a post screening strategy including collection of a second TFT at 10-14 days of age should be considered. 
Biochemical criteria used in the decision to start treatment
  • If capillary TSH concentration from blood obtained on neonatal screening is ≥ 40 mu/L whole blood (this is the result which is phoned through from the newborn screening laboratory)
    • Organise a TFT (TSH and FT4) urgently
    • Start levothyroxine treatment as soon as a good venous sample for a TFT (TSH and FT4) can be obtained, and without waiting for the venous TFT blood result (unless venous TFT results are available on the same day)
  • If capillary TSH concentration from blood obtained  on neonatal screening is ≤ 40mu/L whole blood (this is the result which is phoned through from the newborn screening laboratory)
    • Organise a TFT (TSH and FT4) urgently
    • the clinician may wait for results of the venous TFT (TSH and FT4) provided that these results are available the following day ​​
Decision to start treatment on the basis of the venous TFTs (TSH and FT4)

  • if the venous FT4 concentration is below the normal range for age, treatment should be started immediately
  • if the venous TSH > 20mu/L, treatment should be started even if FT4 is normal
  • if the venous TSH concentration is 6-20 mu/L beyond 21 days in a well baby with a FT4 concentration within the age-specific reference range, either:
    • start levothyroxine treatment immediately and retest, off-treatment, at a later stage
    • or withhold treatment but retest TFT 1 to 2 weeks later to re-evaluate the need for treatment
  • Direct parents to the following information:
Thyroid Imaging
  • Imaging should never delay the initiation of levothyroxine treatment
  • If levothyroxine is commenced, the baby should have a thyroid USS (this can be done as a routine investigation and following commencement of levothyroxine)
  • A thyroid uptake scan (radioisotope) should be organised, if available, and undertaken within 5 to 7 days of starting levothyroxine​​
Follow Up of babies with an elevated TSH result
Initial treatment of babies with congenital hypothyroidism
  • The baby should be seen the same day or within 24 hours of the result being called through from the newborn screen laboratory
  • Levothyroxine should be initiated immediately after confirmatory bloods test results are available 
  • The initial starting dose is 10-15 microgram/Kg (max 50 microgram) per day given orally
    • If severe CHT with FT4 <5 pmol/l highest starting dose 10-15 microgram/kg/day
    • If mild CHT with FT4 >10 pmol/l lowest starting dose of 10 microgram/kg/day
    • If normal range FT4 even lower starting dose could be considered of 5-10 microgram/kg/day
  • Levothyroxine tablets should be crushed and administered using a small spoon, in a few millilitres of water. If possible it should not be given in milk due to interaction with calcium, which may reduce enteral absorption of levothyroxine. Do not dissolve in a bottle of milk as the powder will stick to the inside of the bottle resulting in inadequate dosing
  • Levothyroxine liquid is available in a variety of concentrations, and is not routinely recommended due to the high risk of prescribing and dispensing errors associated with its use. It has a higher bioavailability and should not be used interchangeably with tablets.
  • Parents should be provided with written instruction on levothyroxine treatment
Discharge Planning
  • Ensure that parents:
    1. Understand the reasons for the need for excellent medicine adherence
    2. Have been shown how to administer levothyroxine
    3. have been given information about online resource for suspected congenital hypothyroidism from Public Health England (insert link)
    4. have been informed of date of next blood test and where to go
    5. have been informed of the timings of the TFT surveillance required (next section)
  • thyroid imaging booked
  • follow-up appointment booked with the local lead for paediatric endocrinology at relevant DGH - ​Congenital Hypothyroidism is suspected
Monitoring of babies and children with congenital hypothyroidism treated with levothyroxine
  • TSH concentrations should be maintained in the age -specific reference range. 
  • FT4 concentrations should be maintained in the upper half of the age-specific reference range. 
  • The first follow-up examination should take place 1-3 weeks after treatment with levothyroxine
  • If on levothyroxine 50 microgram/day, review 1 week after starting treatment with a TFT. 
  • Repeat clinical and biochemical (TSH and FT4) evaluation should be undertaken every 2 weeks until normalisation of the TSH, thereafter the frequency can be reduced to every 1-3 months. 
​
*Clinical practice point 
The interpretation of the TFT following 1-2 weeks of levothyroxine treatment is to confirm that the FT4 is in the normal range. The TSH may not have returned to normal but should be lower than at diagnosis. If there is no improvement check parental understanding of medicine administration, whether the importance medicine adherence is understood or whether there are other issues.

More frequent evaluations should be undertaken if compliance is questioned or abnormal values are obtained. Failure to comply with treatment must be addressed urgently and may be a safeguarding issue.

Steady state TSH levels are usually achieved after 4 consecutive weeks on the same dose of levothyroxine. 

Therefore the time interval between TFTs to check whether a dose adjustment of levothyroxine is required should be 4 weeks (not earlier), so that a decision can be made whether or not the levothyroxine dose should change.

Any levothyroxine dose changes are usually in steps of 12.5 micrograms (i.e. half tablet
Follow Up frequency after three months of age
  • 0-1 years:  1-3 monthly
  • 1-4 years: 2-4 monthly
  • > 4 years: 3-12 monthly
Factors that may lead to elevated TSH whilst on levothyroxine treatment
Incorrect timing of TFT measurement: measurement of serum fT4 and TSH concentrations before or at least 4 hours after the last (daily) LT4 administration.
  • Under-dosed with levothyroxine
  • Incorrect drug administration
  • Medicine non-adherence
  • Gastrointestinal problems, malabsorption
  • Interaction with food substances and supplements. Can be mitigated by spacing at least 2 hours apart from levothyroxine administration:
    • Soy milk
    • Dietary fibre
    • Calcium supplements or treatment
    • Magnesium
    • Iron
    • Antacids, Gaviscon (high magnesium and aluminium content)
    • Caffeine
    • Tannins (from tea)
  • Interaction with the following medication:
    • Amiodarone
    • Proton pump inhibitors (e.g., omeprazole)
    • Infacol (simeticone)
    • Enzyme-inducing drugs (e.g., carbamazepine, phenytoin)
  • Assay interference: biotin (vitamin B7) in supplements can interfere with thyroid immunoassays and lead to false high or low results (discuss with biochemist for a TFT assessment by alternative laboratory)
Implementation

  • The guideline will be displayed on the PIER website and can be accessed by all healthcare professionals working within Wessex. This guideline will be disseminated to network centre leads within the Wessex Paediatric Endocrine Network. Treatment of congenital hypothyroidism will be managed locally by the paediatric endocrinology network lead at each DGH  (details here).
Process for Monitoring Effectiveness 

  • Effectiveness of the guideline will be monitored by feedback to the lead author.

Patient Information Leaflets
References
  1. Van Trotsenburg et al. 2020–2021 Consensus Guidelines Update- An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid 2021;31(3);387-419
  2. Congenital hypothyroidism: initial clinical referral standards and guidelines. UK Newborn Screening Programme Centre, 2013
  3. https://www.gov.uk/government/publications/congenital-hypothyroidism-screening-laboratory-handbook
  4. UK standards for Paediatric Endocrinology, BSPED & RCPCH, 2019 https://www.bsped.org.uk/media/1580/uk-standards-for-paediatric-endocrinology-2019.pdf
  5. Burch HB. Drug Effects on the Thyroid. N Engl J Med 2019;381:749-61
Document Version: 
1.2

Lead Author: 
Dr Carl Taylor, Salisbury

Co-Author: 
Professor Justin Davies, Southampton
Approving Network:
Wessex Paediatric Endocrine Network

Date of Approval: 
09/2024
Review Date:
09/2027