Pulmonary Effects of Triiodothyronine (T3) and Hydrocortisone (HC) Supplementation in Preterm Infants less than 30 Weeks Gestation: Results of the THORN Trial—Thyroid Hormone Replacement in Neonates

Abstract

The THORN trial was a multicenter, randomized, doubleblind, placebo-controlled clinical trial to test the hypothesis that administration of triiodothyronine (T 3 ) and hydrocortisone would decrease mortality and respiratory morbidity in preterm infants of less than 30 wk gestation. Two hundred fifty-three infants were randomized to receive either 6 g·kg Ϫ1 ·d Ϫ1 of T 3 with 1 mg·kg Ϫ1 ·d Ϫ1 of hydrocortisone or 5% dextrose (placebo) as a continuous i.v. infusion for 7 d. The dose was halved on d 5. Our first primary outcome was death or ventilator dependence at 1 wk, and the second was death or oxygen dependence at 2 wk. The overall mortality rate for both groups was 11.4%. Relative risk of death or ventilator dependence at 1 wk, treated versus placebo, was 0.87, p ϭ 0.2, and death or oxygen dependence at 2 wk, 1.00, p ϭ 0.9. We examined the relationship between free T 3 (FT 3 ) and free thyroxine (FT 4 ) levels in the first 7 d and the primary outcome death or ventilator dependence at 1 wk in all 253 babies. We found significant positive correlations of p ϭ 0.05 for FT 3 and p ϭ 0.002 for FT 4 . Thus the higher the FT 3 and FT 4 levels, the better the outcome. No beneficial effects of T 3 and hydrocortisone were shown. In this study, although FT 3 levels were doubled by the treatment infusion, FT 4 levels were significantly suppressed. The lack of any beneficial effect of T 3 in our study may be explained by suppression of A number of studies have demonstrated that premature babies have low levels of T 3 and T 4 (1-5) and that hypothyroxinemia has been associated with developmental problems (6 -8) and increased respiratory morbidity (9, 10). Consequently, several studies have examined thyroid hormone substitution in preterm infants, but most of these have involved small numbers of subjects. One large study of T 4 given to babies of less than 30 wk gestation assessed neurodevelopmental outcome and found no overall beneficial effect (11). However mental outcome in a subgroup of T 4 -treated infants less than 27 wk gestation was significantly better than in the placebo infants when tested at 2 y of age. Two studies examining respiratory factors as end points, one giving T 4 (12) and another T 3 (13), have not shown any clear-cut benefit.In spite of improvements in neonatal care during the past few decades (14), most tertiary level neonatal units have seen an increase in the incidence (15) of bronchopulmonary dysplasia (chronic lung disease) defined as an oxygen requirement at the age of 4 wk or beyond 36 wk conceptual age. Much of the increase can be attributed to the increasing survival of very premature babies born before 30 wk gestational age, which in turn raises the question of why these infants develop chronic lung disease when pulmonary surfactants are readily available.

Do Cortisol Concentrations Predict Short-Term Outcomes in Extremely Low Birth Weight Infants?

“…28 To evaluate whether these increases in adverse outcomes and elevated cortisol concentrations were related to exposure to inflammation, we performed a subgroup analysis of infants exposed to chorioamnionitis. No differences in outcomes according to cortisol levels were found in this group.…”

Airway Expression of the Epithelial Sodium Channel α-Subunit Correlates With Cortisol in Term Newborns

“…44 In clinical settings, administration of thyroid hormones to preterm infants or antenatal stimulation of thyroid hormone production have failed to improve the respiratory outcome. [45][46][47] In humans, the role of thyroid hormones in airway sodium transport and lung liquid clearance therefore remains unclear.…”

Dopamine Administration in Very Low Birth Weight Preterm Infants:Emerging Issues on Endocrine Effects

“…Consequently, thyroxine levels at newborn screening may convey relevant prognostic information [120], with higher values associated to higher survival rate and less severe lung disease [156]. The positive association between hypothyroxinemia and serious respiratory illness could be explained by a relative lung immaturity, due to lack of thyroid hormones contribution to surfactant production [157], or as a sign of ESS [101,113,120,137].…”

“…Although THOP was initially interpreted as a physiological delay of hypothalamic-pituitary thyroid axis maturation and was therefore not treated with hormone supplementation [101,102,117], the observation that even a brief period of thyroid insufficiency during the critical neurodevelopmental period after preterm birth may cause clinical damages opened new concerns on this point, and clinical studies were performed to analyze whether thyroxin supplementation should be systematically administered in preterm neonates below 32 weeks [104]. As regards to short-term clinical outcome, no reduction of mortality and morbidity was observed in neonates treated with thyroxine [115,156,167,168]. As regards to neurodelopmental outcome, no beneficial effect of T4 supplementation was demonstrated in preterm infants born at 25 to 28 weeks of gestation on growth and psychomotor development at 12 and 24 months of age [122].…”

“…Recently, a single T3 injection at 22-26 h of life followed by a daily T4 e for 6 weeks in infants < 28 weeks GA was demonstrated to induce a short-lasting increase in plasma T3, with increase of T4 and FT4 during the period of T4 administration, but without effects on the cardiovascular system [176]. The lack of any positive effect of T3 administration may be explained by FT4 suppression, probably as a consequence of TSH suppression [156]. Basing on these obsevations, T3 administration in preterm infants cannot be supported [176].…”