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

Supplemental Iodide for Preterm Infants and Developmental Outcomes at 2 Years:an RCT

Background The recommendation for enteral iodide intake for preterm infants is 30–40 μg/kg/day and 1μg/kg/day for parenteral intake. Preterm infants are vulnerable to iodide insufficiency and thyroid dysfunction. The hypothesis tested whether, compared to placebo, iodide supplementation of preterm infants improves neurodevelopment. Methods A randomized controlled trial of iodide supplementation versus placebo in infants <31 weeks’ gestation. Trial solutions (sodium iodide or sodium chloride; dose 30μg/kg/day) were given within 42 hours of birth to the equivalent of 34 weeks’ gestation. The only exclusion criterion was maternal iodide exposure during pregnancy or delivery. Whole blood levels of thyroxine, thyrotropin and thyroid binding globulin were measured on four specific postnatal days. The primary outcome was neurodevelopmental status at two years’ of age, measured using the Bayley-III scales. The primary analyses are by intention-to-treat and data are presented also for survivors. Results 1,273 infants (637 intervention, 636 placebo) were recruited from 21 UK neonatal units. 131 infants died, and neurodevelopmental assessments were undertaken in 498 iodide and 499 placebo supplemented infants. There were no significant differences between the intervention and placebo groups in the primary outcome: mean difference Cognitive score, -0.34, 95% confidence interval (CI) -2.57 to 1.89; Motor composite score, 0.21, 95% CI -2.23 to 2.65; Language composite score, -0.05, 95%CI -2.48 to 2.39. There was evidence of weak interaction between iodide supplementation and hypothyroxinemic status in the Language composite score and one subtest score. Conclusions Overall iodide supplementation provided no benefit to neurodevelopment measured at 2 years of age

Iodine supplementation for the prevention of mortality and adverse neurodevelopmental outcomes in preterm infants

BACKGROUND: Parenteral nutrition solutions, artificial formulas, and human breast milk contain insufficient iodine to meet recommended intakes for preterm infants. Iodine deficiency may exacerbate transient hypothyroxinaemia in preterm infants and this may be associated with adverse neonatal and longer-term outcomes. OBJECTIVES: To assess the evidence from randomised controlled trials that dietary supplementation with iodine reduces mortality and morbidity in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 1), Ovid MEDLINE, Ovid Embase, Ovid Maternity & Infant Care Database, and CINAHL to February 2018. We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared supplementing enteral or parenteral feeds with iodine (as iodide salt) versus placebo or no supplementation in preterm infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted data. We analysed treatment effects as described in the individual trials and reported risk ratios (RR) and risk differences for dichotomous data, and mean differences (MD) for continuous data, with 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and planned to explore potential causes of heterogeneity in sensitivity analyses. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: Two randomised controlled trials fulfilled the eligibility criteria. Both trials used methods to limit bias including allocation concealment and blinding of clinicians and investigators to the allocated intervention. The trials enrolled 1394 infants. One trial recruited 1273 participants. Most participants were born very preterm (less than 32 weeks' gestation) and about one-third were extremely preterm (less than 28 weeks' gestation). Analyses found no effect of iodine supplementation on mortality before hospital discharge (typical RR 1.01, 95% CI 0.72 to 1.42; 2 studies, 1380 infants) or on neurodevelopmental assessments at two years post-term (Bayley Scales of Infant and Toddler Development, Third Edition main domain composite scores: cognitive: MD -0.30, 95% CI -2.44 to 1.84; motor: MD 0.20, 95% CI -2.15 to 2.55; language: MD -0.10, 95% CI -2.50 to 2.30; 1 study, 1259 infants). There were no differences in the proportion of infants who died or had a composite score less than 85 in any main Bayley domain (RR 1.05, 95% CI 0.94 to 1.17; 1 study, 1259 infants), or had visual impairment (RR 0.63, 95% CI 0.28 to 1.45; 1 study, 1092 infants) or auditory impairment (RR 1.05, 95% CI 0.51 to 2.16; 1 study, 1093 infants). Using GRADE methods, we assessed the evidence for the effects on mortality and neurodevelopment outcomes as high-certainty. AUTHORS' CONCLUSIONS: The available trial data, predominantly from one large, high-quality multicentre study published in 2017, do not show any evidence of beneficial effects of iodine supplementation for preterm infants. Given the high certainty of these estimates of effect, further trials of this intervention in this population are unlikely to be considered research priorities

Neurodevelopmental Outcomes at 42 Months After Thyroxine Supplementation in Infants Below 28 Weeks' Gestation: A Randomized Controlled Trial.

Background: Infants below 28 weeks' gestation have low thyroid hormone plasma levels compared with more mature infants and this may contribute to their risk of developmental disability. We aimed at determining the effect of supplementation with levothyroxine (LT4) for extremely premature infants born below 28 weeks' gestations on neurodevelopmental outcomes at 42 months. Methods: An explanatory double-blind, randomized, placebo-controlled trial consecutively recruited 153 infants below 28 weeks' gestation from 5 neonatal units in the United Kingdom. Infants were either supplemented with LT4 started intravenously during the first 5 days after birth and then changed to oral LT4 when enteral feeds were fully established (8 μg/kg birthweight/day as a single daily dose) or given placebo until 32 weeks' corrected gestational age. Neurodevelopmental outcomes at 42 months (range 40-43) were evaluated in 59 of these infants (30 LT4-supplemented, 29 placebo) by using Bayley III Mental and Psychomotor Developmental Indices. Cognition outcomes was correlated with plasma free thyroxine (fT4) level at 36 weeks and diffusion tensor imaging (DTI) markers. Results: The LT4 supplemented group performed significantly better in motor, language, and cognitive function domains. The mean of the difference between each group (95% confidence intervals [CI], p-value) was motor domain 6.96 ([0.55-13.38], p = 0.034); language domain 8.93 ([0.16-17.70], p = 0.041); and cognition domain 6.35 ([0.14-12.55], p = 0.045). Neurodevelopmental outcome at 42 months had some associations with the trial's primary outcome (subarachnoid space width and motor outcome, p = 0.03), plasma fT4 level at 36 weeks (fT4 and cognition outcome, p = 0.01), and DTI at 36 weeks with cognition outcomes (p > 0.05). Conclusion: Our data suggest that early supplementation with LT4 may improve long-term neurodevelopment in infants born below 28 weeks' gestation, but larger trials are warranted as the current reported improvements shown are not strong enough to warrant a change in practice

