Does hydrocortisone affect brain development in the preterm? Finally the answer… maybe not, or maybe

There are some observational studies that suggest that maybe hydrocortisone in relatively short courses, and moderate doses, may not have much effect on brain development, or at least on brain structure and volumes. A new study from 2 groups in Geneva and Utrecht (if you get Linda De Vries and Petra Huppi together watch out, there’s something great about to happen!) compared the term MRI of very preterm infants who either did (n=73) or did not (matched controls) receive hydrocortisone for early BPD in a fairly prolonged treatment protocol (not always followed) which started at 5 mg/kg and lasted about 22 days.  Kersbergen KJ, de Vries LS, van Kooij BJ, Isgum I, Rademaker KJ, van Bel F, Huppi PS, Dubois J, Groenendaal F, Benders MJ: Hydrocortisone Treatment for Bronchopulmonary Dysplasia and Brain Volumes in Preterm Infants. The Journal of pediatrics 2013. They were unable to find any effect of the hydrocortisone on imaging studies. The only beef I have about this paper is that they state that the infants were matched for several clinical variables as well as being ‘segmented with the same automatic method.’ I have no idea what that means (its also in the abstract), why didn’t the reviewers get them to explain it? Or is it just me, is it obvious? Tam EWY, Chau V, Ferriero DM, Barkovich AJ, Poskitt KJ, Studholme C, Fok ED-Y, Grunau RE, Glidden DV, Miller SP: Preterm Cerebellar Growth Impairment After Postnatal Exposure to Glucocorticoids. Science Translational Medicine 2011, 3(105):105. In contrast this observational study of postnatal steroid use found adverse effects on the cerebellum with both hydrocortisone and dexamethasone. In the years covered (2006 to 2009) about 20% of the babies in each center received postnatal hydrocortisone, about 20% of the babies at UBC, but none at UCSF received postnatal dexamethasone.  The major inclusion criterion was being below 33 weeks, That seems like a lot of postnatal steroids for babies that are relatively mature, but I will get back to that. This graph shows the effects of different factors on cerebellar volume, with the lower of the 2 panels being the results from multivariate modeling. Dexamethasone seems to have a greater effect, but hydrocortisone was  certainly associated with a smaller cerebellum in this study. Our former fellow, Étienne Fortin- Pellerin (now on staff in Sherbrooke) and we have just published about our recent increase in postnatal steroid use, (Fortin-Pellerin E, Petersen C, Lefebvre F, Barrington KJ, Janvier A: Evolving neonatal steroid prescription habits and patient outcomes. Acta Paediatr 2013) which is now almost exclusively hydrocortisone, we have increased from 20% of steroid use (shortly after the joint AAP/CPS statement) in infants under 28 weeks gestation, to 35% in more recent years. Although we do discuss steroid use with parents before giving them, it has become rare for parents to not agree with us to give steroids in those babies we think might benefit. Our clinical long term neurological and developmental outcomes are worse in those infants than non-steroid treated infants, but that is without adjusting for risk factors or other variables, so we can’t say from our data how important the steroids alone are, rather than the often difficult clinical situation that the babies have experienced. On the other hand my good friend and, recently, my colleague at Sainte Justine, has previously published a paper (Lodygensky GA, Rademaker K, Zimine S, Gex-Fabry M, Lieftink AF, Lazeyras F, Groenendaal F, de Vries LS, Huppi PS: Structural and Functional Brain Development After Hydrocortisone Treatment for Neonatal Chronic Lung Disease. Pediatrics 2005, 116(1):1-7.) also with Linda De Vries and Petra Huppi, and the rest of their outstanding groups, which showed no effect on MRI indices of brain development, or on development, using the WISC scores at 8 years of age. So where are we now? It looks like hydrocortisone is probably safer than dexamethasone, but is it completely safe for long term outcomes? You probably know what I going to say next, we need an RCT, And fortunately we are getting at least 1, maybe more. Onland W, Offringa M, Cools F, De Jaegere A, Rademaker K, Blom H, Cavatorta E, Debeer A, Dijk P, van Heijst A et al: Systemic hydrocortisone to prevent bronchopulmonary dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial. BMC Pediatrics 2011, 11(1):102. A dutch multicenter group has organized a trial. Nehal Parikh and coworkers have published a pilot project (Parikh NA, Kennedy KA, Lasky RE, McDavid GE, Tyson JE: Pilot randomized trial of hydrocortisone in ventilator-dependent extremely preterm infants: effects on regional brain volumes. The Journal of pediatrics 2013, 162(4):685-690 e681.) with 44 babies randomized which showed no effect of hydrocortisone on brain structure, but was obviously very underpowered. I hope they are proceeding to an adequately powered trial. We might before too long be able to know for sure what the long term outcome effects, and short-term benefits of hydrocortisone for treatment of evolving BPD truly are. Its about time.

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research. Bookmark the permalink.

4 Responses to Does hydrocortisone affect brain development in the preterm? Finally the answer… maybe not, or maybe

  1. Luis Fabian Perez says:

    Dear Dr. Barrington, would you please tell me something about the use of steroid in the treatment of hemodynamic alterations. Thank you

  2. Michael Assaad says:

    Great read. Thanks for looking at such a controversial topic. My question: I assume in those trials that they will follow the subjects clinically as well with regards to development etc? And this is probably more of a trainee question but have imaging findings of atrophy etc been well correlated to a child’s clinical outcome? Thx

    • The on-going large prospective trials are certainly going to look at long term outcomes. There is some correlation with reduced brain volume and poorer outcome, it is not a simple one to one, but there are associated developmental difficulties. The reduction in brain volume may not just be ‘atrophy’ however, it may be enhanced apoptosis, a reduction in glial tissue etc etc. There are animal studies examining these mechanisms, some of which were published many years ago.

  3. Madoussou says:

    Great team, thanks you so much to take care of my baby.

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