Does routine hydrocortisone, started at 7 to 14 days of age among infants <30 weeks GA and/or <1250g birth weight who were ventilator dependent and at increased risk for BPD, affect their long term developmental progress? (Halbmeijer NM, et al. Effect of Systemic Hydrocortisone Initiated 7 to 14 Days After Birth in Ventilated Preterm Infants on Mortality and Neurodevelopment at 2 Years’ Corrected Age: Follow-up of a Randomized Clinical Trial. JAMA. 2021;326(4):355-7).
That is the question addressed by this follow-up of babies enrolled in the STOP-BPD study. As you may remember, that study used a 22 day tapering course of hydrocortisone, starting at 5 mg/kg/d for 7 days, and had the beloved primary outcome “death or arbitrary dichotomised definition of lung injury”. The trial showed no real difference in the primary outcome 71% HC, 74% control, but mortality diverged starting at about 7 days after enrolment, and was “statistically significantly” different at 36 weeks PMA (16% vs 24%), but not quite “significant” by discharge (20% vs 28%).
As I mentioned previously, the trial included very few babies under 24 weeks, as they were not receiving active care in Holland, where the study was mostly performed, and active care was rare in the Flanders region of Belgium which accounted for most of the non-Dutch centres, Liège and Charleroi were also involved, which are in Wallonia, but I don’t know what their approach was or if they enrolled any babies <24 weeks. As I have also mentioned, and has been shown many times, centres which don’t intervene at <24 weeks, or at <25 weeks, have poor outcomes at 24, or 25, weeks compared to centres which are active at lower gestational ages. Survival for the study participants was much lower than I would expect in my centre, even taking into account the selection of a higher-risk group, ventilator dependent on oxygen at 7 to 14 days of age.
Another problem with this study, especially with regards to long-term outcomes, is the frequent treatment of control babies with steroids (principally hydrocortisone) either after the study drug period, according to protocol, if they were thought to be at high risk of dying, or outside of the protocol. 108 of the original 190 control babies received hydrocortisone during their hospitalisation.
By the 2 year follow up there were a small number of extra deaths in each group, so the mortality was now 22% (HC) vs 30% (control); 95% confidence limits for absolute difference in percentage mortality are -17% to +1%.
There were no substantial differences in any measured developmental or neurological outcome. A dichotomised “NDI”, largely driven, as usual, by scores on the Bayley Scales of Infant Development (version III), was found in 44% of hydrocortisone, vs 47% of control survivors. I presume that the total dose of HC given to the HC babies was probably higher than the total dose given to controls, so this does give some reassurance that development, including motor and cognitive development as measured by Bayley, was not adversely affected. Cerebral Palsy, blindness and deafness were all a little less common among the HC babies.
Despite the limitations, this trial does suggest that long term development is not very seriously affected by the intervention tested, a total of 72.5 mg/kg of hydrocortisone, among infants of 24 weeks and more who are considered to be at high risk of BPD at 7 to 14 days of life, at least in comparison to relatively liberal use of rescue hydrocortisone if there seems a higher risk of death.
There is a modest difference in mortality favouring the HC group, despite rescue HC among controls. Can a similar study be performed in centres with active treatment at 22 and 23 weeks? Centres which will likely already have a lower mortality than this study’s intervention group, but which probably already use some steroids in babies at high risk? (In the CNN all the centres with very immature babies have some use of steroids for BPD, but it is very variable). It would be difficult to perform such a study, and some rescue use of steroids will have to be allowed in order to make the study feasible, but I think it is essential in order to answer the questions we still have about when to give steroids for lung disease, which dose, of which molecule, for how long.
Neonatal Research 
If the primary driver of outcome in this context is timing of extubation (earlier = better) and the cumulative steroid dose is related to adverse steroid effects THEN perhaps better to design a study with hydrocortisone weaned off much more quickly as any individual infant is successfully extubated. One size fits all seems too blunt an axe when we have a readily assessable index of short term steroid efficacy – successful extubation.
We know that steroids reduce lung inflammation during evolving BPD, which improves gas exchange, which might prevent death in those at greatest risk, in some babies this allows extubation, but I am not sure that should be the focus of our research. Surely we give steroids because we want to reduce mortality firstly, but also because we want to improve long term pulmonary health. As steroids have been shown to impair lung development in some animal models, we need to look much closer at what they do to longer term, clinically important, pulmonary outcomes. Off the top of my head, only Rosamund Jones follow up of the UK dexamethasone trial has really examined this, and they had more than 50% treatment of controls with steroids, so very difficult to interpret. In the long run, if we extubate babies sooner and end up with poorer pulmonary development, or neurological or developmental outcomes, then I don’t think the babies have benefitted. I think that earlier extubation is of value to the families, but only if there aren’t adverse impacts on lung or brain development.
I do agree that we can often wean steroids faster than in this study, and perhaps a trial design should allow faster weaning, with the possibility of slowing down weaning among those that deteriorate as the dose is reduced, and risk re-intubation.