Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.
BACKGROUND
Chronic lung disease remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis. Corticosteroids have been used to either prevent or treat chronic lung disease because of their potent anti-inflammatory effects.


OBJECTIVE
To examine the relative benefits and adverse effects of postnatal corticosteroids commenced within the first seven days of life to preterm infants at risk of developing chronic lung disease.


METHODS
We sought randomised controlled trials (RCTs) of postnatal corticosteroid therapy from the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 8), MEDLINE (1966 to August 2013), handsearching paediatric and perinatal journals, and by examining previous review articles and information received from practising neonatologists. We contacted authors of all studies, where possible, to confirm details of reported follow-up studies, or to obtain any information about long-term follow-up where none had been reported.


METHODS
We selected RCTs of postnatal corticosteroid treatment within the first seven days of life (early) in high-risk preterm infants for this review. Most studies evaluated the use of dexamethasone but we also included studies that assessed hydrocortisone, even if it was used primarily to manage hypotension.


METHODS
We extracted and analysed data regarding clinical outcomes that included mortality, chronic lung disease, death or chronic lung disease, failure to extubate, complications during the primary hospitalisation, and long-term health outcomes.


RESULTS
Twenty-nine RCTs enrolling a total of 3750 participants were eligible for inclusion in this review. The overall risk for bias was probably low as all were randomised controlled trials, and most trials have used rigorous methods. There were significant benefits for the following outcomes: lower rates of failure to extubate and decreased risks of chronic lung disease at both 28 days and 36 weeks' postmenstrual age, death or chronic lung disease at 28 days and 36 weeks' postmenstrual age, patent ductus arteriosus and ROP, including severe ROP. There were no significant differences in the rates of neonatal or subsequent mortality, infection, severe intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis or pulmonary haemorrhage. Gastrointestinal bleeding and intestinal perforation were important adverse effects. The risks of hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure were also increased. In the 12 trials that reported late outcomes, several adverse neurological effects were found at follow-up examinations, including developmental delay (not defined), cerebral palsy and abnormal neurological examination. However, major neurosensory disability was not significantly increased, either overall in the seven studies where this outcome could be determined, or in the two individual studies where the rates of cerebral palsy or abnormal neurological examination were significantly increased. Moreover, the rates of the combined outcomes of death or cerebral palsy, or of death or major neurosensory disability, were not significantly increased. Dexamethasone was used in most studies (n = 20); only nine studies used hydrocortisone. In subgroup analyses by type of corticosteroid, most of the beneficial and harmful effects were attributable to dexamethasone; hydrocortisone had little effect on any outcomes except for an increase in intestinal perforation and a borderline reduction in patent ductus arteriosus.


CONCLUSIONS
The benefits of early postnatal corticosteroid treatment (≤ 7 days), particularly dexamethasone, may not outweigh the adverse effects of this treatment. Although early corticosteroid treatment facilitates extubation and reduces the risk of chronic lung disease and patent ductus arteriosus, it causes short-term adverse effects including gastrointestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure. Long-term follow-up studies report an increased risk of abnormal neurological examination and cerebral palsy. However, the methodological quality of the studies determining long-term outcomes is limited in some cases; the surviving children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. There is a compelling need for the long-term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all randomised trials of early postnatal corticosteroid treatment. Hydrocortisone in the doses and regimens used in the reported RCTs has few beneficial or harmful effects and cannot be recommended for the prevention of chronic lung disease.
Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, Victoria, Australia, 3052.
Lex W
LW
Doyle
Richard A
RA
Ehrenkranz
Henry L
HL
Halliday
D000280:Administration, Inhalation; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D003907:Dexamethasone / Q000009:adverse effects / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000009:adverse effects / Q000627:therapeutic use; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000517:prevention & control*; D008171:Lung Diseases / Q000517:prevention & control*; D010102:Oxygen Inhalation Therapy / Q000706:statistics & numerical data; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D003907:Dexamethasone; D006854:Hydrocortisone