EBNEO Commentary: Effect of systemic hydrocortisone initiated 7-14days after birth in ventilated preterm infants on mortality and neurodevelopment at 2years' corrected age.

Abstract

Halbmeijer NM, Onland W, Cools F, Swarte R, van der Heide-Jalving M, Merkus MP, van Kaam AH. Effect of Systemic Hydrocortisone Initiated 7–14 Days after Birth in Ventilated Preterm Infants on Mortality and Neurodevelopment at 2 years' Corrected Age. JAMA 2021; 324 (6):355–357. PMID 34313697. The safety and effectiveness of postnatal corticosteroids (PCS) to prevent or treat BPD remain an active area of research. After fluctuations in their popularity over the past 40 years, PCS remain widely used as treatments for extremely preterm infants with evolving BPD in neonatal intensive care units worldwide. The Cochrane Library has two reviews of PCS, based on the timing of drug commencement: ‘early’ use (<8 days of age)1 and ‘late’ use (>7 days of age).2 Dexamethasone and hydrocortisone have been the primary systemic PCS of interest. Dexamethasone has been studied more extensively than hydrocortisone as ‘early’ therapy (21/32 randomised trials on the Cochrane review were on Dexamethasone) and despite an important reduction in rates of death or BPD rate at 36 weeks' PMA, the incidence of cerebral palsy is higher (RR 1.42, 95% CI 1.06–1.91)2 in these infants who received Dexamethasone. The PREMILOC3 trial in 2016 attempted to assess the effect of ‘early’ systemic hydrocortisone use in premature neonates treated within the first 10 days of life and despite the early cessation of the trial, demonstrated improved survival without BPD at 36 weeks' PMA (OR 1.48, 95% CI 1.02–2.16, p = 0.04) with no increased risk for long-term neurodevelopmental impairment at 22 months' corrected age.4 From this study, it was postulated that hydrocortisone may be the early PCS of choice for the prevention of BPD. The STOP-BPD trial is the first to address the ‘late’ use of hydrocortisone in infants at high risk of BPD. It reported no important difference in the primary composite outcome of death or BPD at 36 weeks' PMA (70.7% hydrocortisone vs 73.7% in placebo, p = 0.54), although there was a reduction in mortality at 36 weeks' PMA (15.5% vs 23.7%, OR 0.59; 95% CI 0.35–0.995 p = 0.048). The authors acknowledged that the study was not powered to detect smaller differences in the primary outcome, also limiting the ability to detect important differences at 2 years. At the 2-year follow-up assessment, the composite outcome of death and NDI was not statistically significantly different (OR 0.79 95% CI 0.51–1.22 p = 0.28). However, the reduced risk of death in the hydrocortisone group persisted. The risk of death was lower in the hydrocortisone group (39/181 vs 56/190) by 8%, a clinically important effect size, even if the result did not reach accepted levels of statistical significance. These results demonstrate that dichotomous composite endpoints in neonatal trials, where the components that are not equal in importance, can be fraught.5 We note the high rate of open-label hydrocortisone use within this trial. Table 26 in the primary study shows that 108/190 (57%) infants in the placebo group eventually received ‘rescue’ hydrocortisone for their clinical status. This may have reduced the power of the trial to demonstrate beneficial or harmful effects of hydrocortisone, both in the short (36 weeks' PMA) and longer term (2 years). This study further fuels the discussion regarding the interaction between baseline BPD risk and the treatment effect of PCS on longer term outcomes in extremely preterm infants.7 Patient selection, timing and choice of systemic PCS remain topics of research. Current trials are underway of alternative methods of administering PCS to prevent BPD in the sickest preterm infants.8 https://ebneo.org/stop-bpd-2-years Prof Peter Davis is co-author for the cited reference 6 and was a co-investigator for the DART study. A/Prof Brett Manley and Prof Peter Davis are current co-investigators on the PLUSS trial of intratracheal budesonide. A/Prof Brett Manley is a co-author on the updated Cochrane Reviews of early and late postnatal corticosteroids which are in press at time of writing.