Thyroid hormones for preventing neurodevelopmental impairment in preterm infants.

BACKGROUND: Observational studies have shown an association between transiently low thyroid hormone levels in preterm infants in the first weeks of life (transient hypothyroxinemia) and abnormal neurodevelopmental outcome. Thyroid hormone therapy might prevent this morbidity.

OBJECTIVES: To assess whether thyroid hormone therapy in preterm infants without congenital hypothyroidism results in clinically important changes in neonatal and long term outcomes in terms of benefits and harms.

SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register, MEDLINE, previous reviews including cross references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching in the English language.

SELECTION CRITERIA: All trials using random or quasi-random patient allocation, in which thyroid hormone therapy (either treatment or prophylaxis) was compared to control in premature infants.

DATA COLLECTION AND ANALYSIS: Primary clinical outcomes included measures of neurodevelopmental outcome and mortality. Assessment of trial quality, data extraction and synthesis of data, using relative risk (RR) and weighted mean difference (WMD), were performed using standard methods of the Cochrane Collaboration and its Neonatal Review Group.

MAIN RESULTS: Nine studies were identified that compared thyroid hormone treatment to control. Four randomized and one quasi-randomized study met inclusion criteria. All studies enrolled preterm infants < 32 weeks gestation, but used different timing, dose and duration of treatment with thyroid hormones. Four studies used thyroxine, whereas Amato 1989 used triiodothyronine. Only two studies with neurodevelopmental follow-up were of good methodology. All studies were of small size with the largest, van Wassenaer 1997, enrolling 200 infants. Meta-analysis of five studies found no significant difference in mortality to discharge (typical RR 0.70, 95% CI 0.42, 1.17) in infants who received thyroid hormone treatment compared to controls. Meta-analysis of two studies found no significant difference in the Bayley MDI or PDI performed at 7-12 months. van Wassenaer 1997 found no significant differences in the Bayley MDI and PDI at 24 months, incidence of cerebral palsy (RR 0.72, 95% CI 0.28, 1.84), death and cerebral palsy (RR 0.70, 95% CI 0.43, 1.14) or the RAKIT IQ score (WMD -2.10, 95% CI -7.91, 3.71) at 5.7 years of age. Fraction of inspired oxygen was lower in infants receiving triiodothyronine in one small quasi-randomized study, but not in infants receiving thyroxine in a randomized study. Duration of mechanical ventilation and incidence of chronic lung disease were not reduced in infants receiving early thyroid hormone therapy.

REVIEWER'S CONCLUSIONS: This review does not support the use of thyroid hormones in preterm infants to reduce neonatal mortality, improve neurodevelopmental outcome or to reduce the severity of respiratory distress syndrome. An analyses of data from one study which showed benefits in infants 24-25 weeks gestation was not prespecified and should be treated with caution. The small number of infants included in trials incorporated in this review limits the power of the meta-analysis to detect clinically important differences in neonatal outcomes. Future trials are warranted and should be of sufficient size to detect clinically important differences in neurodevelopmental outcomes. They should consider enrolling those infants most likely to benefit from thyroid hormone treatment such as infants born at less than 27 weeks gestation.