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    • By AllThingsNeonatal in All Things Neonatal
      Given that today is world prematurity day  it seems fitting to talk about prematurity at the absolute extreme of it.
      It has been some time since as a regional program we came to accept that we would offer resuscitation to preterm infants born as early as 23 weeks gestational age.  This is perhaps a little later in the game that other centers but it took time to digest the idea that the rate of intact survival was high enough to warrant a trial of resuscitation.  This of course is not a unilateral decision but rather a decision arrived at after consultation with the family and interprofessional team.  To be sure it is not an easy one.  Other centers have argued that resuscitation should be offered to those infants as young as 22 weeks gestational age and data now exists due to enough centres doing so to provide families with some guidance as to expected survival rates and importantly the likelihood of disability. This topic has been covered previously in /2015/09/25/winnipeg-hospital-about-to-start-resuscitating-infants-at-23-weeks/. Why cover this topic again?  Well an article on CNN might have something to do with it.
      Resuscitating Below 22 weeks
      This week as I was perusing the news I came across a rather shocking article on CNN. Born before 22 weeks, ‘most premature’ baby is now thriving.  The article tells the tale of a baby delivered at 21 weeks and 4 days that now as a three year old is reaching appropriate milestones without any significant impairments.  It is a story that is filled with inspiration and so I am not mistaken I am delighted for this child and their family that this outcome has occurred.  When the lay press latches onto stories like this there is no doubt a great deal of sensationalism to them and in turn that gathers a lot of attention.  This in turn is a great thing for media.
      A Few Caveats Though
      With the exception of pregnancies conceived through IVF the best dating we have is only good to about +/- 5 days when an early first trimester ultrasound is performed or the date of the last menstrual period is fairly certain.  A baby though who is born at 21 weeks + 4 days may in fact be 22 +3 days or even more depending on when the dating was done (second trimester worse).  Let’s not take away though from the outcome being this good even at 22 weeks.  That is a pretty perfect outcome for this family but the point is that this baby may in fact be older than 21 weeks.
      Secondly, there are millions of babies born each year in North America.  Some of these infants are born at 22 weeks.  How do they fare overall?  From the paper by Rysavy et al from 2015 the results are as follows.

      If you look at the overall rate of survival it is on an average of 5.1%.  If you take a look though at those infants in whom resuscitation is provided that number increases to a mean of 23%.  Intact survival is 9% overall.  The odds aren’t great but they are there and I suspect the infant in the article is one of those babies.  Flipping the argument though to the glass is half empty, 91% of infants born at 22 weeks by best estimate who are offered resuscitation will have a moderate or severe disability if they survive.  I am not saying what one should do in this situation but depending on how a family processes the data they will either see the 110 chance of intact survival as a good thing or a 9/10 chance of death or disability as a very bad thing.  What a family chooses though is anyone’s best guess.
      Should we resuscitate below 22 weeks if the family wishes?
      I guess in the end this really depends on a couple things.  First off, how certain are the dates?  If there is any degree of uncertainty then perhaps the answer is yes.  If the dates are firm then I at least believe there is a barrier at which futility is reached.  Perhaps this isn’t at 21 weeks as some patients may indeed be older but think about what you would offer if a family presented at 20 weeks and wanted everything done.  What if it were 19 weeks?  I suspect the point of futility for all lies somewhere between 19-21 weeks.
      As I prepare to attend the annual meeting in Ottawa tomorrow for the Fetus and Newborn Committee I think it is prudent to point out just how difficult all of this is.  The current statement on Counselling and management for anticipated extremely preterm birth I think hits on many of these issues.  The statement is the product on not only the think tank that exists on this committee but was the product of a national consultation.  I know I may be biased since I sit on the committee but I do believe it really hits the mark.
      Should we be thinking about resuscitating at 21 weeks?  For me the answer is one clouded by a whole host of variables and not one that can be easily answered here.  What I do think though is that the answer in the future may be a yes provided such infants can be put onto an artificial placenta.  Even getting a few more weeks of growth before aerating those lungs is necessary may make all the difference.  The NICUs of tomorrow certainly may look quite different than they do now.
