Recent publications

Even though the blog has been quiet recently, other academic output has continued…

In the NICU we are often faced with babies with late- or early- onset sepsis. The worst cases develop shock, which carries a significant mortality; they may survive if they receive intensive treatment. We have no idea really which treatments are helpful, and which are harmful. We try to follow physiologic principles but without much confidence that we are doing the right thing; we have been analyzing our treatments to try and figure out which interventions are helpful, and which might not work.

What often happens is that babies have standard interventions, (antibiotics, fluid boluses, dopamine or epinephrine infusions…) and when things are not going well we introduce other therapies, such as steroids or norepinephrine.

The first of these two studies looked at steroids: Altit G, et al. Corticosteroid Therapy in Neonatal Septic Shock-Do We Prevent Death? American journal of perinatology. 2017. We examined the responses to steroid, almost always hydrocortisone, therapy for babies in septic shock (i.e. hypotensive and not responding to first line inotropes). As this was not a research protocol, but just desperately trying to save babies who were in dire straits, the use of steroids was variable. But usually was after their response to either dopamine or epinephrine was inadequate. After starting hydrocortisone we were able, almost always, to reduce the doses of, or stop, other catecholamines. As time has progressed we have tended to use steroids earlier, sometimes before getting to high doses of catecholamines…

We compared episodes of septic shock among preterm babies who received steroids in addition to their inotrope, to those who did not receive hydrocortisone. We would expect the babies who received steroids to be more sick, and indeed their inotrope use index was higher, and they received inotropes for longer than the comparison group. Babies in both groups almost always had cultures that were positive, apart from a few cases of severe NEC with negative cultures. The babies receiving steroids were more immature. Mortality was significant 22% of those who did not get steroids, and 40% among those who did, reflecting their increased severity of illness (the difference may have been a chance difference by statistical testing). There were further deaths in both groups prior to discharge, and among survivors severe BPD was frequent. Because of the severe BPD we examined survival to follow-up at one year corrected age, in fact there were no more deaths after discharge. When we statistically corrected for gestational age and duration of inotrope use, there were more deaths among the babies who received hydrocortisone than those that did not.

We looked at the hemodynamic responses to the hydrocortisone and found a rapid improvement in blood pressure, starting within 6 hours, this was followed by a progressive reduction in inotrope requirements, mostly after the first 6 hours, and an improvement in urine output, starting after the blood pressure had increased. As you can see in table 4, these babies, who had a GA at birth on average of 26 weeks, and were about 2 weeks old, on average had mean blood pressures when we started the steroids of only 28 mmHg.

The second study examined our use of norepinephrine in another group of babies with septic shock. Before moving to Sainte Justine I don’t think I had ever used norepinephrine in a newborn infant, but the experience in adults, which shows a better hemodynamic profile in sepsis with norepinephrine compared to other catechols, led us to use norepinephrine in septic shock, mostly late-onset septic shock or NEC with shock.

Rizk MY, et al. Norepinephrine infusion improves haemodynamics in the preterm infants during septic shock. Acta Paediatr. 2017. We looked though our pharmacy database to find preterm babies who had received norepinephrine, all of whom were considered to be in septic shock. The 30 babies were already receiving either epinephrine or dopamine before we started norepinephrine, and nevertheless were very hypotensive, they were on average 26 weeks gestation, and 18 days old, but had a mean blood pressure of just over 20. We started the norepinephrine almost always at 0.1 microg/kg/min, and increased progressively, most babies not needing more than 0.2 microg/kg/min, but occasionally we went as high as 0.6. On average it took about 6 hours to achieve blood pressure and urine output within the normal range for each baby; they were oliguric when norepinephrine was started (mean urine output less than 2 mL/kg/h). We were able to commence reducing the other inotropes at that point, with all but 2 babies having reversal of their shock. Those 2 died, and one other for whom palliative care was started, for a mortality of 10% during the shock episode.  There were 7 other deaths before discharge for an overall mortality of 33%. Long term outcomes were poor, with frequent disabling cerebral palsy and low Bayley scores.

Both of these studies have serious limitations of course, we don’t know if these babies would have done as well, or better, without these interventions, but there are very few studies examining therapies in septic shock, so we thought it worthwhile to examine our practice, to see how we can study this phenomenon for the future. A previous study on norepinephrine  in preterm babies, who were mostly septic, showed a more rapid reversal of shock than our study, but started at a much higher dose (0.4 microg/kg/min) and took 24 hours to see improvement of oliguria. Their infants were also a little more mature (27 weeks), and had younger postnatal age (mean 1.5 days of age) and were sometimes being treated for PPHN, rather than sepsis.

