Treatment of extremely low gestational age neonates (ELGANS) with thyroid hormone

TOPIC: Treatment of transient hypothyroxinemia of prematurity

Title: Phase 1 trial of four thyroid hormone regimens for transient hypothyroxinemia in neonates of less than 28 weeks’ gestation .

Authors: La Gamma EF, van Wassenaer AG, Ares S, Golumbek SG, Kok JH, Quero J, Hong T, Rahbar MH, Morreale de Escobar G, Fisher DA, & Paneth N .

Reference: Pediatrics 124: e258 – e268, 2009

Summary

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 24-26/7 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/day) and continuous or bolus daily infusions of either 4 or 8 µg/kg/day of T4 for 42 days. T4 was accompanied by 1 µg/kg/day of 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/day treatment arm showed a significant elevation in all treatment epochs (P <0.002 versus all other groups). Total T4 (TT4) remained elevated in the first 7 days in all hormone-treated subjects (P <0.05 versus placebo or iodine arms). After 14 days, both 8 µg/kg/day arms as well as the continuous 4 µg/kg/day arm produced a sustained elevation of the mean and median TT4 above 7 µg/dL (90 nMol/L; P <0.002 versus placebo). The least suppression of TSH was achieved in the 4 µg/kg/day T4 continous infusion arm. Although not pre-hypothesized, the duration of mechanical ventilation was significantly lower in the continuous 4 µg/kg/day T4 arm and in the 8 µg/kg/day T4 bolus arm (P <0.05 versus remaining arms). ROP (retinopathy of prematurity) was significantly lower in the combined 4 treatment arms than in the combined placebo and iodine arms (P <0.04). NEC (necrotizing entoerocolitis) was higher in the combined 8 µg/kg/day arms (P <0.05 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/day) for 42 days. Future trials will be needed to assess the long-term neurodevelopmental effects of such supplementation.

Commentary

Although the survival of extremely premature infants has improved remarkably in the last few decades, there continues to be an unacceptably high incidence of morbidity in these infants. More than 50% of babies <30 weeks gestation develop transient hypothyroxinemia, the severity of which is related to the degree of immaturity and the Online Pokies etiology of which is complex. Several retrospective, cohort studies in the past have documented an apparent relationship between thyroid hormone status and both developmental delay and disabling cerebral palsy. However, a causal relationship could not be determined since the serum T4 in premature infants, as in adults, has been shown to reflect the severity of the underlying illness and risk of death. Therefere, whether or not hypothyroxinemia of prematurity should be treated remains highly controversial.

In the most thorough prior study to date, Van Wassenaer et al. carried out a placebo-controlled, double blind trial of L-thyroxine treatment, using 8 μg/kg per day given for 6 weeks in 200 infants less than 30 weeks gestation1. Although overall no difference in cognitive outcome was found, there was an 18-point increase in the Bayley Mental Development Index score in the subgroup of T4-treated infants < 27 weeks gestation, when re-evaluated at 2 years of age. Of some concern was the additional finding that treatment was associated with a 10-point decrease in mental score (P = 0.03) in infants > 27 weeks gestation. When the cohort was re-evaluated at 10 years of age, the difference in IQ was no longer significant, although modest differences in motor achievement and the need for special education persisted.

The present multicenter study, while providing further important data, demonstrates once again the complexity of the issue. Overall, the continuous 4 µg/kg treatment arm (i.e., half the dosage used in the previous Dutch study), combined with 1 µg/kg T3 for the first 14 postnatal days, provided the optimal combination of improved circulating thyroid hormone levels without suppression of serum TSH concentrations. However, the benefits versus adverse effects of the different treatment arms were mixed. There was a significant reduction in the duration of mechanical ventilation and/or retinopathy of prematurity (ROP) in one or other therapeutic regimens but an increased incidence of necrotizing entoerocolitis (NEC). The neurocognitive outcome, of particular concern in this patient population, remains to be determined.

Thus, while the authors of the present study are to be congratulated for an excellent and difficult pilot study, the benefits versus risks of thyroid hormone substitution and even the optimal treatment regimen to use continue to be unclear. Until such data become available, every effort should be made to treat the primary illness and to avoid drugs (e.g., dopamine, steroids) that are known to suppress TSH. However, I would agree with the recent recommendations that, at present time, infants be treated only in the context of a clinical trial and, optimally, such therapy be reserved for those who are hypothyroxinemic2,3.

1. Van Wassenaer AG et al. N Engl J Med 336: 21-26, 1997 2. Williams et al. Early Hum Dev 82: 797-802, 2006 3. Osborne DA, Hunt RW. The Cochrane Rev. (4): 1-91, 2007

Summary and Commentary prepared by Rosalind S. Brown (Related to Chapter 15 of TDM)