Neonatal Research

Hartling L, et al. Benefits and Harms of Treating Gestational Diabetes Mellitus: A Systematic Review and Meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2013 (open access). A very comprehensive review, as is usual from this source, I can’t pretend to have read it all in detail, but the conclusions are: Treating GDM reduces macrosomia (which in turn leads to less shoulder dystocia), but not neonatal hypoglycemia, there is no real evidence of harm.

Ishii N, Kono Y, Yonemoto N, Kusuda S, Fujimura M, for the Neonatal Research Network J. Outcomes of Infants Born at 22 and 23 Weeks’ Gestation. Pediatrics. 2013. 36% of the infants born alive at 22 to 22 weeks 6 days survived to 3 years of age, and 63% of those born at 23 weeks. The rates of severe CP and moderate to severe developmental delay at 3 years were high among the 22 and 23 week infants. The survival rates are very impressive, we need to find ways to reduce impairments.  They also present outcomes for more mature infants up to 25 weeks, and some summary data about in-hospital complications. The rates of BPD are incredibly low, only 30% at 23 weeks, severe intracranial hemorrhage was common at 22 and 23 weeks, over 20%, and a very high proportion had RoP requiring therapy, 30% right up to 25 weeks. This suggests some ways to reduce impairments, I don’t know if they use prophylactic indomethacin, but that intervention reduces severe hemorrhage, and PDA ligation without adverse effects, in a population with such a high risk of severe bleeds, that would be worth considering. Secondary analysis of the TIPP data showed in one high risk group (boys) that developmental outcomes were better with indomethacin treatment. Overall, it is true there was no effect on developmental delay, but the incidence of severe bleeds in the controls was much lower than this, 13%.

Corvaglia L, Aceti A, Mariani E, Legnani E, Ferlini M, Raffaeli G, et al. Lack of efficacy of a starch-thickened preterm formula on gastro-oesophageal reflux in preterm infants: a pilot study. The journal of maternal-fetal & neonatal medicine. 2012;25(12):2735-8. A cross-over study of a new formula with amylopectin. There were fewer reflux episodes, but no difference in total acid exposure of the lower esophagus, and no effect on non-acid reflux. One could ask ‘why bother?’  They start the article stating 

Gastro-oesophageal reflux (GOR) is commonly diagnosed in preterm infants in neonatal intensive care units (NICUs); it is known to cause morbidity, prolong hospital stay and is associated with some relevant complications, such as aspiration of gastric content and oesophagitis.

I beg to differ. GOR is commonly diagnosed, yes: ‘known to cause morbidity’, little or no evidence. The authors state that they enrolled infants with ‘symptomatic’ reflux; the list of symptoms they give  ‘frequent regurgitations, post-prandial desaturations, chewing, hiccupping and back arching’ are not statistically more frequent in infants with more frequent GOR on esophageal impedance/pH monitoring than in infants with less frequent reflux.

I think the NIH just stole one of my titles, which was so innovative and unexpected, that I don’t believe they just had the same idea, they must read this blog. A new perspective article in the PNEJM, from, among others, Francis Collins (the NIH director), is titled ‘In support of SUPPORT’. I am going to call my lawyers to complain about infringement of my intellectual property rights. As for the content, well it is strong statement in support of er.. SUPPORT.

A large group of people, ethicists, pediatricians and neonatologists also signed a letter just published in PNEJM, that was called just ‘OHRP and support’, and, as I was one of the signatories, I can’t really complain about that title. But the letter could be considered auto-plagiarism, as it repeats something that I already wrote elsewhere, i.e. ‘Public citizen are full of shit’- no, not really, some of the authors were reluctant, can’t understand why…

It seems that all the public criticism of the OHRP ruling has made them reconsider their actions. OHRP have now issued  a new letter withdrawing the sanctions against the SUPPORT group, and specifically against the IRB in Birmingham. The letter still states that OHRP were right, but they now think that maybe the details of their response were incorrect. Much easier to write that, than an honest letter that said ‘we messed up, and listened too much to poorly informed detractors’.

One thing in that retraction letter that I really disagree with is this idea:

`Doctors are required even in the face of uncertainty to do what they view as being best for their individual patients. Researchers do not have the same obligation’

I was nearly sick. YES WE DO! And it is an obligation that we take very seriously.

I think this comment is based on a very old fashioned idea of what medicine is all about. OHRP seems to think that doctors somehow know, by their clairvoyant insight, endowed when they pass their final exams, the best course of action for their patient, and they should go ahead and treat according to their ESP. I’d rather treat according to my EBM.

Good modern science based medicine is all about making a decision with your patient (or their family) based on their particular situation, the evidence base which exists, their values and desires, and the final calculation of risk and benefit. ‘In the face of uncertainty’ means that there is no clear answer. So, for example, I have a 3 day old baby at 25 weeks with a large PDA, who is still intubated, and no current clear signs of hemodynamic compromise. The OHRP thinks that I should decide whether or not to treat based on my view of what is best. Very often (as in this situation) my view is that I don’t know what is best, that is the only honest evaluation of that situation. If I don’t know what is best, then I can guess, use prejudice, treat according to what happened the last time, phone a friend, check what day of the week it is, or toss a coin.

Which of those satisfies my obligation to my patient?

They all do to some extent, because I am uncertain. The most ethical approach is the last one. To toss a coin. And to do so in the setting of a prospective experiment, where the data will be collected, the comparison of the different approaches can be made objectively, and the results made available to colleagues around the world. That fully satisfies my ethical obligation to do the best for my individual patient, and also means that sometime in the future I will have the knowledge to make a better decision, that there will be less uncertainty.

Also, at least if I toss the coin, if in the future it turns out that one of the 2 courses of action, giving ibuprofen, or not giving ibuprofen, is proven to be preferable, then at least 50% of my babies will have had the right treatment.  That is better than finding out that maybe 100% of them got the worse treatment!

To suppose that researchers are somehow working to a different ethical standard is entirely mistaken. My first responsibility is to my patient, and if I am reasonably certain that one arm of a comparative trial is not in their best interest, then I am morally obliged to not ‘toss the coin’ but to treat according to that best interest.

There are many ethicists, clinicians and clinical researchers who ‘get it’, the signatories of the letter in the PNEJM for example, why don’t the OHRP?

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!