Neonatal Thyrotoxicosis (971)

Any infant whose mother has a current or past history of hyperthyroidism is potentially at risk of neonatal thyrotoxicosis.  ‘At risk’ infants should be identified by maternal history and the measurement of TRAbs in the mother during pregnancy.  Current maternal thyroid function may be misleading as the mother may still have circulating thyroid receptor antibodies, despite being euthyroid or hypothyroid, if she is currently receiving treatment with anti-thyroid medication or following thyroid ablative therapy (surgery or radioactive iodine).  
N.B. mothers with thyroid disease frequently have Thyroid Peroxidase (TPO) antibodies reported – these are not a risk factor for hyperthyroidism in the neonate and do not require any neonatal investigations

Reporting TRAb results

The lab are not reporting a reference range or value for TRAb measurements. They will be reporting it as either positive or negative, cutoffs for each are shown below.

TRAb

• <3.1 U/L Negative
• ≥3.1 U/L Positive

High risk mothers

• Current thyrotoxicosis on antithyroid medication (Carbimazole or Propylthiouracil)
• Previous thyrotoxicosis treated with radioactive iodine or thyroid surgery
• Any mother with positive TRAbs

Low risk mothers

• Previous thyrotoxicosis treated only with antithyroid medication.
  Mother now euthyroid and off anti-thyroid treatment.
• Mothers with negative TRAbs

Negligible risk

• Maternal hypothyroidism (unless due to surgery or radioactive iodine - see above)

All mothers with a current or past history of thyrotoxicosis (high and low risk groups) should have their antibody titres measured at booking.  If positive these should be repeated later in pregnancy (antibody titres often fall toward the end of pregnancy).  See obstetric guideline

If thyroid antibodies are detected  (TRAb >2 U/L ) then this should be indicated in the ‘paediatric alert’ section of the maternal notes.  Paediatric staff should be informed as soon as the baby has delivered. 

N.B. Where there is a history of thyrotoxicosis in the mother but no TRAb titres are available the baby should be managed as ‘High Risk’ .

No further action is required for the negligible risk group or for the low risk group if thyroid antibodies are not detected at booking.

N.B. Only babies whose mothers have POSITIVE TRAbs require investigation (or those for whom no TRAb measurement is available from the current pregnancy)

Infants with Neonatal Thyrotoxicosis may present at birth and the remainder usually become symptomatic over the first 10 days of life.   These infants may be critically unwell therefore clinical assessment for signs of thyrotoxicosis and initial investigations should be performed very shortly after birth. 

• Confirm maternal TRAb titres are positive, during current pregnancy, if no TRAb results available send infant TRAb titres and treat infant as high risk.
• Ask if there is a family history of neonatal thyroid disease.
• Examine for features of neonatal thyrotoxicosis. See below.  
• Send following investigations (ideally from cord blood and ensure sample is labelled and request form states cord blood – this will allow lab to distinguish between maternal and infant results.)
  • freeT4, TSH (requires a minimum of 1ml in lithium heparin).
  • TRAb (needs to be a serum sample so requires 0.5ml in yellow topped bottle)
  • Infant TRAb, results will be available within 7 – 10 days

N.B. in the first few days of life it is common to find that TSH and free T4 are both raised.  This is a normal acute phase response and is not hyperthyroidism.  TSH is suppressed in thyrotoxicosis (TSH <0.2milliunits/L).

Normal reference ranges:  TRAb Negative, fT4: 6-30picomol/L, TSH: 0.2-15 milliunits/L

Subsequent management is based on the results of these initial investigations

     Normal Thyroid Function and absent/low (baby’s) TRAb levels. 

N.B. TRAb levels are performed on a weekly basis, the day will depend on how many samples received that week. It may be possible to have a TRAb level within 24-48 hours of sending sample depending on when the analysis is run that week. The labs anticipate that all results should be availabe within 7- 10 days. In the situation of no TRAb levels being available follow up as below (infants with Normal TFTs and raised TRAb)

• Follow up as outpatient at 10-14 days. No further investigation unless symptomatic. 
• Prior to discharge, parents should be advised of the features of neonatal hyperthyroidism see below and advised to contact the unit if symptomatic. 

