Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants.
BACKGROUND
Many preterm infants who survive go on to develop chronic lung disease (CLD). This is true in infants who have had respiratory distress syndrome (RDS) and in infants without RDS. This is probably due to persistence of inflammation in the lung. Corticosteroids have powerful anti-inflammatory effects and have been used to treat established CLD. However, it is unclear whether any beneficial effects outweigh the adverse effects of these drugs.


OBJECTIVE
To determine the effect of late (> 7 days) postnatal corticosteroid treatment compared to control (placebo or nothing) in the preterm infant with CLD.


METHODS
Randomised controlled trials of postnatal corticosteroid therapy were sought from the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE 1966 through May 2008, hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. When possible, authors of all studies were contacted to confirm details of reported follow-up studies or to obtain any information about long-term follow-up where none had been reported.


METHODS
Randomised controlled trials (RCTs) of postnatal corticosteroid treatment initiated after seven days after birth in preterm infants with or developing CLD were selected for this review.


METHODS
Data regarding clinical outcomes including mortality, CLD (including need for home oxygen, or need for late rescue with corticosteroids), death or CLD, failure to extubate, complications in the primary hospitalisation (including infection, hyperglycaemia, glycosuria, hypertension, echodensities on ultrasound scan of brain, necrotising enterocolitis (NEC), gastrointestinal (GI) bleeding, GI perforation, intraventricular hemorrhage (IVH), severe retinopathy of prematurity (ROP), and long-term outcomes (including blindness, deafness, cerebral palsy and major neurosensory disability), were abstracted and analysed using RevMan 5


RESULTS
Nineteen RCTs enrolling a total of 1345 participants were eligible for this review. Late steroid treatment was associated with a reduction in neonatal mortality (at 28 days) but not mortality at discharge or latest reported age. Beneficial effects of delayed steroid treatment included reductions in failure to extubate by 3, 7 or 28 days, CLD at both 28 days and 36 weeks' postmenstrual age (overall and in survivors), need for late rescue treatment with dexamethasone, discharge to home on oxygen therapy, and death or CLD at both 28 days and 36 weeks' postmenstrual age (PMA). There was a trend towards an increase in risk of infection and GI bleeding but not NEC. Short-term adverse affects included hyperglycaemia, glycosuria and hypertension. There was an increase in severe ROP (overall and a trend in survivors) but no significant increase in blindness. There was trend towards a reduction in severe IVH 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.


CONCLUSIONS
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 (see also review of "Early postnatal corticosteroids for preventing chronic lung disease in preterm infants"), this review of postnatal corticosteroid treatment for CLD 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 to infants who cannot be weaned from mechanical ventilation and to minimise the dose and duration of any course of treatment.
Halliday
Henry L
HL
Perinatal Room, Royal-Jubilee Maternity Service, Royal Maternity Hospital, Grosvenor Road, Belfast, Northern Ireland, UK, BT12 6BA. h.halliday@qub.ac.uk
Ehrenkranz
Richard A
RA
Doyle
Lex W
LW
D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D003907:Dexamethasone / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000188:drug therapy* / Q000401:mortality; D008171:Lung Diseases / Q000188:drug therapy* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D003907:Dexamethasone