    • By kbarrington in keith barrington's neonatalresearch.org
      The group in Newcastle in the UK has studied parents who suffered the loss of a twin. This is an unfortunately common experience in the NICU, twins and higher order multiples are much more likely to be born prematurely (for triplets it is actually quite rare to be born at full term), and for one twin to die, while the other is still being cared for in the NICU, happens frequently.
      Richards J, et al. Mothers' perspectives on the perinatal loss of a co-twin: a qualitative study. BMC Pregnancy Childbirth. 2015;15:143.
      Richards J, et al. Health professionals' perspectives on bereavement following loss from a twin pregnancy: a qualitative study. J Perinatol. 2016;36(7):529-32.
      I remember as a young neonatologist (and yes, I can remember that far back) when this happened, we thought it was kind, when baby "Smith 1" died, that baby "Smith 2" should just become baby "Smith". Motivated by concern for the parents, and not wanting to emphasize the loss of the other twin each time we talked about the surviving twin, we basically effaced the memory of the dead twin from our conversation.
      I now think that was a major error, and this research confirms that thought. Although we were trying to decrease the pain of parents who were going through the loss of one twin, while still trying to care for the surviving twin (or triplet(s)); I think it was likely often experienced as trying to erase the memory of one of their babies. In my NICU we now make great efforts to use the first, given, name of each baby (unless the parents haven't yet decided), and talk about the babies among ourselves using both given and family names. I think that is a better way to refer to our patients, and stops the avoidance, we don't call the surviving baby "Smith twin 2", but "John Smith", and acknowledge the death of baby "Jane Smith". I think over the years we have come to understand many things which mark the experience of parents who have lost one of twins. But what really makes a difference to parents going through this cruelly painful experience; to have to remain in the NICU where one baby has died, while caring for another who might still be very sick?
      The studies from Newcastle shed some light on that experience. Here is one quote from the mothers' paper :
      From comments like that, and a thematic, qualitative, analysis of interviews with 14 mothers who had lost one of twins (some before birth, others after) the team have developed guidelines for helping mothers in such a situation. The concept of "grief on hold' is, I think, really important. These mothers don't feel like they can really grieve the dead baby, as they are trying to hold it together for the emotional needs of the surviving infant.
      The guidelines they have developed are available on their website, together with films made with parents speaking about their loss, and downloadable resources, available in several languages, including the pdf of a slide presentation, and a 2 page leaflet for parents.  http://www.neonatalbutterflyproject.org
    • By kbarrington in keith barrington's neonatalresearch.org
      The APTS (Australian placental transfusion study) trial has just appeared on line. This was a high-quality multicenter, international RCT of immediate cord clamping (less than 10 seconds) compared to delayed clamping (60 seconds) for babies born less than 32 weeks gestation. (Tarnow-Mordi W, et al. Delayed versus Immediate Cord Clamping in Preterm Infants. the FPNEJM 2017.)
      Another trial arriving almost simultaneously is a smaller trial from the UK, which compared cord clamping at less than 20 seconds to clamping at at least 2 minutes, with reuscitation staring with the cord intact in the intervention group. (Duley L, et al. Randomised trial of cord clamping and initial stabilisation at very preterm birth. Archives of disease in childhood Fetal and neonatal edition. 2017.) I will come back to that trial in part 2.
      The benefits of delayed cord clamping for term babies are quite obvious from the RCTs, and basically show a significantly improved Hemoglobin/Iron status for the first year of life, which seems to lead to some improvement in fine motor function, in the long term, with no important down-side. The higher bilirubin levels among late-clamped babies do not lead to more phototherapy, if modern restrictive phototherapy guideline are followed.
      The only real disadvantage is that it is much harder to give blood to a public cord blood bank after delayed clamping. Public banks have been the source of stem cells for bone marrow transplants for hundreds of children (and as far as I know adults as well) so this should not be dismissed...
      For the preterm baby I thought that much of the evidence had been over-hyped, with claims of reduced IVH, and reduced NEC, based on tiny numbers from tiny trials, with no robust evidence of benefit, apart from higher hemoglobins, probably leading to fewer transfusions. What we really needed was a large RCT with enough power to answer questions about  efficacy and safety.
