I feel like this has been a story in the making for some time. Next to caffeine, the story of prophylactic hydrocortisone must be one of my more popular topics and has been covered more than once before as in A Shocking Change in Position. Postnatal steroids for ALL microprems or Early Hydrocortisone: Short term gain without long term pain. and the last post Hydrocortisone after birth may benefit the smallest preemies the most! After reporting on this topic about once a year, a recent paper may wrap it all up in a bow for the holidays and present to us the conclusion after all this work on the topic. I was extremely interested in this topic not just because I believe this therapy may have a future in the standard approach to neonatal care for VLBWs but because I have served on the CPS Fetus and Newborn committee with two of the authors of the paper. Dr. Lacaze and Dr. Watterberg have an exceptional understanding of this topic and so when they band together with other experts in the field I take notice.
An Individual Patient Data Meta-Analysis
If you have read my previous posts then you know the story of why hydrocortisone given over the first 10-12 days of life might help those born before 30 weeks or < 1250g. In essence the concept is that it has been shown previously that many infants with relative adrenal insufficiency may go on to develop BPD. If you treat all such infants at risk you could theoretically reduce BPD. Typically after a few studies examining a similar topic come out, one can combine them in a meta-analysis using aggregate data (averages of effect sizes for the individual studies) and see what the larger sample shows. Another way to do it though is to go back to the original data and examine the infants at a more granular level allowing a greater identification and control of variables that might influence outcomes. This is what the authors led my Michele Shaffer did here in the paper Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis. There were a total of 5 studies on this topic but one study of 40 patients no longer had individual data so was excluded from analysis leaving 4 to look at. The details of the four studies are shown below. You can see that the inclusion criteria differed slightly but in general these were all infants up to 27 – 29 completed weeks and 500 – 1250g maximum who were treated with regimens as shown in the table.
What were the results?
Treatment with early low-dose hydrocortisone was associated with greater odds of survival without BPD at 36 weeks PMA after adjustment for sex, gestational age, and antenatal steroid use (aOR, 1.45; 95% CI, 1.11-1.90; I 2 = 0%). Also found were lower individual odds of BPD (aOR, 0.73; 95% CI, 0.54-0.98; I 2 = 0%), but not with a significant decrease in death before 36 weeks PMA (aOR, 0.76; 95% CI, 0.54-1.07; I 2 = 0%). Importantly although death by 36 weeks was not different, a decrease in death before discharge (aOR, 0.70; 95% CI, 0.51-0.97; I 2 = 0%) was found. Also noted and important was a reduction in medical treatment for PDA OR 0.72 (0.56-0.93)
All of these outcomes sound important but in a subgroup analysis other interesting findings emerged.
When dividing the patients into those less then 26 weeks and those at or greater than that gestational age, the benefits appear to be limited to those in the latter group. Levels of significance are high once you reach that GA suggesting that issues affecting those at younger gestational ages are less amenable to treatment. On the other hand one could say that the benefits seen at 26 – 29 weeks GA are relatively strong using a glass is half full approach. An important outcome worth noting is that while spontaneous intestinal perforation is noted to be a risk with prophylactic hydrocortisone, when you remove indomethacin from the equation the risk disappears. For those units using prophylactic hydrocortisone one would likely need to choose between the two but if you are like our unit where we don’t have that option this may be one strategy to consider.
In terms of risk to giving such therapy the big one noted in the paper was an increase in risk for late onset sepsis. Interestingly, this was limited though to the group under 26 weeks GA. In essence then the messaging would appear to be that under 26 weeks there may be less benefit to such treatment and therefore the increased risk of late onset sepsis without such benefits on BPD would suggest not using it in this GA group.
Where do we land then?
It would be easy to cast this aside I suppose as the group you are most worried about (22-25 weeks) doesn’t seem to really benefit but has a risk of late onset sepsis. That leaves us though with the group from 26-29 weeks. They do seem to benefit and may do so to a significant degree. They do develop BPD and to be honest we don’t have much outside of trying our best to use gentle ventilation to ameliorate their course in hospital. It is worth noting that the one group that does seem to show the greatest benefit are those exposed to chorioamnionitis. It is this group in particular that may be the best target for this intervention and I gather this has been discussed at a recent EPIQ meeting.
If one says no to trying this approach then the question that needs to be asked is whether doing nothing for this group is better than supporting them with hydrocortisone? If your centre’s rates of BPD are top notch then maybe you don’t want to add something in. If not though maybe it is time to rock the boat and try something different.
This must be one of my favourite topics as I have been following the story of early hydrocortisone to reduce BPD for quite some time. It becomes even more enticing when I have met the authors of the studies previously and can see how passionate they are about the possibilities. The PREMILOC study was covered on my site twice now, with the first post being A Shocking Change in Position. Postnatal steroids for ALL microprems? and the second reviewing the 22 month outcome afterwards /2017/05/07/early-hydrocortisone-short-term-gain-without-long-term-pain/.
The intervention here was that within 24 hours of birth babies born between 24-27 weeks gestational age were randomized to receive placebo or hydrocortisone 1 mg/kg/d divided q12h for one week followed by 0.5 mg/kg/d for three days. The primary outcome was rate of survival without BPD at 36 weeks PMA. The finding was a positive one with a 9% reduction in this outcome with the use of this strategy. Following these results were the two year follow-up which reported no evidence of harm but the planned analysis by gestational age groupings of 24-25 and 26-27 weeks was not reported at that time but it has just been released this month.
Is there a benefit?
Of the original cohort the authors are to be commended here as they were able to follow-up 93% of all infants studied at a mean age of 22 months. The methods of assessing their neurological status have been discussed previously but essentially comprised standardized questionnaires for parents, assessment tools and physical examinations.
