Published online July 5, 2009
PEDIATRICS Vol. 124 No. 2 August 2009, pp. e258-e268 (doi:10.1542/peds.2008-2837)

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ARTICLE

Phase 1 Trial of 4 Thyroid Hormone Regimens for Transient Hypothyroxinemia in Neonates of <28 Weeks' Gestation

Edmund F. La Gamma, MD^a, Aleid G. van Wassenaer, MD, PhD^b, Susana Ares, MD, PhD^c, Sergio G. Golombek, MD, MPH^a, Joke H. Kok, MD, PhD^b, Jose Quero, MD, PhD^c, Ting Hong, MD, PhD^d,e, Mohammad H. Rahbar, PhD^f, Gabriella Morreale de Escobar, PhD^g, Delbert A. Fisher, MD^h and Nigel Paneth, MD, MPH^d,e

^a Department of Neonatal-Perinatal Medicine, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, New York Medical College, Valhalla, New York
^b Department of Neonatology, Emma Children's Hospital-Academic Medical Center, Amsterdam, Netherlands
^c Neonatology Unit, University Hospital La Paz
^g Instituto de Investigaciones Biomedicas, Autonomous University of Madrid and Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain; Departments of
^d Epidemiology
^e Pediatrics and Human Development, Michigan State University, East Lansing, Michigan
^f Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Houston, Texas
^h Quest Diagnostics Nichols Institute, San Juan Capistrano, California

BACKGROUND: Transiently low levels of thyroid hormones occur in 50% of neonates born 24–28 weeks' gestation and are associated with higher rates of cerebral palsy and cognitive impairment. Raising hormone levels shows promise for improving neurodevelopmental outcome.

OBJECTIVE: To identify whether any of 4 thyroid hormone supplementation regimens could raise T₄ and FT₄ without suppressing TSH (biochemical euthyroidism).

METHODS: Eligible subjects had gestational ages between 24 and 27 weeks and were randomized <24 hours of birth to one of six study arms (n = 20–27 per arm): placebo (vehicle: 5% dextrose), potassium iodide (30 µg/kg/d) and continuous or bolus daily infusions of either 4 or 8 µg/kg/d of T₄ for 42 days. T₄ was accompanied by 1 µg/kg/d T₃ during the first 14 postnatal days and infused with 1 mg/mL albumin to prevent adherence to plastic tubing.

RESULTS: FT₄ was elevated in the first 7 days in all hormone-treated subjects; however, only the continuous 8 µg/kg/d treatment arm showed a significant elevation in all treatment epochs (P < .002 versus all other groups). TT₄ remained elevated in the first 7 days in all hormone-treated subjects (P < .05 versus placebo or iodine arms). After 14 days, both 8 µg/kg/d arms as well as the continuous 4 µg/kg/d arm produced a sustained elevation of the mean and median TT₄, >7 µg/dL (90 nM/L; P < .002 versus placebo). The least suppression of THS was achieved in the 4 µg/kg/d T₄ continuous infusion arm. Although not pre-hypothesized, the duration of mechanical ventilation was significantly lower in the continuous 4 µg/kg/d T₄ arm and in the 8 µg/kg/d T₄ bolus arm (P < .05 versus remaining arms). ROP was significantly lower in the combined 4 thyroid hormone treatment arms than in the combined placebo and iodine arms (P < .04). NEC was higher in the combined 8 µg/kg/d arms (P < .05 versus other arms).

CONCLUSIONS: Elevation of TT₄ with only modest suppression of TSH was associated with trends suggesting clinical benefits using a continuous supplement of low-dose thyroid hormone (4 µg/kg/d) for 42 days. Future trials will be needed to assess the long-term neurodevelopmental effects of such supplementation.

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Key Words: thyroxine • triiodothyronine • hypothyroxinemia • thyroid hormone • monodeiodinase • extremely low birth weight neonate • transient hypothyroxinemia • nonthyroidal illness • euthyroid sick syndrome • cerebral palsy • prematurity • randomized • controlled trial

Abbreviations: CP—cerebral palsy • CLD—chronic lung disease • DSMB—data safety monitoring board • D5W—5% dextrose water • ELGAN—extremely low gestational age neonate • FT₄—free circulating thyroxine • GM—germinal Matrix • I2—Iodine • IVH—intraventricular hemorrhage • NEC—necrotizing enterocolitis • PO—per os • PVL—periventricular leukomalacia • ROP—retinopathy of prematurity • T₃—triiodothyronine • TT₃—total circulating T₃ • T₄—thyroxine • TT₄—total circulating T₄ • TBG—thyroid-binding globulin • THOP—transient hypothyroxinemia of prematurity

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Accepted Mar 31, 2009.

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