      The APTS trial gives that power, with over 1500 babies randomized, and, although much smaller, the trial from England is the second largest trial, with over 260 babies. The remaining trials that have been quoted as the justification for the worldwide movement for delayed clamping in the preterm, have mostly been tiny, with sample sizes between 32 and 200.
      What did the APTS trial show? Speaking in the strictest sense it showed no difference between groups in the primary outcome. The primary outcome was a composite outcome of death, serious brain injury, late-onset sepsis, necrotising enterocolitis or severe retinopathy. When the study was planned bronchopulmonary dysplasia was also part of the primary outcome, but with changes in practice the authors found that the incidence of "BPD" was much higher than expected (many babies were on respiratory support with positive pressure and 21% oxygen at 36 weeks post-menstrual age), so during the trial, before the final data were analysed, BPD was deleted from the composite outcome. When you look at the individual components of the composite outcome, there is no sign of a benefit for any of the components of that composite, except one, that is mortality.

      When only one part of a composite outcome is positive, but it is much less frequent than the remaining parts, the overall composite may well be negative. This is one of the problems with composite outcomes, you can actually lose power for the most important part of the composite, whereas these composites are usually being used to try to increase power!
      The outcome of death should therefore strictly be considered to be a secondary outcome, and therefore treated with some scepticism. I'll come back to this point.
      Also important is the fact that 26% of the delayed clamping group did not get 60 seconds of delay, which was most often due to concerns about the neonatal status (70% of the time). This was unavoidable given the design, as most centers were not resuscitating babies with the cord intact. 20% of the delayed clamping group got the cord clamped before 30 seconds, the other 6% who did not follow protocol it was between 30 and 60 seconds.
      It would be interesting to have a "per-protocol" analysis of mortality results, which I would guess would show a greater difference between groups, as babies who had the delayed clamping interrupted because of concerns about neonatal status might well have a higher mortality. There is an analysis of the per-protocol effects on the primary outcome (in the supplementary appendix) which shows a difference (which may just be due to chance, p=0.2) : 37% with immediate clamping, and 33% with delayed clamping, but no mention of the components of that outcome.
      There is also a report of the causes of death in the supplementary appendix, causes which cover the entire range of causes of death among very preterm babies. The biggest single cause was septicemia, which was also the cause that showed the biggest difference between groups, 2.2% immediate clamping, and 0.5% delayed clamping.
      There is also an analysis in detail of head ultrasound findings which show no tendency to be different in any aspect between groups.
      Finally there were many fewer babies who needed blood transfusions with the delayed clamping (61% with immediate clamping, 52% with delayed clamping) but more babies with polycythemia (2% had hematocrit >65% with immediate clamping, 6% with delayed clamping, 1% over 70% immediate, 2% with delayed). There was no clinically important difference in bilirubin concentrations (mean was 3 micromoles higher with delayed).
      Overall then, a potential decrease in mortality, a decrease in the number of babies receiving transfusion, with a very small increase in polycythemia, which was probably not due to chance (p<0.001).
      What to do with these results? Well, as yet there is no signal for a clinically important harm of delayed cord clamping; with the proviso that babies who are intended to have delayed cord clamping may often have the cord clamped early. I think that a clinical approach planning for delayed clamping at, or perhaps after 60 seconds, is consistent with the best evidence, it will decrease the number of babies receiving transfusions, and might decrease mortality.
      We also need an updated systematic review and meta-analysis. But for that you will have to wait for part 3!
    • By AllThingsNeonatal in All Things Neonatal
      Given that many preterm infants as they near term equivalent age are ready to go home it is common practice to discontinue caffeine sometime between 33-34 weeks PMA.  We do this as we try to time the readiness for discharge in terms of feeding, to the desire to see how infants fare off caffeine.  In general, most units I believe try to send babies home without caffeine so we do our best to judge the right timing in stopping this medication.  After a period of 5-7 days we generally declare the infant safe to be off caffeine and then move on to other issues preventing them from going home to their families.  This strategy generally works well for those infants who are born at later gestations but as Rhein LM et al demonstrated in their paper Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial., after caffeine is stopped, the number of intermittent hypoxic (IH) events are not trivial between 35-39 weeks.  Caffeine it would seem may still offer some benefit to those infants who seem otherwise ready to discontinue the medication.  What the authors noted in this randomized controlled trial was that the difference caffeine made when continued past 34 weeks was limited to reducing these IH events only from 35-36 weeks but the effect didn’t last past that.  Why might that have been?  Well it could be that the babies after 36 weeks don’t have enough events to really show a difference or it could be that the dose of caffeine isn’t enough by that point.  The latter may well be the case as the metabolism of caffeine ramps up during later gestations and changes from a half life greater than a day in the smallest infants to many hours closer to term.  Maybe the caffeine just clears faster?
