Neurodisability in extreme preterm infants: 

a trial of iodine supplementation in parenterally fed infants, I2S2

Project Coordinators: Robert Hume and Fiona Williams 

Background: The aetiology of cerebral damage and neurodisability in extreme preterm infants is multifactorial; this project focuses on transient hypothyroxinaemia. 

Thyroid hormone is essential for normal development of the human brain in-utero and for the first two years of life.  Damage through deficiency of thyroxine (T4) is irreversible.  Transient hypothyroxinaemia in preterm infants is common and evident in 41% of infants <28 weeks gestation and in 23% of infants of 28-30 weeks gestation.  Recent studies have linked low plasma T4 in preterm infants with later neurodevelopmental deficits in motor and cognitive function.  The aetiology of transient hypothyroxinaemia is not clear and may have contributions from the withdrawal of maternal-placental thyroxine transfer, hypothalamic-pituitary-thyroid immaturity, infant iodine deficiency, developmental constraints on the synthesis and peripheral metabolism of iodothyronines, and non-thyroidal illness.

Iodine is essential for the synthesis of T4.  Mild and moderate deficiencies of iodine are associated with neuro-cognitive deficits in infants and children.  Parenteral nutrition is routinely used immediately post delivery in all extremely preterm infants.  Commercially available parenteral solutions for infants render infants vulnerable to negative iodine balance and insufficiency, which may contribute to transient hypothyroxinaemia.  In extreme preterm infants, parenteral nutrition provides 95% of caloric intake of the sickest infants in 23-27 weeks gestation on day 7 and 51% at day 28.

This trial is a randomised, triple blinded, controlled trial of iodine supplementation in extreme preterm infants. It aims to answer whether iodine supplementation of parenterally fed infants can improve neurodevelopmental outcome – in the first instance at 2.0 years corrected age.  Patient safety will be monitored closely.  The study procedures, dosages and volumes have been piloted in Dundee.  

Eligibility:  Infants born < 31 weeks gestation

Study treatment:  Supplementation of parenterally fed infants with sodium iodide or placebo (sodium chloride) supplied by the study (0.4 ml/kg/dose/day; 30 micrograms iodide/chloride per kg/day); started within 42 hrs of birth; individual infants will be involved from birth until 34 corrected weeks gestation.

Main outcome measures: Neurodevelopmental outcome at 2.0 years corrected age.  Guthrie Card blood for analysis of T4, TSH and TBG on postnatal day 7, 14 and 28 postpartum and 34 corrected weeks gestation.

Recruitment numbers: 1063 infants less than 31 weeks gestation

Setting:  15-20 Neonatal units in the UK and Ireland

Study Duration: 5 years, iodine supplementation RCT (2.5 years), Neurodevelopmental follow up (2.5 years)

Funding: An outline application was accepted by the Medical Research Council; a full application was submitted in February 2008.