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

Thyroid Function in 509 Premature Newborns Below 31 Weeks of Gestational Age : Evaluation and Follow-up

Preterm and low birth weight (LBW) neonates may present with thyroid dysfunction during a critical period for neurodevelopment. These alterations can be missed on routine congenital hypothyroidism (CH) screening which only measures thyroid stimulating hormone (TSH). The objective of this study was to evaluate a protocol for thyroid function screening (TFS) six years after national implementation. Serum TSH and free thyroxine (fT4) were measured during the second week of life in neonates below 31 weeks. Patients with abnormal TFS (fT4 5 mU/L) were followed up with repeated tests until normal levels were reported. Patients who were still on levothyroxine (LT4) at three years of age were re-evaluated. Five-hundred and nine neonates were included. Thyroid dysfunction was detected in 170 neonates (33%); CH n=20 (3.9%) including typical CH n=1; delayed TSH elevation CH n=19; hypothyroxinemia of prematurity (HOP) n=15 (2.9%); and transient hyperthyrotropinemia n=135 (26.5%). Twenty-one neonates (4.1%) were treated (20 for CH and 1 for HOP). At 3-year follow-up only three patients were diagnosed with permanent CH and still need treatment. LBW infants tended to have TSH levels higher than those with adequate weight. This protocol was able to detect thyroid dysfunction in preterm neonates who were not identified by the current program based on TSH determination in whole-blood. This thyroid dysfunction seems to resolve spontaneously in a few months in the great majority of neonates, but in some cases LT4 could be needed. There is a critical need for specific guidelines regarding the follow-up and re-evaluation of transient CH in preterm neonates

Eur J Endocrinol

When newborn screening (NBS) for congenital hypothyroidism (CH) using thyroid-stimulating hormone (TSH) as a primary screening test was introduced, typical TSH screening cutoffs were 20-50\u2009U/L of whole blood. Over the years, lowering of TSH cutoffs has contributed to an increased prevalence of detected CH. However, a consensus on the benefit deriving from lowering TSH cutoffs at screening is lacking. The present paper outlines arguments both for and against the lowering of TSH cutoffs at NBS. It includes a review of recently published evidence from Australia, Belgium and Italy. A section focused on economic implications of lowering TSH cutoffs is also provided. One issue that bears further examination is the extent to which mild iodine deficiency at the population level might affect the association of neonatal TSH values with cognitive and developmental outcomes. A debate on TSH cutoffs provides the opportunity to reflect on how to make NBS for CH more effective and to guarantee optimum neurocognitive development and a good quality of life to babies with mild as well as with severe CH. All authors of this debate article agree on the need to establish optimal TSH cutoffs for screening programs in various settings and to ensure the benefits of screening and access to care for newborns worldwide.CC999999/Intramural CDC HHS/United States2018-01-11T00:00:00Z28694389PMC5763485vault:2582

Thyroid dysfunction in preterm infants born before 32 gestational weeks

Background Thyroid hormones are critical for growth and brain development during the newborn period and infancy. Because of delayed maturation of the hypothalamic-pituitary-thyroid axis in preterm infants, thyroid dysfunction is common, and thyroid stimulating hormone (TSH) elevation is often delayed in preterm infants. The objective of this study was to determine the incidence of thyroid dysfunction requiring levothyroxine treatment and to identify its risk factors in preterm infants. Methods A retrospective cohort study was performed on preterm infants who were born before 32 gestational weeks and admitted to a single tertiary academic center for more than 8 weeks between January 2008 and December 2014. In these infants, serial thyroid function tests (TFTs) measuring serum TSH and free thyroxine (fT4) were routinely performed at 1, 3, and 6 weeks of postnatal age. Results Of the 220 preterm infants enrolled, 180 infants underwent TFTs at 1, 3, and 6 weeks of postnatal age and were included in the study. Of the 180 infants, 35 infants (19.4%) were started on levothyroxine treatment based on the results of serial TFTs. Among the 35 infants who were treated with levothyroxine, 16 infants (45.7%) had normal results on the initial TFT. Three of these 16 infants continued to have normal results on the second TFT. Thyroid dysfunction requiring levothyroxine treatment was significantly associated with maternal pregnancy-induced hypertension (adjusted odds ratio 2.64, 95% confidence interval 1.02–6.81). Conclusions Thyroid dysfunction requiring levothyroxine treatment occurred in nearly one-fifth of preterm infants born before 32 gestational weeks. Nearly half of the preterm infants who were treated with levothyroxine had normal TSH and fT4 levels at 1 week of postnatal age. The findings of the present study suggest that serial TFTs is important to find preterm infants who require levothyroxine treatment