      Follow-up Study attempts to answer that very question.
      Recognizing the possibility that levels of caffeine were falling too low after 36 weeks the authors of the previous study begun anew to ask the same question but this time looking at caffeine levels in saliva to ensure that sufficient levels were obtained to demonstrate a difference in the outcome of frequency of IH.  In this study, they compared the original cohort of patients who did not receive caffeine after planned discontinuation (N=53) to 27 infants who were randomized to one of two caffeine treatments once the decision to stop caffeine was made.  Until 36 weeks PMA each patient was given a standard 10 mg/kg of caffeine case and then randomized to two different strategies.  The two dosing strategies were 14 mg/kg of caffeine citrate (equals 7 mg/kg of caffeine base) vs 20 mg/kg (10 mg/kg caffeine base) which both started once the patient reached 36 weeks in anticipation of increased clearance.  Salivary caffeine levels were measured just prior to stopping the usual dose of caffeine and then one week after starting 10 mg/kg dosing and then at 37 and 38 weeks respectively on the higher dosing.  Adequate serum levels are understood to be > 20 mcg/ml and salivary and plasma concentrations have been shown to have a high level of agreement previously so salivary measurement seems like a good approach.  Given that it was a small study it is work noting that the average age of the group that did not receive caffeine was 29.1 weeks compared to the caffeine groups at 27.9 weeks.  This becomes important in the context of the results in that earlier gestational age patients would be expected to have more apnea which is not what was observed suggesting a beneficial effect of caffeine even at this later gestational age.  Each patient was to be monitored with an oximeter until 40 weeks as per unit guidelines.
      So does caffeine make a difference once term gestation is reached?
      A total of 32 infants were enrolled with 12 infants receiving the 14 mg/kg and 14 the 20 mg/kg dosing.  All infants irrespective of assigned group had caffeine concentrations above 20 mcg/mL ensuring that a therapeutic dose had been received.  The intent had been to look at babies out to 40 weeks with pulse oximetry even when discharged but owing to drop off in compliance with monitoring for a minimum of 10 hours per PMA week the analysis was restricted to infants at 37 and 38 weeks which still meant extension past 36 weeks as had been looked at already in the previous study.  The design of this study then compared infants receiving known therapeutic dosing at this GA range with a previous cohort from the last study that did not receive caffeine after clinicians had determined it was no longer needed.
      The outcomes here were measured in seconds per 24 hours of intermittent hypoxia (An IH event was defined as a decrease in SaO2 by ⩾ 10% from baseline and lasting for ⩾5 s).  For graphical purposes the authors chose to display the number of seconds oxygen saturation fell below 90% per day and grouped the two caffeine patients together given that the salivary levels in both were therapeutic.  As shown a significant difference in events was seen at all gestational ages.
      Putting it into context
      The scale used I find interesting and I can’t help but wonder if it was done intentionally to provide impact.  The outcome here is measured in seconds and when you are speaking about a mean of 1200 vs 600 seconds it sounds very dramatic but changing that into minutes you are talking about 20 vs 10 minutes a day.  Even allowing for the interquartile ranges it really is not more than 50 minutes of saturation less than 90% at 36 weeks.  The difference of course as you increase in gestation becomes less as well.  When looking at the amount of time spent under 80% for the groups at the three different gestational ages there is still a difference but the amount of time at 36, 27 and 38 weeks was 229, 118 and 84 seconds respectively without caffeine (about 4, 2 and 1 minute per day respectively) vs 83, 41, and 22 seconds in the caffeine groups. I can’t help but think this is a case of statistical significance with questionable clinical significance.  The authors don’t indicate that any patients were readmitted with “blue spells” who were being monitored at home which then leaves the sole question in my mind being “Do these brief periods of hypoxemia matter?”  In the absence of a long-term follow-up study I would have to say I don’t know but while I have always been a fan of caffeine I am just not sure.