What does this mean overall?

We desperately need prospectively controlled trials in infants with sepsis and hemodynamic compromise. In the meantime, use of steroids and/or use of norepinephrine are usually followed by hemodynamic improvement in babies who remain in hypotensive shock despite a single inotrope. That, I think is about all we can say, from these studies and others. Are such interventions much better than waiting or increasing the doses of the primary inotropes? Do they improve survival or other important outcomes?

As mortality is very high in these babies, RCTs of interventions would not need to be huge in order to have power to detect a clinically important difference in mortality; long-term adverse outcomes are also common, and moderately sized trials could also be informative for those outcomes.

Posted in Neonatal Research | Tagged , , , | 2 Comments

What to do with mild encephalopathy?

Therapeutic hypothermia improves the chances of babies with moderate or severe hypothermia of surviving without serious disability; referrals for evaluation for therapeutic hypothermia have exploded in our center, and many others, now that this advance is widely acknowledged. Many of the babies referred had a difficult start in life, needing resuscitation and having low umbilical cord blood pH, but have only mild encephalopathy, often with a combination of signs of Sarnat stage 1 and 2.

I actually think it is a mistake to believe that we can clearly classify infants into stage 1, 2 or 3 encephalopathy, although it is a very useful classification there are many babies that have some features of stage 2 and some of stage 3, or some of stage 1 and some of stage 2. We have developed a local evaluation system that will often give babies a stage of “1.7” for example, and then are not sure whether we should cool them or not. Are they a “mild” or a “moderate”?

In general, as the randomized trials show very little adverse effect, and the benefits are clear for moderate encephalopathy, we tend to cool babies who are possibly eligible. Occasionally a decision in the other direction has come back to haunt us, when a baby who seemed to just have classical stage 1 encephalopathy then has a convulsion at 12 hours of age (for example) and we have missed the boat.

One thing that has recently given me pause is the idea that induced hypothermia in non-asphyxiated animal models might have adverse effects on cerebral development. There is at least one study (in neonatal rats) showing a decrease in hippocampal cell proliferation following therapeutic hypothermia in non-asphyxiated animals. (I thought there was another study in piglets also, but I can’t find it right now (please send it to me if you find such an article)). If that is also the case in human babies, and there are adverse CNS effects in the non-asphyxiated, but beneficial effects in the asphyxiated, then there may be babies that we are currently treating with hypothermia who are not having a benefit, but may, rather, be having a negative effect.

But also, it may well be that mild encephalopathy is not as benign as we used to think. I was taught, based on good data (published by my mentor and great friend Neil Finer), that stage 1 encephalopathy did not increase impairment, stage 3 babies were all either dead or seriously impaired at 1 year of age, and stage 2 babies were in between (about 40% serious impairment). If stage 1, mild encephalopathy babies all do well, then we should spare them the rigours of therapeutic hypothermia, and the possible theoretical risks: is this true?

My concerns about this situation are obviously shared by others, there is an explosion of articles about babies with mild encephalopathy recently.

Murray DM, et al. Early EEG Grade and Outcome at 5 Years After Mild Neonatal Hypoxic Ischemic Encephalopathy. Pediatrics. 2016. This well-done study (from the great group in Cork) compared outcomes among 22 babies with mild encephalopathy who were evaluated at 5 years of age to 30 controls. The mild encephalopathy group had significantly lower IQ scores (99 on average) compared to the controls (mean=117, smart kids, the Irish!), the mean IQs for the moderate encephalopathy group were similar to the mild infants, but they had a range of other problems, so fewer of them were considered “non-impaired” at 5 years. The EEG at 24 hours (but not so much at 6 hours) helped to predict the full scale IQ at 5 years.

Gagne-Loranger M, et al. Newborns Referred for Therapeutic Hypothermia: Association between Initial Degree of Encephalopathy and Severity of Brain Injury (What About the Newborns with Mild Encephalopathy on Admission?). American journal of perinatology. 2016;33(2):195-202. This study from Pia Wintermark and the group at McGill (the second best group in Montreal ;-)), showed that, of the babies referred for possible hypothermia, there were 50 who had mild encephalopathy at admission who had an MRI, 20 of them had MRI abnormalities and 5 of those had very severe abnormalities. In the figure below BG/W score is a score for MRI abnormalities in the basal ganglia and white matter.

