Neuro Development

Background

Premature infants are at risk of cerebral handicap and an adverse neurodevelopmental outcome is the major unsolved consequence of the compromised pregnancy. There are about 7500 extreme preterm infants born annually in the UK; 25% have neurological abnormalities, 9% visual and 11% hearing impairments. The population as a whole has a reduction in IQ of 7-10 points; 50% require specialist school support.  The aetiology of neurodisability in extreme preterm infants is multifactorial and complex.

The Group’s programme of work has been established since 1985 and is founded on the developmental-translational cycle with diseases entities, which impact on postnatal brain development, at its heart.

We have active collaborations with neonatologists in 25 hospitals in the UK; psychologists; nutritionists; and specialists in thyroid hormone metabolism and catecholamine metabolism.  The Group’s research encompasses two main themes: transient neonatal hypothyroxinaemia and iodine status, with three large and ongoing projects:

The I2S2 trial of iodine supplementation of preterm infants

The aetiology of cerebral damage and neurodisability in extreme preterm infants is multifactorial; this project focuses on transient hypothyroxinaemia (low blood thyroxine).

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. But, thyroxine supplementation is not universally effective and is detrimental to some infants. The aetiology of transient hypothyroxinaemia is not clear and may have contributions from the withdrawal of maternal-placental thyroxine transfer, hypothalamic-pituitary-thyroid immaturity, 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 neurocognitive 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 likely contributes to transient hypothyroxinaemia. In extreme preterm infants, parenteral nutrition can provide 95% of caloric intake of the sickest infants in 23-27 weeks gestation on day 7 and 51% at day 28. Iodine insufficiency in infants also may be exacerbated by maternal iodine deficiency, even in the UK.

Research Question: Does iodine supplementation of extreme preterm infants (≤30 week’s gestation) improve neurodevelopment outcome at 2 years corrected (for prematurity) age?

Trial treatment: The intervention was sodium iodide diluted to a total iodine content of 75 microgram/ml and the placebo was sodium chloride diluted to a total chloride content 75 microgram/ml. Randomisation was within 42 hours of birth and infants received trial solutions until the equivalent of 34 week’s gestation.

Primary outcome measure: Neurodevelopmental outcome at 2 years corrected age (assessed by trial assessors)

Recruitment target numbers: 1330 infants

Setting: 21 Neonatal units in the UK recruited infants to the trial (see table). But as 42% of preterm infants were transferred from their recruiting hospital to a Continuing Care Site for surgery, for specialist opinion or to be closer to home – 76 additional hospitals in the UK were involved in the trial.

Recruiting hospitals in I2S2

Trial timetable

Pilot work for I2S2 began in Dundee in 2000 and funding for a full trial was awarded to us in July 2008. I2S2 began recruitment in March 2010 and finished recruitment in December 2012. Assessment at 2 years corrected age with the Bayley-III developmental test will be completed by May 2015 and the trial results will be published thereafter.

I2S2 is funded by the Efficacy and Mechanism Evaluations programme of NIHR; sponsored by the University of Oxford, with full ethics (08/S0501/31) and MHRA approval – CTA number (21584/0251/001); and registered with clinical trials (NCT00638092) and EudraCT number (2008-001024-31).

Trial team

University of Dundee
Fiona Williams
Robert Hume
Simon Ogston
Peter Willatts
Jennifer Watson
Deirdre Plews
Patricia Black
Gail Morrison
University of Oxford, National Perinatal Epidemiology Unit, Clinical Trials Unit
Ursula Bowler
Kayleigh Morgan
Ed Juszczak
Peter Brocklehurst

I2XS Iodine Excess

Does exposure to iodine cause transient hypothyroidism?

As part of our programme of work, we are investigating the use of iodine in the management of infants during the neonatal period who have been born preterm. Apart from the iodine received via their nutrition (e.g. breast milk, formula milk, parenteral nutrition) some infants may also be exposed via iodinated contrast media (which is given to visualise the placements of a long line for delivery of parenteral nutrition) or from povidone-iodine (which is used for skin antisepsis).

The brain is dependent upon iodine for normal growth and development during gestation and for the first two to three years of life; but, paradoxically too much as well as too little iodine can compromise the developing brain. Some, now rather old, research suggests that exposure to excess iodine from contrast media and /or povidone iodine for maternal skin cleansing during labour may cause transient hypothyroidism in extreme preterm infants. Such exposure might be associated with poor neurodevelopment.

The rationale for using iodinated contrast media, to visualise the placement of central venous catheters, is to minimise the threat of a serious adverse outcome resulting from a wrongly positioned catheter. Use of contrast media has been associated with a reduction in serious complication from 1.8% to 0.05%. The literature about the adverse consequences of using iodinated contrast media is limited. As a consequence there is variation in the use of contrast media in neonatal intensive care units across the UK.

Key Points

  • Thyroxine is critical for the developing human brain and this supply is compromised whether serum T4 levels are reduced through transient hypothyroxinaemia, which has a contribution from iodine deficiency, or from transient hypothyroidism caused by iodine excess.
  • Maternal exposure to iodine (e.g. povidone-iodine use for skin disinfectant during Caesarean section or vaginal delivery) might result in neonatal iodine overload.
  • Breast feeding and neonatal iodine exposure (e.g. via the mother, for umbilical cord care or for skin disinfectant) results in maximal neonatal iodine overload.
  • The impact of iodine overload in infants when iodine deficiency is endemic is greater than to those born into iodine sufficient environments.
  • Preterm infants are more vulnerable to the effects of iodine exposure compared to term infants.
  • British National Formulary for Children 2005 lists neonates under 32 weeks and infants under 1.5kg as contra-indications for the use of iodine

Main research question: What is the incidence of transient hypothyroidism following exposure to iodine in infants less than 32 weeks gestation?

Project status: pilot work (funded by Tenovus (Scotland), Anonymous Trust) is ongoing in collaboration with 7 neonatal units in the UK, and a systematic review has recently been published.

Aitken J, Williams FLR. A systematic review of thyroid function in preterm neonates exposed to topical iodine. Archives Disease Childhood Fetal and Neonatal Edition 2013: doi:10.1136/archdischild-2013-303799I

To find out more, please contact Fiona Williams, Reader, Developmental Epidemiology or visit the website.

Updated December 2013