Low-Dose Hydrocortisone May Increase Survival without Bronchopulmonary Dysplasia in Extremely Preterm Neonates

EBM Focus - Volume 11, Issue 18

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Reference - PREMILOC trial (Lancet 2016 Apr 30;387(10030):1827) (level 2 [mid-level] evidence)

  • Bronchopulmonary dysplasia (BPD) is common in extremely preterm infants, but prevention strategies are limited.
  • Low-dose hydrocortisone IV given within 24 hours of birth to neonates born at gestational age 24-27 6/7 weeks significantly increased survival without BPD at 36 weeks postmenstrual age and improved other respiratory outcomes.
  • There were no significant differences in adverse events comparing low-dose hydrocortisone vs. placebo and a follow-up study is currently underway to assess the long-term safety of this intervention.

BPD is a major cause of morbidity and mortality in extremely preterm infants (born at gestational age < 28 weeks) and is associated with poor neurodevelopmental outcomes (Pediatr Rev 2012 Jun;33(6):255). The American Academy of Pediatrics (AAP) recommends treatment with early low-dose hydrocortisone to help prevent BPD in specific populations, especially infants exposed to chorioamnionitis (Pediatrics 2010 Oct;126(4):800). However hydrocortisone therapy is not without risks and the AAP found insufficient evidence to recommend its use in all infants at risk of BPD due to an increased risk of spontaneous gastrointestinal perforation, mostly in patients with early concomitant indomethacin use (Pediatrics 2004 Dec;114(6):1649). A large randomized trial (the PREMILOC trial) was recently performed to further investigate the potential benefits of low-dose hydrocortisone in preterm neonates.

The PREMILOC trial randomized 523 extremely preterm infants born at gestational age 24-27 6/7 weeks within 24 hours of birth to low-dose hydrocortisone vs. placebo for 10 days. The low-dose hydrocortisone regimen included 0.5 mg/kg hydrocortisone hemisuccinate IV 2 times daily for 7 days then once daily for 3 days (8.5 mg/kg cumulative dose). Ibuprofen for the treatment of patent ductus arteriosus was not allowed during the first 24 hours of life to decrease the risk for spontaneous gastrointestinal perforation. The trial was terminated early due to financial issues, but the analysis still showed a significant benefit in several outcomes with low-dose hydrocortisone therapy. Comparing low-dose hydrocortisone vs. placebo at 36 weeks postmenstrual age, low dose hydrocortisone was associated with increased survival without BPD (60% vs. 51%, p = 0.04, NNT 12) as well as increased weaning from any supplemental oxygen (55% vs. 45%, p = 0.04, NNT 10). Low-dose hydrocortisone was also associated with a higher rate of infants extubated by day 10 and a lower rate of patent ductus arteriosus ligation, but the individual rates of mortality and BPD were not significantly different between the two groups. There were no significant differences in serious adverse events such as gastrointestinal perforation, necrotizing enterocolitis, pulmonary hemorrhage, or the need for insulin.

Corticosteroids are commonly used for the prevention of BPD in extremely preterm infants, but the evidence supporting their use has been limited. With a treatment duration shorter than those used in previous trials, the PREMILOC trial found a benefit of hydrocortisone at the lowest reported cumulative dose. This low cumulative dose did not appear to increase the risk of short-term adverse events. Indeed, this trial found no increase in the risk of gastrointestinal perforation previously observed with low-dose hydrocortisone therapy, likely due to the delay of nonsteroidal antiinflammatory drugs for the treatment of patent ductus arteriosus. Overall, the results of this trial suggest that low-dose hydrocortisone for 10 days may improve early respiratory outcomes in extremely preterm infants, but these results should be cautiously considered until further information is available. A follow-up study is currently underway to assess the long-term safety and neurodevelopmental outcomes as these infants reach 18-22 months of age.

For more information, see the Bronchopulmonary dysplasia and Evaluation and management of the premature infant topics in DynaMed Plus. DynaMed users click here and here.