The authors note that many of the mild encephalopathy babies worsened clinically during the first hours of life.

Walsh BH, et al. The Frequency and Severity of Magnetic Resonance Imaging Abnormalities in Infants with Mild Neonatal Encephalopathy. The Journal of pediatrics. 2017. This study from Terrie Inder’s group in Boston examined the prevalence of MRI abnormalities among babies who were cooled; they had 48 babies with mild encephalopathy, more than half of whom had an MRI abnormality during the first week. They were just as likely to have watershed injuries as babies with more severe encephalopathy, but less likely to have basal ganglia injuries.

One thing that happens when you cool babies with mild encephalopathy is that they often appear uncomfortable, they are irritable and cry a great deal, and may seem to need sedation. We sometimes, therefore, consider interrupting the cooling, or add potentially toxic sedatives to their therapy. Sometimes the babies improve so much that they don’t have many signs of encephalopathy, and we think they no longer qualify for hypothermia. Although we don’t know for sure what to do for such babies, this study is informative. Lally PJ, et al. Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy. Archives of disease in childhood Fetal and neonatal edition. 2017. This article reports 10 babies in whom hypothermia was discontinued early, in each case because they had improved so much they no longer seemed eligible for the treatment. Half of them nevertheless had MRI abnormalities, and 20% had abnormal long-term outcomes at 2 years of age.

Prempunpong C, et al. Prospective research on infants with mild encephalopathy: the PRIME study. J Perinatol. 2017. This is a prospective multi-center cohort of babies with mild encephalopathy who were not treated with hypothermia, led by my friend and former fellow Guilherme Sant’anna. Their definition of an adverse neurological outcome was an abnormal aEEG within the first 9 hours of life, an abnormal MRI, or an abnormal neurological exam at discharge. Of the 54 babies with adequate data, just over half, (n=28) had abnormalities.

I am still not sure how to put all this together. The studies used for my own training, when you examine the data more closely, do show, even 40 years ago, a small signal suggesting worse outcomes for babies who had mild, Sarnat stage 1, HIE.

This now seems to be confirmed. Mild encephalopathy following perinatal adverse events is probably not benign; even serious outcomes may sometimes follow. For the moment, I think if I am unsure about whether to cool a baby, and they have clear signs of being at least a Sarnat stage 1 HIE, then I will start therapeutic hypothermia, and try to continue for 72 hours. What to do for the babies that are very uncomfortable and seem to need sedation isn’t clear to me, I think a morphine infusion is probably the least toxic alternative, but I am not at all sure about that.

But…. the studies showing the greatest proportion of adversely affected infants after mild HIE are those of babies who were treated with hypothermia, when you compare them to studies of mild HIE babies who were not cooled.

One interpretation of this could be that hypothermia worsens the outcomes of mild HIE. Another might well be that we are good at selecting the babies, among the mildly affected, who are more severely impacted, and that we don’t cool the babies at lowest risk. This is always a problem with observational studies, causation is impossible to ascribe.

There is really only one way to answer these unknowns.

You probably don’t need to guess…

A large multi-center RCT of therapeutic hypothermia is essential; criteria for cooling in such a trial need to be exquisitely clearly defined, so that they can be applied prospectively for future generations.

Posted in Neonatal Research | Tagged , , | 6 Comments

The last word on delayed cord clamping in the preterm? part 3.

Lo and behold. Fogarty M, et al. Delayed Versus Early Umbilical Cord Clamping for Preterm Infants: A Systematic Review and Meta-Analysis. Am J Obstet Gynecol. 2017.

Some of the authors of the APTS trial have performed an updated systematic review, to put into context the results of their trial, which is exactly what should be done in such a circumstance. Their review includes the data from the trial I discussed in part 2, as they were available already (in the figure below they are listed as Duley 2016).

This review found 27 trials of delayed clamping that enrolled babies of less than 37 weeks gestation; most, as mentioned before, were tiny. When looking at the effects on mortality (for which there were 19 trials that reported the outcome) the results of the APTS trial were in fact not significant (at conventional levels of statistical significance) for death before discharge; which seems different to the published results, but the published results were for death before 36 weeks. As you can see from the figure below, death before discharge was 58 vs 79, rather than the 50 vs 70 for death before 36 weeks in the publication from the FPNEJM (the Formerly Prestigious New England Journal of Medicine); death before discharge had a relative risk of 0.73 95% CI 0.53 to 1.01.

There was little heterogeneity in the results,  and, as you can see here, the mortality results depend largely on the latest 2 trials, which together contribute 77% of the weight for the meta-analysis.

