A randomised, controlled trial of iodide supplementation in preterm infants
Lead Research Organisation:
University of Oxford
Department Name: National Perinatal Epidemiology Unit
Abstract
Thyroxine is a hormone produced by the thyroid gland and is essential for normal brain development. Low serum thyroxine levels (hypothyroxinaemia) are common in extreme preterm infants (under 31 weeks gestation) and this hypothyroxinaemia is associated with neurodevelopmental compromise. About 7500 extreme preterm infants are born per annum in the UK; with an estimated 20% disability rate, assuming 70% survival.
Iodide is required for synthesis of thyroxine. Extreme preterm infants are initially exclusively parenterally fed (directly into the blood stream) and enteral feeds (directly into the gastro-intestinal tract) are gradually introduced and increased as clinically appropriate. Parenteral nutrition solutions are severely iodide deficient and infants are in negative iodide balance while on total parenteral nutrition.
Our study aims to determine whether nutritional supplementation with iodide compared to non-supplemented infants enables extreme preterm infants to achieve a positive iodide balance and whether this protects brain development in this group of infants.
This study will recruit infants born between 24 and 31 weeks gestation from a pool of 21 neonatal units in the UK. Infants will be randomised to receive a daily iodide supplement or not until they are the equivalent of 34 weeks gestation. Thyroid hormone levels will be measured during the trial and data will be collected about illnesses and events during the prenatal and postnatal periods. Neurodevelopment will be assessed in all infants at two years of age using established developmental tests.
For further background information see www.euthyroid.org
Iodide is required for synthesis of thyroxine. Extreme preterm infants are initially exclusively parenterally fed (directly into the blood stream) and enteral feeds (directly into the gastro-intestinal tract) are gradually introduced and increased as clinically appropriate. Parenteral nutrition solutions are severely iodide deficient and infants are in negative iodide balance while on total parenteral nutrition.
Our study aims to determine whether nutritional supplementation with iodide compared to non-supplemented infants enables extreme preterm infants to achieve a positive iodide balance and whether this protects brain development in this group of infants.
This study will recruit infants born between 24 and 31 weeks gestation from a pool of 21 neonatal units in the UK. Infants will be randomised to receive a daily iodide supplement or not until they are the equivalent of 34 weeks gestation. Thyroid hormone levels will be measured during the trial and data will be collected about illnesses and events during the prenatal and postnatal periods. Neurodevelopment will be assessed in all infants at two years of age using established developmental tests.
For further background information see www.euthyroid.org
Technical Summary
BACKGROUND
Thyroxine (T4) is essential for normal brain development. Transient hypothyroxinaemia (low serum T4 levels) is common in extreme preterm infants and associated with adverse neurodevelopment. Iodide is essential for thyroxine synthesis and inadequate amounts in parenteral nutrition result in iodide deficiency in preterm infants. The aetiology of transient hypothyroxinaemia is multi-factorial and correction of iodide deficiency is essential before modification of other factors.
RESEARCH QUESTION
Does iodide supplementation of extreme preterm infants change neurodevelopment outcome?
METHODS
A randomised, triple blinded, controlled trial of iodide supplementation versus placebo.
DESIGN
Infants less than 31 weeks gestation will be recruited, over 2 years, from a pool of 21 UK Neonatal Intensive Care Units; written support has been received from these units. Infants will be randomised to receive supplementation of sodium iodide or placebo (sodium chloride) until 34 corrected weeks gestation. Blood will be collected on Guthrie Cards for analysis of thyroid hormone levels on postnatal days 7, 14, 28 and 34 weeks corrected gestational age. A range of epidemiological data will be collected. Neurodevelopment will be assessed using the Bayley-III Score at 2 years corrected age.
PRIMARY OUTCOME
Neurodevelopmental outcome at 2 years corrected age.
SECONDARY OUTCOMES
Blood levels of T4, TSH and TBG; illness type and severity, hearing and vision impairment, drug use, nutritional status, bilirubin level, cause of death, glucose homeostasis at time of discharge.
This study is powered on the primary outcome. With 1063 infants we can detect, at 2 years corrected age, a difference of 0.5 standard deviations in the Bayley-III score at a power of 90% and significance level of 5%. Recruitment will take 2 years which allows for a recruitment rate of 50%. The study has sufficient power to enable sub-group analysis of the primary outcome and we shall be able to detect changes in the Bayley-III score of 0.5 sd in infants less than 28 weeks and also for the very sickest infants (i.e. BAPM Level 1).
EXPLOITATION OF RESULTS
If this work shows benefit to the supplemented neonates there will be worldwide clinical support for iodide supplementation for preterm infants. In addition, the current iodide recommendation of 1mcg/kg/day extends to term infants, and children up to 15 kg (3-4 years of age) who are also likely to benefit. The pragmatic means to achieve iodide sufficiency in parenterally fed infants is to ensure that the nutrition is adequate.
Thyroxine (T4) is essential for normal brain development. Transient hypothyroxinaemia (low serum T4 levels) is common in extreme preterm infants and associated with adverse neurodevelopment. Iodide is essential for thyroxine synthesis and inadequate amounts in parenteral nutrition result in iodide deficiency in preterm infants. The aetiology of transient hypothyroxinaemia is multi-factorial and correction of iodide deficiency is essential before modification of other factors.
RESEARCH QUESTION
Does iodide supplementation of extreme preterm infants change neurodevelopment outcome?
METHODS
A randomised, triple blinded, controlled trial of iodide supplementation versus placebo.
DESIGN
Infants less than 31 weeks gestation will be recruited, over 2 years, from a pool of 21 UK Neonatal Intensive Care Units; written support has been received from these units. Infants will be randomised to receive supplementation of sodium iodide or placebo (sodium chloride) until 34 corrected weeks gestation. Blood will be collected on Guthrie Cards for analysis of thyroid hormone levels on postnatal days 7, 14, 28 and 34 weeks corrected gestational age. A range of epidemiological data will be collected. Neurodevelopment will be assessed using the Bayley-III Score at 2 years corrected age.
PRIMARY OUTCOME
Neurodevelopmental outcome at 2 years corrected age.
SECONDARY OUTCOMES
Blood levels of T4, TSH and TBG; illness type and severity, hearing and vision impairment, drug use, nutritional status, bilirubin level, cause of death, glucose homeostasis at time of discharge.
This study is powered on the primary outcome. With 1063 infants we can detect, at 2 years corrected age, a difference of 0.5 standard deviations in the Bayley-III score at a power of 90% and significance level of 5%. Recruitment will take 2 years which allows for a recruitment rate of 50%. The study has sufficient power to enable sub-group analysis of the primary outcome and we shall be able to detect changes in the Bayley-III score of 0.5 sd in infants less than 28 weeks and also for the very sickest infants (i.e. BAPM Level 1).
EXPLOITATION OF RESULTS
If this work shows benefit to the supplemented neonates there will be worldwide clinical support for iodide supplementation for preterm infants. In addition, the current iodide recommendation of 1mcg/kg/day extends to term infants, and children up to 15 kg (3-4 years of age) who are also likely to benefit. The pragmatic means to achieve iodide sufficiency in parenterally fed infants is to ensure that the nutrition is adequate.
