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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>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.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN89493983</p

Increasing illness severity in very low birth weight infants over a 9-year period

BACKGROUND: Recent reports have documented a leveling-off of survival rates in preterm infants through the 1990's. The objective of this study was to determine temporal changes in illness severity in very low birth weight (VLBW) infants in relationship to the outcomes of death and/or severe IVH. METHODS: Cohort study of 1414 VLBW infants cared for in a single level III neonatal intensive care unit in Delaware from 1993–2002. Infants were divided into consecutive 3-year cohorts. Illness severity was measured by two objective methods: the Score for Neonatal Acute Physiology (SNAP), based on data from the 1(st )day of life, and total thyroxine (T(4)), measured on the 5(th )day of life. Death before hospital discharge and severe intraventricular hemorrhage (IVH) were investigated in the study sample in relation to illness severity. The fetal death rate was also investigated. Statistical analyses included both univariate and multivariate analysis. RESULTS: Illness severity, as measured by SNAP and T(4, )increased steadily over the 9-year study period with an associated increase in severe IVH and the combined outcome of death and/or severe IVH. During the final 3 years of the study, the observed increase in illness severity accounted for 86% (95% CI 57–116%) of the variability in the increase in death and/or severe IVH. The fetal death rate dropped from 7.8/1000 (1993–1996) to 5.3/1000 (1999–2002, p = .01) over the course of the study. CONCLUSION: These data demonstrate a progressive increase in illness in VLBW infants over time, associated with an increase in death and/or severe IVH. We speculate that the observed decrease in fetal death, and the increase in neonatal illness, mortality and/or severe IVH over time represent a shift of severely compromised patients that now survive the fetal time period and are presented for care in the neonatal unit

TIPIT: A randomised controlled trial of thyroxine in preterm infants under 28 weeks gestation: Magnetic Resonance Imaging and Magnetic Resonance Angiography protocol

<p>Abstract </p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p><b>Trial registration</b></p> <p>Current Controlled Trials ISRCTN89493983</p

The association of neonatal morbidity with long-term neurological outcome in infants who were growth restricted and preterm at birth: secondary analyses from TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe)

Objective To study the relationship between neonatal morbidity (NNM) and two‐year neurodevelopmental impairment (NDI) in surviving children after early fetal growth restriction (FGR). Design Secondary analysis of a European randomised trial (TRUFFLE) of delivery for very preterm fetuses dependent on venous Doppler or cardiotocographic criteria. Setting Tertiary perinatal centres, participants in TRUFFLE. Population 402 surviving children after early FGR. Methods Prospective data were collection from the recognition of FGR until the corrected age of two years. We studied the association between NNM and NDI, retaining trial allocation in all statistical models. NNM included any of bronchopulmonary dysplasia, brain injury, sepsis or necrotising enterocolitis. NDI was a composite of Bayley cognitive score < 85, cerebral palsy or severe sensory impairment. Main outcome measure NDI in relation to NNM. Results NNM occurred in 104 cases (26%) and was more frequent in 17 of 39 infants with NDI (44%) than in the 87 of 363 infants with normal outcome (24%) [odds ratio 2.5 (95% CI, 1.3–4.8); P = 0.01]. In 22 of 39 NDI cases (56%) there was no preceding NNM. NNM was inversely related to gestational age, but NDI did not vary by gestational age. In multivariable analyses, cerebral ultrasound abnormalities were most strongly associated with NDI, together with trial group allocation, birthweight ratio, infant sex and Apgar score. Conclusions With the exception of cerebral ultrasound abnormalities, commonly used NNMs are poor markers of later NDI and should not be used as surrogate outcomes for NDI

The association of neonatal morbidity with long-term neurological outcome in infants who were growth restricted and preterm at birth: secondary analyses from TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe)

Objective To study the relationship between neonatal morbidity (NNM) and two-year neurodevelopmental impairment (NDI) in surviving children after early fetal growth restriction (FGR). Design Secondary analysis of a European randomised trial (TRUFFLE) of delivery for very preterm fetuses dependent on venous Doppler or cardiotocographic criteria. Setting Tertiary perinatal centres, participants in TRUFFLE. Population 402 surviving children after early FGR. Methods Prospective data were collection from the recognition of FGR until the corrected age of two years. We studied the association between NNM and NDI, retaining trial allocation in all statistical models. NNM included any of bronchopulmonary dysplasia, brain injury, sepsis or necrotising enterocolitis. NDI was a composite of Bayley cognitive score <85, cerebral palsy or severe sensory impairment. Main outcome measure NDI in relation to NNM. Results NNM occurred in 104 cases (26%) and was more frequent in 17 of 39 infants with NDI (44%) than in the 87 of 363 infants with normal outcome (24%) [odds ratio 2.5 (95% CI, 1.3-4.8); P = 0.01]. In 22 of 39 NDI cases (56%) there was no preceding NNM. NNM was inversely related to gestational age, but NDI did not vary by gestational age. In multivariable analyses, cerebral ultrasound abnormalities were most strongly associated with NDI, together with trial group allocation, birthweight ratio, infant sex and Apgar score. Conclusions With the exception of cerebral ultrasound abnormalities, commonly used NNMs are poor markers of later NDI and should not be used as surrogate outcomes for ND