So where does this leave us? There is certainly no good evidence of a disadvantage of planning delayed clamping, compared to immediate clamping. Other outcomes: any IVH, severe IVH, PVL, a combination of serious persistent CNS abnormalities on ultrasound, late onset sepsis, NEC, RoP, were not different between early and late clamping. Hematocrit is increased by about 2.7%, and about 20% fewer babies receive a blood transfusion after delayed clamping. There are more babies with a hematocrit over 65% after delayed clamping, but no increase in partial exchange transfusions to treat them. Peak bilirubin levels are slightly higher after delayed clamping.

I remain a little sceptical about the advantages of delayed clamping beyond reducing transfusion requirements, the impact on mortality is basically from one trial (APTS) with an effect on mortality which might have been due to chance (p=0.07 from the Yates corrected chi-square), with a contribution from the Duley trial, with an individual p value of 0.12. I am should also sceptical about the relevance to my practice of a study such as Ranjit 2015, who only enrolled infants between 30 and 36+6/7 gestation who did not need resuscitation, but had a 10% mortality in the early clamping group.

For relatively uncommon events we often have to rely on systematic review to be confident about the impact of an intervention, but meta-analysis of multiple very small trials is known to be problematic, and often inflates the apparent impact of an intervention. I think though it is unlikely we will have more large trials of planned delayed clamping in the very preterm compared to early clamping. I did a quick search of clinicaltrials.gov and couldn’t find such a trial, there are, in contrast, trials comparing cord milking to delayed clamping.

Reassuring is the subgroup analysis of babies of less than 28 weeks gestation, which also showed a decrease in mortality (RR=0.7, 95% CI 0.51, 0.95), but that includes only 996 babies from 3 trials, (871 of whom were from APTS).

Why might delayed clamping reduce mortality without reducing individually any of the primary causes of mortality? It is possible that an improved perinatal adaptation could lead to more stable babies in the first hours of life that decreases a whole spectrum of later causes of death, but it is hard to understand why deaths from late onset sepsis would be reduced, for example.

In my opinion, if we take into account all the limitations in these data I am not absolutely convinced that delayed clamping leads to decreased mortality, but I think that, on balance, it probably does.

My take home message is that planned delayed cord clamping should now be the standard for the preterm infant. The benefits on reduction of transfusion without any harm detected for the baby or the mother, and a probable reduction in mortality, are important, and there is no signal for an adverse impact.

What next? The Duley trial was, of course, quite different to APTS, examining resuscitation with an intact placental circulation. The extra organization and equipment required for this approach should be justified, I believe, by a trial comparing A. planned delayed clamping at 1 minute but with clamping as soon as the baby is thought to need active resuscitation to B. planned delayed clamping at 2 minutes (or more) with active intervention as soon as thought necessary, the cord only being clamped early if there are technical obstacles.

I don’t think you should, ethically, randomize preterm babies to planned immediate clamping. The alternative would be to only randomize infants who were thought to need immediate intervention, and to compare immediate clamping to resuscitation with an intact cord, but that I think would be technically more difficult to do, and would probably require a waiver of consent.

 

Posted in Neonatal Research | Tagged , , , | 3 Comments

The last word on delayed cord clamping in the preterm? Part 2.

I mentioned the second trial I wanted to discuss at the beginning of part 1. 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.

This trial compared immediate (<20 seconds) cord clamping to a minimum of 2 minute clamping for babies less than 32 weeks gestation; the delayed clamping group were placed on a firm surface that allowed medical interventions as necessary with the baby still attached to the umbilical cord and placenta. It was initially planned as a feasibility trial, the ability to perform a full trial being the major outcome for the study.

The authors extended the enrolment into this pilot trial while they tried to get funding for a larger RCT (unfortunately they were not succesful) so they ended up enrolling 270 babies who were randomized at less than 32 weeks and thought likely to deliver at less than 32 weeks. Two babies in each group actually delivered after 32 weeks, and some randomized babies (n=6) delivered at 36 weeks or later and were not included in the trial. Leaving a substantial sample size, for a pilot trial, of 270. As this was initially a pilot, to prove feasibility of a future larger trial, the planned analysis was changed to compare clinical outcomes between groups when the trial was extended. The main outcomes are said in the article to be “survival and intraventricular hemorrhage (all grades)”. They authors state that these were intended to be the primary outcomes for the future complete RCT, but the published protocol states that the primary outcome was to be ‘survival without neurosensory disability at 2 years of age’.

