Title:
Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants.

Abstract:
Many preterm infants who survive go on to develop chronic lung disease. This is probably due to persistent inflammation in the lungs. Corticosteroids have powerful anti-inflammatory effects and have been used to treat established chronic lung disease. However, it is unclear whether any beneficial effects outweigh the adverse effects of these drugs.
To determine the relative benefits and adverse effects associated with late (> 7 days) postnatal systemic corticosteroid treatment compared with control (placebo or nothing) in the preterm infant with evolving or established chronic lung disease.
We sought randomised controlled trials (RCTs) of postnatal corticosteroid therapy from the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 8), MEDLINE (1966 through August 2013), handsearching paediatric and perinatal journals, and by examining previous review articles and information received from practising neonatologists. When possible, we contacted authors of all studies to confirm details of reported follow-up studies or to obtain any information about long-term follow-up where none had been reported.
We selected RCTs of postnatal corticosteroid treatment initiated after seven days after birth in preterm infants with evolving or established chronic lung disease for this review.
We extracted and analysed data regarding clinical outcomes including mortality, chronic lung disease, death or chronic lung disease, failure to extubate, complications in the primary hospitalisation, and long-term health outcomes
Twenty-one RCTs enrolling a total of 1424 participants were eligible for this review. All were randomised controlled trials, but the methods for random allocation were not always clear. Allocation concealment, blinding of the intervention and blinding of the outcome assessments were mostly satisfactory. Late steroid treatment was associated with a reduction in neonatal mortality (at 28 days), but not mortality at discharge or latest reported age. Benefits of delayed steroid treatment included reductions in failure to extubate by three, seven or 28 days, chronic lung disease at both 28 days and 36 weeks' postmenstrual age, need for late rescue treatment with dexamethasone, discharge on home oxygen, and death or chronic lung disease at both 28 days and 36 weeks' postmenstrual age. There was a trend towards an increase in risk of infection and gastrointestinal bleeding, but not necrotising enterocolitis. Short-term adverse affects included hyperglycaemia, glycosuria and hypertension. There was an increase in severe retinopathy of prematurity, but no significant increase in blindness. There was a trend towards a reduction in severe intraventricular haemorrhage, but only 247 infants were enrolled in five studies reporting this outcome. The trends to an increase in cerebral palsy or abnormal neurological examination were partly offset by a trend in the opposite direction in death before late follow-up. The combined rate of death or cerebral palsy was not significantly different between steroid and control groups. Major neurosensory disability, and the combined rate of death or major neurosensory disability, were not significantly different between steroid and control groups. There were no substantial differences between groups for other outcomes in later childhood, including respiratory health or function, blood pressure or growth, although there were fewer with a clinically important reduction in the forced expired volume in one second (FEV1) on respiratory function testing.
The benefits of late corticosteroid therapy may not outweigh actual or potential adverse effects. Although there continues to be concern about an increased incidence of adverse neurological outcomes in infants treated with postnatal steroids, this review of postnatal corticosteroid treatment for chronic lung disease initiated after seven days of age suggests that late therapy may reduce neonatal mortality without significantly increasing the risk of adverse long-term neurodevelopmental outcomes. However, the methodological quality of the studies determining the long-term outcome is limited in some cases; in some studies the surviving children have only been assessed before school age, when some important neurological outcomes cannot be determined with certainty, and no study was sufficiently powered to detect increased rates of important adverse long-term neurosensory outcomes. Given the evidence of both benefits and harms of treatment, and the limitations of the evidence at present, it appears prudent to reserve the use of late corticosteroids for infants who cannot be weaned from mechanical ventilation and to minimise the dose and duration of any course of treatment.