Normal Thyroid Function but (baby’s) TRAb POSTIVE or unknown

• Repeat fT4 and TSH on day 3-5 and again at day 10-14 to detect later onset hyperthyroidism. Prior to repeating bloods check results of infant TRAb titres and if Negative, bloods not required, almost all will be back prior to day 10.
• Prior to discharge, parents should be advised of the features of neonatal hyperthyroidism see below and advised to contact the unit if symptomatic. 
• Infants with TRAb Positive results, are at risk of late onset hyperthyroidism as TRAbs remain in the infant circulation for up to 6 weeks, there have been reports of development of hyperthyroidism as late as day 45. Therefore infants with normal thyroid function but raised TRAb should be followed up at 4 weeks and 2-3months to ensure no signs of late onset hyperthyroidism

Abnormal Thyroid Function

• If fT4 >30 and TSH < 0.2, or there are symptoms or signs of hyperthyroidism then the baby is potentially hyperthyroid and should be discussed urgently with the duty Neonatal Consultant as pharmacological treatment may be required.  Liaison with a consultant paediatric endocrinologist should be considered for babies with thyrotoxicosis.
• Occasionally infants whose mothers have been on antithyroid medication may be hypothyroid.

Drug therapy

Monotherapy with carbimazole may be sufficient in an asymptomatic infant with biochemical evidence of hypoerthyroidism. However in a symptomatic infant concurrent therapy with propranolol and/or iodine may be required.

• Carbimazole - 250 micrograms/kg/dose 3 times daily until euthyroid.  Higher doses, up to 1mg/kg/day, may be required if the infant is in thyrotoxic crisis.
  Carbimazole reduces the uptake of iodine by the thyroid and blocks thyroid hormone synthesis by preventing the organification and coupling of iodothyronine residues.  It does not inhibit the release of pre-formed thyroid hormones and may take a number of weeks to render the infant euthyroid.  
  Agranulocytosis may occur during treatment with Carbimazole.
  
  
• Propranolol - 250–500 micrograms/kg/dose every 6–8 hours initially adjusted according to response. Propranolol helps control symptoms caused by adrenergic stimulation. In addition, it inhibits deiodination of T4 to T3.
  
  
• Lugol’s Iodine solution (Aqueous Iodine Oral Solution) – 0.05 ml, 3 times a day for 1 week.
  Lugol’s Iodine is used in infants with haemodynamic instabillity. It helps rapidly block thyroid hormone synthesis, blocks thyroid hormone release and promptly reduces free thyroid hormone concentrations.  The effects are temporary and co-administration of carbimazole is essential.

The aim of treatment is to abolish hyperthyroidism without causing hypothyroidism.  Treatment must be titrated against the clinical response.  Propranolol may be stopped once clinically euthyroid.

TFTs

These should be measured at regular intervals aiming to achieve T4 measurements in the normal range.  fT4 – 6 - 30 pmol/L  and a TSH level between 0.05 - 5mU/L 
N.B. TSH may remain suppressed for 2-3 weeks even with adequate therapy

FBC

Carbimazole may cause agranulocytosis in 0.03% of patients.  The FBC should be measured after 1 week of treatment.  This should be repeated at any stage if there are suggestive symptoms (fever, mouth ulcers, rash).

The half life of TRABs is about 12 days.  Treatment may therefore be required for 8-12 weeks.  Following successful cessation of carbimazole there is usually no need for further follow-up

Head and Neck

• Goitre
• Periorbital Oedema
• Exopthalmos

CNS

• Irritable
• Jittery
• Poor sleeping
• Microcephaly – head <5th centile

CVS

• Tachycardia
• Arrhythmias
• Flushing
• Sweating
• Hypertension

GI

• Increased appetite
• Diarrhoea / vomiting
• Excess weight loss
• Hepatosplenomegaly

Other

• Bruising + petechiae due to thrombocytopaenia
• Jaundice