How does treatment with thyroxine for 6 weeks postnatally given to preterm infants born under 28 weeks' gestation affect

Hypothyroidism is a condition where there is a lack of thyroid hormone in the body. Thyroid hormones are important for normal brain development and growth. Children who are born with low thyroid hormones have severe learning difficulties if they are not treated early. Babies born very early are at increased risk of developmental delay. Such premature babies often have low levels of thyroid hormone in their blood during the first weeks of life. A few babies born very early have received thyroid hormone treatment and this has been found to improve development. However, such replacement therapy is not generally used in clinical practice.

The study protocol is based on recent evidence that very preterm babies are lacking in sufficient thyroid hormones and may benefit from thyroid hormone treatment at an early stage. Recent guidelines from the National Institute for Clinical Excellence emphasise the need for rigorous evaluation of treatments in children.

The proposed study is a randomised controlled trial of thyroid hormone replacement in babies born very early to determine hormonal effects, growth and brain size in relation to thyroid hormone levels.

Infants born at extreme prematurity (before 28 weeks gestation) are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone (hypothyroidism) which occurs in up to 69% of these infants. Among infants born at term, the disability associated with hypothyroidism in the immediate postnatal period can be prevented by giving supplementary thyroid hormone: even mild thyroid hormone insufficiency can produce measurable, but preventable deficits in neuropsychological functions. At present there is uncertainty amongst clinicians about the most appropriate way of responding to hypothyroidism in extremely premature infants and most adopt a ‘wait and see‘ approach and do not treat this apparent deficiency. Recent guidelines from the National Institute for Clinical Excellence emphasise the need for rigorous evaluation of therapeutic strategies in children rather than treating them on an ad hoc basis. The literature suggests that some, but not all, forms of thyroid supplementation may reduce the incidence of disability in infants born at extreme prematurity. However, the indications for thyroid supplementation remain unclear. The literature also indicates that several areas of uncertainty will hamper randomised controlled studies of this topic. These areas include: the optimal timing of monitoring, whether it is appropriate to use reference ranges based on cord blood values and the relationship between HPT and HPA axes.

This research will examine issues central to the design of pragmatic efficacy studies using an explanatory trial in which infants are randomly assigned to thyroid supplementation (LT-4) or placebo for 6 weeks postnatally, and assessments made of the effect of thyroid supplementation on brain size, somatic growth, hypothalamic-pituitary-adrenal axis and relationship of thyroid status and thyroid gland size.

The results of this study will contribute to decisions about which confounding variables to assess in large-scale studies. By examining the extent of variability in key intermediate outcomes and important potential confounders, we will contribute to refined sample size calculations for future trials on long term effects on neurodevelopmental outcome. This work will contribute to a reduction in childhood disability by indicating the most efficient ways to conduct large-scale trials of promising interventions for hypothyroidism in preterm infants.