Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial

Summary

Background

Bronchopulmonary dysplasia, a major complication of extreme prematurity, has few treatment options. Postnatal steroid use is controversial, but low-dose hydrocortisone might prevent the harmful effects of inflammation on the developing lung. In this study, we aimed to assess whether low-dose hydrocortisone improved survival without bronchopulmonary dysplasia in extremely preterm infants.

Methods

In this double-blind, placebo-controlled, randomised trial done at 21 French tertiary-care neonatal intensive care units (NICUs), we randomly assigned (1:1), via a secure study website, extremely preterm infants inborn (born in a maternity ward at the same site as the NICU) at less than 28 weeks of gestation to receive either intravenous low-dose hydrocortisone or placebo during the first 10 postnatal days. Infants randomly assigned to the hydrocortisone group received 1 mg/kg of hydrocortisone hemisuccinate per day divided into two doses per day for 7 days, followed by one dose of 0·5 mg/kg per day for 3 days. Randomisation was stratified by gestational age and all infants were enrolled by 24 h after birth. Study investigators, parents, and patients were masked to treatment allocation. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. We used a sequential analytical design, based on intention to treat, to avoid prolonging the trial after either efficacy or futility had been established. This trial is registered with ClinicalTrial.gov, number NCT00623740.

Findings

1072 neonates were screened between May 25, 2008, and Jan 31, 2014, of which 523 were randomly assigned (256 hydrocortisone, 267 placebo). 255 infants on hydrocortisone and 266 on placebo were included in analyses after parents withdrew consent for one child in each group. Of the 255 infants assigned to hydrocortisone, 153 (60%) survived without bronchopulmonary dysplasia, compared with 136 (51%) of 266 infants assigned to placebo (odds ratio [OR] adjusted for gestational age group and interim analyses 1·48, 95% CI 1·02–2·16, p=0·04). The number of patients needed to treat to gain one bronchopulmonary dysplasia-free survival was 12 (95% CI 6–200). Sepsis rate was not significantly different in the study population as a whole, but subgroup analyses showed a higher rate only in infants born at 24–25 weeks gestational age who were treated with hydrocortisone (30 [40%] of 83 vs 21 [23%] of 90 infants; sub-hazard ratio 1·87, 95% CI 1·09–3·21, p=0·02). Other potential adverse events, including notably gastrointestinal perforation, did not differ significantly between groups.

Interpretation

In extremely preterm infants, the rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was significantly increased by prophylactic low-dose hydrocortisone. This strategy, based on a physiological rationale, could lead to substantial improvements in the management of the most premature neonates.

Funding

Assistance Publique-Hôpitaux de Paris.

Introduction

Bronchopulmonary dysplasia is a leading cause of mortality and short-term and long-term respiratory morbidity in extremely preterm infants (born between 24⁺⁰ and 27⁺⁶ weeks of gestation), and is strongly associated with poor neurocognitive outcome.¹ The incidence of bronchopulmonary dysplasia reported by the Neonatal Research Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in extremely low gestational age neonates (born before 28 weeks of gestation) is 40%² and reported to be 26% in France.³ Owing to improvements in perinatal care and improved survival of the most premature babies, the bronchopulmonary dysplasia clinical profile of the disorder has changed. Bronchopulmonary dysplasia in the most premature infants is characterised by fewer but larger alveoli, mild fibrosis, and persistent inflammation that plays a key part in its pathogenesis.¹ Beginning in utero, the inflammatory process can be aggravated by several postnatal factors including mechanical ventilation, exposure to inhaled oxygen and other sources of oxidants such as parenteral nutrition, sepsis, and patent ductus arteriosus. Because of their anti-inflammatory properties, corticosteroids, primarily dexamethasone, became widely used in the 1990s for the prevention and treatment of bronchopulmonary dysplasia.⁴ Unfortunately, the benefits of early dexamethasone treatment did not outweigh its short-term and long-term adverse effects, and its toxic effects led to a decrease in its use, greatly limiting treatment options.⁵

Research in context

Evidence before this study

After extremely preterm birth, bronchopulmonary dysplasia is a leading cause of neonatal mortality and respiratory morbidity, and a major risk factor for poor neurocognitive outcome. Despite extensive preclinical and clinical investigations, treatment options to prevent this chronic lung disease are very limited. We searched MEDLINE and the Cochrane Database of Systematic Reviews for full-text articles published in English between Jan 1, 1980, and Dec 31, 2014, reporting phase 3, randomised, clinical trials and cohort studies relevant to our study, with the search terms “postnatal steroids”, “very preterm infants”, “bronchopulmonary dysplasia”, and “hydrocortisone”. Although infants treated with hydrocortisone showed improved survival in a pilot study, other larger clinical trials were either discontinued or did not have the statistical power to yield firm conclusions. Accordingly, the Cochrane Collaboration advised against the use of systemic steroids as a part of standard care for ventilated preterm infants at the present time.

Added value of this study

Our results show that a minimal dosage of prophylactic hydrocortisone significantly improves the rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age in extremely preterm infants.

Implications of all the available evidence

Prophylactic low-dose hydrocortisone seems to be beneficial in extremely preterm infants and follow-up investigations at the corrected age of 18–22 months should further confirm the high benefit-risk ratio of this strategy.

Because low cortisol concentrations in the first postnatal week have been linked to the development of bronchopulmonary dysplasia,⁶ Watterberg and colleagues tested the hypothesis that hydrocortisone replacement would decrease its incidence. However, although a randomised pilot study⁷ showed improved survival without bronchopulmonary dysplasia in infants treated with hydrocortisone, a larger trial was stopped because of an increased risk of gastrointestinal perforation in this group, mostly linked to the concomitant use of non-steroidal anti-inflammatory drugs to treat patent ductus arteriosus.⁸ This unfinished trial did not show any substantial improvement of the primary outcome in the overall study population, but subgroup analysis suggested a positive effect of hydrocortisone on neonatal mortality and survival free of bronchopulmonary dysplasia in chorioamnionitis-exposed infants. Two other trials9, 10 also showed promising effects, but were either discontinued or not sufficiently powerful to answer the question of hydrocortisone efficacy. As a result, the Cochrane Collaboration concluded that neither inhaled nor systemic steroids could be recommended as part of standard practice for ventilated preterm infants at the present time.¹¹ Despite these guidelines, however, the non-standardised and off-label use of corticosteroids in extremely preterm neonates continues.¹²

To overcome the shortcomings reported so far and promote the rational use of hydrocortisone for the prevention of bronchopulmonary dysplasia, we therefore designed a new randomised, double-blind, placebo-controlled trial using a lower dose of hydrocortisone in extremely preterm neonates.