60% of the umbilical cords in the delayed clamping group were indeed clamped at 2 minutes or later, 22% were between 20 seconds and 2 minutes, leaving 18% (about 24 babies) who had early cord clamping in the babies randomized to attempted delayed clamping with stabilization measures with an intact cord. One of the commonest reasons for early clamping in babies randomized to delayed clamping was that the cord was too short, a factor that apparently became less frequent with increasing experience.

Almost all of the delayed clamping group were clamped between 2 and 2.5 minutes, but several did go on quite a bit longer, up to 4 minutes, and one brave team clamped the cord of a baby at about 7 minutes.

Similar to the APTS trial, there is really no sign of a signal for a significant benefit of delayed clamping for IVH, severe IVH, NEC, treatment for retinopathy or sepsis.

There were fewer deaths with delayed clamping, although they had relatively lower power, and the results may have been due to chance, 15/135 died with early clamping, 7/135 died in the group randomized to delayed clamping, Relative Risk 0.47 (95% Confidence Intervals 0.20 to 1.11). As with the APTS trial, causes of death were quite varied, and the gestational ages of the babies who died included some relatively mature babies.

Here is table 3 with the mortality figures and causes.

There were somewhat fewer babies receiving blood transfusions in the delayed clamping group, 52% with early clamping and 47% with late, no increase in the use of phototherapy, very slightly more NEC (8 cases early clamping, 5 cases late clamping), and slightly less culture positive sepsis (33 cases early clamping, 30 cases late clamping). Severe IVH was practically identical between groups.

An interesting trial, congratulations to the team for organizing the ability to do this trial, and for extending the enrolment to achieve a reasonable sample size, as I mentioned before this is the second largest trial of delayed clamping in the preterm. Individually, this trial shows no clear evidence of benefit, and no evidence of harm, a further trial of this approach is warranted, the question now will be what should the control group be for a future trial, given the APTS trial results? Should it be early clamping, or delayed clamping at 60 seconds unless the babies need resuscitation (like the intervention group in APTS)?

I think the first thing that is needed is a new systematic review, with meta-analysis where appropriate. So on to part 3!

 

Posted in Neonatal Research | Tagged , , | Leave a comment

The last word on delayed cord clamping for preterms? Part 1.

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!

Posted in Neonatal Research | Tagged , , | 1 Comment

Guidelines to help parents who have lost one of twins

Many readers of this blog will recognize the name of Nick Embleton as someone who has done a great deal of nutrition research, and research into the intestinal microbiome of very preterm infants.

He also has a major interest in parents’ experiences of perinatal loss; his group 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 :

What I got a lot of … the doctor at the time really quite upset me… she often said to me, ‘At least you’ve still got one’, and that was one of the worst things that anyone could possibly say. ‘You’ve still got [surviving twin] though’ and I know I’m really grateful I still have[surviving twin] but that’s like saying to someone that has a child of four and six and the six year old one dies, ‘well you’ve still got the other one, so that’s ok’. And it was really quite upsetting. I knew that she didn’t mean it in any nasty way’.

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

Posted in Neonatal Research | Tagged , , | 1 Comment

Antibiotics are dangerous, unless you actually need them.

In response to my previous post Claus Klingenberg wrote a comment in which he mentioned a recent systematic review that he had published with a group of colleagues. This review of a small number of RCTs (9) and a larger number of observational studies (38) examined the effects of prolonging or broadening the spectrum of antibiotic therapy on individual risks such as NEC and later fungal sepsis, and how those complications impact mortality. (Esaiassen E, et al. Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(7):1858-70).

The RCTs were generally comparisons of different antibiotic regimes, apart from one of routine antibiotics vs no antibiotics. The observational studies were also mostly short vs long courses, and narrow vs broad spectrum. They found:

Prolonged antibiotic exposure in uninfected preterm infants is associated with an increased risk of NEC and/or death, and broad-spectrum antibiotic exposure is associated with an increased risk of IFI.

The authors of the review appropriately did not calculate a pooled Odds Ratio, as the studies are too heterogeneous, but the individual ORs for NEC and/or death range from 1.3 to 7.7, they include numerous observational studies with over 5,000 babies. The studies of invasive fungal infection show in most instances, and particularly in larger studies, an association with the use of third generation cephalopsorins or carbapenems. Specifically among preterm infants, there is an increase in all-cause mortality when antibiotics are given for longer periods in babies with negative cultures.

 

 

 

Posted in Neonatal Research | Tagged , , , | Leave a comment