Neonatal Research

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.

Pejovic NJ, Herlenius E: Unexpected collapse of healthy newborn infants: risk factors, supervision and hypothermia treatment. Acta Paediatrica 2013, 102(7):680-688. There are now a few similar studies and some case reports of this phenomenon. Otherwise healthy normal full term babies who have a cardio-respiratory arrest shortly after being born. Very often they are in skin to skin contact with the mother, often lying prone on the mothers chest, often the mother is exhausted after labour and may fall asleep. This new article adds that they may be distracted by using their smartphones. This was a large cohort study from 5 Stockholm hospitals. The incidence was much higher than other previous studies, 38 per 100,000, the definitions are slightly different in the studies and the data collection details were different, which may account for the differences.

There are also national prospective cohorts (Becher J-C, Bhushan SS, Lyon AJ: Unexpected collapse in apparently healthy newborns – a prospective national study of a missing cohort of neonatal deaths and near-death events. Archives of Disease in Childhood – Fetal and Neonatal Edition 2011 only included events within 12 hours of birth,  Poets A, Urschitz MS, Steinfeldt R, Poets CF: Risk factors for early sudden deaths and severe apparent life-threatening events. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012, 97(6):F395-F397 also included events within 24 hours)

These cohorts had lower frequencies, from Becher in the UK about 5 per 100,000, and the incidence in Germany from Poets was 2.9 per 100,000.

Whatever the incidence it is quite uncommon, but devastating. Mortality is frequent, encephalopathy may occur and long term outcomes may be severely affected. although many will resuscitate quickly and do well. The new article reports use of therapeutic hypothermia, which I think is quite reasonable if there is encephalopathy. 

I think all babies should be observed during the first few hours after birth, the mother should not be left alone in a room with a baby on her chest, but non-intrusive observation to ensure that the baby is OK should be continuous. It could be the father if there is one and if he can stay awake, and is told to keep an eye on the baby. Oh and don’t use your smartphone while breast-feeding!

Keir A: “Please call my baby by her name…”. Acta Paediatrica 2013. This should be self-evident, but this publication in the Acta Paediatrica ‘different view’ section notes that it is not. Knowing whether the baby is a boy or a girl, and knowing their name (if the parents have decided on one) looking the parents in the eye when you talk to them, should we really have to teach doctors to do those things? I guess we do. Annie and I with Barb Farlow have written a review article about making difficult decisions in the NICU that should be published shortly, as a little taster, here is one part of our recommendations for communicating with parents about difficult issues. (As usual this was Annie’s list initially, ‘etiquette based neonatology’, is her copyrighted term for it). The following is a section quoted from the upcoming article.

When you talk to parents:

‘-Limit the number of Health Care Providers attending difficult conversations or complicated deliveries.

-Make sure you do not get interrupted: ask a colleague to cover the delivery room or take your pager.

-A baby is not a “23-weeker” or “a difficult case of NEC”. If a baby has a name, you should know it and use it.

-Have difficult conversations in a place that is suitable for the parents.

-Do the parents want a significant support person present? Wait for that person if time permits.

-Introduce yourself to the parents.

-Explain your role in the team caring for their baby and why you are there.

-Sit down for difficult conversations.

-Listen more than you talk; tolerate silence.

Some may sigh and find this list is obvious and patronizing. Experiences of parents show, however, that these basic human interactions may be neglected

(Janvier A, Farlow B, Wilfond BS: The Experience of Families With Children With Trisomy 13 and 18 in Social Networks. Pediatrics 2012.)’

Sorry to any of my readers who are offended by the ‘olde englishe’ term for solid waste matter, I could have said s**t or crap I guess, but I am getting a bit irritated by the stream of b******s (liquid waste matter from a flying mammal) coming from the source cited.

The campaign by Drs Carome and Wolfe of Public Citizen in the USA against the SUPPORT trial continues. They again show they know nothing about clinical research or about neonatology or about the difference between an arse and an elbow (a second olde englishe expression). They have tried to rebut John Lantos’s refutation of their nonsense, and again show that they seem to think that the babies in the trial were exposed to some risks that the investigators  tried to keep hidden.

They again suggest (and are joined by another commenter) that a 3^rd group receiving ‘standard of care’ should have been enrolled. They are unable to understand that the 2 groups were both already ‘standard of care’.

I added my two penn’orth (another olde englishe expression meaning worth 2 (old) pennies) to the Bioethics Forum. I was a bit rude, so it might get edited, if so, I will repost the unedited version here. Otherwise, go to the link and, if you feel so inclined you can register and add your own comments.

I tried to find a place on the Public Citizen website to leave a comment, but there is nowhere to do so. Which is a little internet version 1.0, but also, for an organization that purports to be ‘the people’s voice’ is an indication that they don’t want to hear the people’s voice.

All of which is quite a shame, the politics of Public Citizen, other than this completely unjustified attack on SUPPORT, are very much in line with my own. They should just shut up and apologize for all this nonsense, but I am pretty sure that will not happen. It is hard to just say, ‘sorry, we were wrong, it was a great study that will improve outcomes for preterm babies, without increasing any kind of risks for the participants, carry on the good work’.

One of the blogs that I follow, and which does not post very frequently, is by David Colquhoun, he is (or was) a professor of pharmacology at University College London, who writes mostly about the inappropriate teaching of quackery as if it were science in the UK. His latest column quotes in its entirety an article about acupuncture that he wrote for “Anesthesia and Analgesia” entitled “Acupuncture is a theatrical placebo: the end of a myth” his co-author is one of the founders of “Science Based Medicine” which publishes a lot of interesting anti-quackery, pro-scientific medicine, posts. This new article by David Colquhoun and Steve Novella is a well written take-down of all the anti-scientific nonsense that purveyors of acupuncture will spout. If you want, or need, a quick rebuttal to those who will try and tell you that acupuncture is proven to work by good scientific studies, you could do no better than to read this.