ABSTRACT
BACKGROUND: In order to assess relationships between thyroid hormone status and findings on brain MRI, a subset of babies was recruited to a multi-centre randomised, placebo-controlled trial of levothyroxine (LT4) supplementation for babies born before 28 weeks' gestation (known as the TIPIT study, for Thyroxine supplementation In Preterm InfanTs). These infants were imaged at term-equivalence. MATERIALS AND METHODS: Forty-five TIPIT participants had brain MRI using diffusion tensor imaging (DTI) to estimate white matter development by apparent diffusion coefficient (ADC), fractional anisotropy (FA) and tractography metrics of number and length of streamlines. We made comparisons between babies with the lowest and highest plasma FT4 concentrations during the initial 4 weeks after birth. RESULTS: There were no differences in DTI metrics between babies who had received LT4 supplementation and those who had received a placebo. Among recipients of a placebo, babies in the lowest quartile of plasma-free thyroxine (FT4) concentrations had significantly higher apparent diffusion coefficient measurements in the posterior corpus callosum and streamlines that were shorter and less numerous in the right internal capsule. Among LT4-supplemented babies, those who had plasma FT4 concentrations in the highest quartile had significantly lower apparent diffusion coefficient values in the left occipital lobe, higher fractional anisotropy in the anterior corpus callosum and longer and more numerous streamlines in the anterior corpus callosum. CONCLUSION: DTI variables were not associated with allocation of placebo or thyroid supplementation. Markers of poorly organised brain microstructure were associated with low plasma FT4 concentrations after birth. The findings suggest that plasma FT4 concentrations affect brain development in very immature infants and that the effect of LT4 supplementation for immature babies with low FT4 plasma concentrations warrants further study.
Subject(s)
Brain/drug effects , Brain/growth & development , Dietary Supplements , Magnetic Resonance Imaging/methods , Thyroxine/blood , Thyroxine/therapeutic use , Anisotropy , Brain Mapping/methods , Diffusion Tensor Imaging/methods , Double-Blind Method , Female , Humans , Infant, Extremely Premature , Infant, Newborn , MaleABSTRACT
BACKGROUND: Babies born before 28 weeks' gestation have lower plasma thyroid hormone concentrations than more mature infants. This may contribute to their risk of poor developmental outcome. Previous studies have suggested that thyroxine supplementation for extremely preterm neonates may be beneficial. The aim of this study was to investigate the effect of administration of supplemental thyroxine to very premature babies on brain size and somatic growth at 36 weeks' corrected gestational age (CGA). METHODS: In this explanatory multicentre double blind randomised placebo controlled trial, 153 infants born below 28 weeks' gestation were randomised to levothyroxine (LT4) supplementation or placebo until 32 weeks' CGA. The primary outcome was brain size assessed by the width of the subarachnoid space measured by cranial ultrasound at 36 weeks' CGA. Lower leg length was measured by knemometry. RESULTS: Babies in the LT4-supplemented and placebo groups had similar baseline characteristics. There were no significant differences between infants given LT4 (n=78) or placebo (n=75) for width of the subarachnoid space, head circumference at 36 weeks' CGA, body weight at 36 weeks' CGA or mortality. Infants who received LT4 had significantly shorter leg lengths at 36 weeks' CGA although adjusted analysis for baseline length did not find a statistical difference. There was a significant correlation between low FT4 and wider subarachnoid space. No unexpected serious adverse events were noted and incidence of adverse events did not differ between the two groups. CONCLUSION: This is the only randomised controlled trial of thyroxine supplementation targeting extremely premature infants. Supplementing all babies below 28 weeks' gestation with LT4 had no apparent effect on brain size. These results do not support routine supplementation with LT4 for all babies born below 28 weeks' gestation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89493983EUDRACT number: 2005-003-09939.
Subject(s)
Hormone Replacement Therapy , Infant, Extremely Premature/blood , Thyroxine/therapeutic use , Adult , Brain/drug effects , Brain/growth & development , Cephalometry , Double-Blind Method , Echoencephalography , England , Female , Gestational Age , Hormone Replacement Therapy/adverse effects , Humans , Infant Mortality , Infant, Newborn , Lower Extremity/growth & development , Male , Organ Size , Subarachnoid Space/diagnostic imaging , Thyroxine/adverse effects , Thyroxine/blood , Thyroxine/deficiency , Time Factors , Treatment Outcome , Young AdultABSTRACT
The conduct of clinical trials in the UK has been affected by the recent introduction of managed clinical networks, clinical research networks and rigorous governance regulations. This commentary considers the challenges that these changes have posed for clinical triallists in the UK, based on experiences derived in the conduct of a multicentre neonatal clinical trial under the conditions that now prevail. We conclude that the considerable skills and knowledge that are now required to be an effective Principal Investigator should be recognised and that application processes, including issuing honorary contracts, should be simplified and centralised.
