High versus low dose of initial thyroid hormone replacement for congenital hypothyroidism.

BACKGROUND: Congenital hypothyroidism (CHT) affects approximately one in 3000 to 4000 infants. CHT is one of the most common preventable causes of learning difficulties. Optimal management of CHT requires early diagnosis and prompt treatment to avoid abnormal neurodevelopmental outcome. One of the main issues in the management of CHT relates to the initial dose of levothyroxine to be used in order to achieve optimal results in terms of intellectual development. Currently, it remains unclear whether high dose thyroid hormone replacement is more effective than low dose in the treatment of CHT. Further research is required to determine an appropriate dose that improves mental and psychomotor developmental outcomes. OBJECTIVES: To determine the effects of high versus low dose of initial thyroid hormone replacement for congenital hypothyroidism. SEARCH STRATEGY: Randomised controlled trials were identified by searching The Cochrane Library, MEDLINE and EMBASE and reference lists of published papers. SELECTION CRITERIA: Randomised controlled clinical trials investigating the effects of high versus low dose of initial thyroid hormone replacement for congenital hypothyroidism were included. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed risk of bias and extracted data. MAIN RESULTS: The initial search identified 1014 records which identified 13 publications for further examination. After screening the full text of the 13 selected papers, only one study evaluating 47 babies finally met the inclusion criteria. Using the same cohort at two different time periods, the study investigated the effects of high versus low dose thyroid hormone replacement in relation to (1) time taken to achieve euthyroid status and (2) neurodevelopmental outcome. The study reported that a high dose is more effective in rising serum thyroxine and free thyroxine concentrations to the target range and earlier normalisation of thyroid stimulating hormone compared to a lower dose. Similarly, full scale intelligence quotient was noted to be significantly higher in children who received the high dose compared to the lower dose. However, the verbal intelligence quotient and performance intelligence quotient were similar in both groups. Growth and adverse effects were not reported in the included trial. AUTHORS' CONCLUSIONS: There is currently only one randomised controlled trial evaluating the effects of high versus low dose of initial thyroid hormone replacement for CHT. There is inadequate evidence to suggest that a high dose is more beneficial compared to a low dose initial thyroid hormone replacement in the treatment of CHT.

TIPIT: a randomised controlled trial of thyroxine in preterm infants under 28 weeks gestation: magnetic resonance imaging and magnetic resonance angiography protocol.

BACKGROUND: Infants born at extreme prematurity are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone described as hypothyroxinaemia, which is recognised to be a frequent phenomenon in these infants. Derangements of critical thyroid function during the sensitive window in prematurity when early development occurs, may have a range of long term effects for brain development. Further research in preterm infants using neuroimaging techniques will increase our understanding of the specificity of the effects of hypothyroxinaemia on the developing foetal brain. This is an explanatory double blinded randomised controlled trial which is aimed to assess the effect of thyroid hormone supplementation on brain size, key brain structures, extent of myelination, white matter integrity and vessel morphology, somatic growth and the hypothalamic-pituitary-adrenal axis. METHODS: The study is a multi-centred double blinded randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks corrected gestational age. The primary outcomes will be width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks corrected gestational age. The secondary outcomes will be thyroid hormone concentrations, the hypothalamic pituitary axis status and auxological data between birth and expected date of delivery; thyroid gland volume, brain size, volumes of key brain structures, extent of myelination and brain vessel morphology at expected date of delivery and markers of morbidity which include duration of mechanical ventilation and/or oxygen requirement and chronic lung disease. Trial registration Current Controlled Trials ISRCTN89493983.

TIPIT: A randomised controlled trial of thyroxine in preterm infants under 28 weeks' gestation.

BACKGROUND: Infants born at extreme prematurity (below 28 weeks' gestation) are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone which is recognised to be a frequent phenomenon in these infants. At present it is unclear whether low levels of thyroid hormone are a cause of disability, or a consequence of concurrent adversity. METHODS: We propose an explanatory multi-centre double blind randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks' corrected gestational age. The primary outcome will be brain growth. This will be assessed by the width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks' corrected gestational. The secondary outcomes will be (a) thyroid hormone concentrations measured at increasing postnatal age, (b) status of the hypothalamic pituitary axis, (c) auxological data between birth and 36 weeks' corrected gestational age, (d) thyroid gland volume, (e) volumes of brain structures (measured by magnetic resonance imaging), (f) determination of the extent of myelination and white matter integrity (measured by diffusion weighted MRI) and brain vessel morphology (measured by magnetic resonance angiography) at expected date of delivery and (g) markers of morbidity including duration of mechanical ventilation and chronic lung disease.We will also examine how activity of the hypothalamic-pituitary-adrenal axis modulates the effects of thyroid supplementation. This will contribute to decisions about which confounding variables to assess in large-scale studies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89493983.

Effect of carbon dioxide on background cerebral electrical activity and fractional oxygen extraction in very low birth weight infants just after birth.

Decreased arterial carbon dioxide tension (PaCO2) results in decreased cerebral blood flow, which is associated with diminished cerebral electrical activity. In such a situation, cerebral fractional oxygen extraction (CFOE) would be expected to increase to preserve cerebral oxygen delivery. This study aimed to determine whether changes in blood gases in infants less than 30 wk' gestation were associated with changes in background electroencephalograms (EEG) and CFOE. Thirty-two very low birth weight infants were studied daily for the first three days after birth. Digital EEG recordings were performed for 75 min each day. CFOE, mean blood pressure and arterial blood gases were measured midway through each recording. EEG was analysed by (a) spectral analysis and (b) manual calculation of interburst interval. Blood pressure, pH and PaCO2 did not have any effect on the EEG. On day one, only PaCO2 showed a relationship with the relative power of the delta frequency band (0.5-3.5 Hz) and the interburst interval. The relative power of the delta band remained within normal limits when PaCO2 was between 24 and 55 mmHg on day one. There was a negative association between PaCO2 and CFOE. The associations between PaCO2 and EEG measurements were strongest on day one, weaker on day two, and absent on day three. The slowing of EEG and increased CFOE at lower levels of PaCO2 are likely to be due to decreased cerebral oxygen delivery induced by hypocarbia. When PaCO2 was higher, there was suppression of the EEG.