      Should we be in a rush to stop caffeine?  Well, given that the long term results of the CAP study suggest the drug is safe in the preterm population I would suggest there is no reason to be concerned about continuing caffeine a little longer. If the goal is getting patients home and discharging on caffeine is something you are comfortable with then continuing past 35 weeks is something that may have clinical impact.  At the very least I remain comfortable in my own practice of not being in a rush to stop this medication and on occasion sending a patient home with it as well.
    • By AllThingsNeonatal in All Things Neonatal
      It would seem that the Opioid crisis is continuing to be front and centre in the news.  Just today the President of the United States declared an Opioid Epidemic Emergency. Of course he was speaking primarily about the damage these drugs do on the family unit and those around them, the impact on the unborn child is significant as well.  If this sounds familiar it is because I have written about this topic recently and in the past in the posts A Magic Bullet to Reduce Duration of Treatment and Hospital Stays for Newborns With NAS and Mandatory Drug-Testing ni PRegnancy: Lesson learned.  I suppose I write about this topic often as at least where I work this is a problem which just won’t go away and takes up a tremendous amount of resources.
      What Can a Large Data Set Tell us?
      Pediatrix medical group that you may well be familiar with has a lot of data that can be mined from the hospitals in their network.  When it comes to buprenorphine there is a lot of data to look at.  In this case the question posed by VN Tolia et al in thier paper Antenatal methadone vs buprenorphine exposure and length of hospital stay in infants admitted to the intensive care unit with neonatal abstinence syndrome was whether there is a difference in infants born to mothers who have been exposed to methadone vs burprenorphine.  Specifically they chose to use length of stay as the primary outcome in a retrospective review of 3364 infants admitted for management of NAS.  Of these infants, 2202 (65%) were exposed to methadone and 1162 (34%) to buprenorphine.  Before we get into what the results actually were it is important to highlight what this study will not tell us.  By looking only at admissions for NAS we do not know whether the use of buprenorphine in mothers actually reduced admission for NAS so we are only speaking of the babies who were afflicted with NAS.
      When looking at the two groups, the median length of stay was 24 days for the methadone group and 21 for the buprenorphine which was found to be significantly different.  In the secondary analysis another interesting finding (at least to me) was noted.  When looking at the percentage of babies with a length of stay > 30 days the difference was significant at 34% vs 22% for buprenorphine.  The authors here did a good job of doing their best to control for factors which could have influenced the results as they did a regression analysis to determine whether other factors such as gestational age, sex, type of treatment provided etc would explain the shortened length of stay and they found that it remained significant controlling for a wide variety of factors.
      Is three days worth it?
      It would be tempting to look at the 3 day median difference and shrug it off as no big deal.  Remember though that we are in an epidemic are we not?  What the study does not account for as well are the number of babies who could have been managed in a postpartum ward and also had a shortened length of stay.  Let’s look at a city though where about 100 babies are admitted a year with NAS.  A three day reduction in length of stay would translate into 300 patient days per year.  By simply changing the medication a woman is being treated with in pregnancy from methadone to buprenorphine we could save almost one NICU bed for the whole year.  That is nothing to sneeze at!  Moreover if the reduction in admission rates are also true another one, two or more beds per year could be spared depending on the effectiveness of the drug.
      In the last post that spoke of using buprenorphine to treat NAS in babies I was concerned about the alcohol content of the syrup for administration in babies.  Here we are talking about treating women rather than babies so this is not a concern (plus they would not be taking the pediatric suspension).  I see little downside to using buprenorphine over methadone so the real question is how do we get the care providers for the mothers to make the switch?  I have a feeling that is coming sooner rather than later.
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  • APTS trial in NEJM   17 members have voted

    1. 1. Will you change your cord clamping practise in very preterm births?

      • No. We practise delayed clamping.
      • No. We practise early clamping.
      • Yes, from delayed to early clamping.
      • Yes, from early to delayed clamping.
      • Other reply.

    Please sign in or register to vote in this poll. View topic
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