Let’s start off with what they didn’t find. There was no difference between those who received placebo vs hydrocortisone in the 26-27 week group but where it perhaps matters most there was. The infants born at 24-25 weeks are certainly some of our highest risk infants in the NICU. It is in this group that the use of hydrocortisone translated into a statistically significant reduction in the rate of neurodevelopmental impairment. The Global Neurological Assessement scores demonstrated a significant improvement in the hydrocortisone group with a p value of 0.02. Specifically moderate to severe disability was noted in 18% compared to 2% in the group receiving hydrocortisone.They did not find a difference in the neurological exam but that may reflect the lack of physical abnormalities with cognitive deficit remaining. It could also be explained perhaps by the physical examination not being sensitive enough to capture subtle differences.
Why might this be?
Adding an anti-inflammatory agent into the early phase of a preemies life might spare the brain from white matter damage. Inflammation is well known to inflict injury upon the developing brain and other organs (think BPD, ROP) so dampening these factors in the first ten days of life could bring about such results via a mechanism such as that. When you look at the original findings of the study though, a couple other factors also pop up that likely contribute to these findings as well. Infants in the hydrocortisone group had a statistical reduction in the rate of BPD and PDA ligations. Both of these outcomes have been independently linked to adverse neurodevelopmental outcome so it stands to reason that reducing each of these outcomes in the most vulnerable infants could have a benefit.
In fact when you add everything up, is there much reason not to try this approach? Ten days of hydrocortisone has now been shown to reduce BPD, decrease PDA ligations and importantly in the most vulnerable of our infants improve their developmental outcome. I think with this information at our fingertips it becomes increasingly difficult to ignore this approach. Do I think this will become adopted widely? I suspect there will be those who take the Cochrane approach to this and will ask for more well designed RCTs to be done in order to replicate these results or at least confirm a direction of effect which can then be studied as part of a systematic review. There will be those early adopters though who may well take this on. It will be interesting to see as these centres in turn report their before and after comparisons in the literature what the real world impact of this approach might be.
Stay tuned as I am sure this is not the last we will hear on this topic!
In our journey as Neonatologists and interdisciplinary teams we are forever seeking to rid or at least reduce the plague of BPD in the patients we care for. The PREMILOC trial was a double-blind, multicenter, randomized, placebo-controlled trial designed to test just that concept by introducing a low dose of hydrocortisone within 24 hours of birth. They enrolled infants born between 24 – 26+6 weeks of gestation and assigned them to receive either placebo or low-dose hydrocortisone 0.5mg/kg twice per day for 7 days, followed by 0.5 mg/kg per day for 3 days. The trial has been the subject of a previous post A Shocking Change in Position. Postnatal steroids for ALL microprems? Although the trial was stopped early due to financial concerns the authors demonstrated a 9% reduction in BPD using this strategy. The theory here in part is that the presence of hydrocortisone reduces inflammation and that this in turn may allow for better growth of lungs with time.
Why Not Adopt The Results Based on These Fantastic Results?
Steroids in preterm infants have a bad name. As discussed in previous posts on the topic the concern in all trials has been the potential impact of such medications on the developing brain. A nice summary of these concerns can be found in a paper in the CMAJ by the other “Canadian Neonatal Blogger” from 2001 in which he quoted the risk of cerebral palsy increasing from about 1 in 6 babies to 1 in 3 if babies born at < 28 weeks were exposed to postnatal steroids. Neurodevelopmental impairment overall would change from 1 in 4 to 1 in 3 if such exposure occurred. This paper and others expressing concerns over the effect of postnatal steroids led to a change in practice from more ubiquitous use to one restrained to only in those cases where the patient was nearing the end of all other options. This meant holding out for such therapy until such patients were at 90% or more O2 and on high mean airway pressures. Although not formally studied I was very concerned at the time with using this approach as I felt it was a “fait de complet” that they would either die or have significant developmental impairment should they survive due to the complications of having such severe BPD. It is critical to note though that the outcomes from these long term studies were in infants exposed to much longer courses of dexamethasone and at high doses that are used today.
Over the years with the development of the DART protocol and other more gentle approaches to steroids we as a group relaxed and certainly rescue courses of lower dose steroids have crept into practice when patients seem to be “stuck” on the ventilator.
The results of the PREMILOC follow-up study are now here and in short they look good. Patients were followed up at an average age of 22 months and included a medical history, anthropometric measures, respiratory status, standardized neurological examination based on specific definitions of disabilities, and quantitative neurodevelopmental assessment using the revised Brunet-L.zine (RBL) scale. Follow-up was 93% in the hydrocortisone and 90% in the placebo arm which is important as we need not worry about the missed patients influencing the results to a significant degree if they had been included. Although some post-hoc analyses were done what I am most interested in is the primary outcome which is shown below.
There was no difference in either neurodevelopment overall or any of the subcategories. This provides a great deal of reassurance to those who provide steroids this way. There will be those however that argue the study is too small. While a larger study might be better able to address whether there is a small difference in outcome I don’t think we will see one anytime soon. It is one of the challenges we face in Neonatology. Unlike the adult world with studies of thousands of patients, due to the small number of patients born at <28 weeks it is always a challenge to recruit into such large volume trials. We can compare trials by doing meta analyses or systematic reviews and perhaps that is where we will head with this study although given that different steroids will have been used (thinking dexamethasone as in the DART study) this will always be left open to question.
Is it worth it?
I suppose the real question here is the following for a parent to consider. “Would you like your baby to receive hydrocortisone shortly after birth with a 7% reduction in the risk of BPD at 36 weeks bearing in mind that although we don’t think there is an impact on long term development we aren’t certain yet”.
I guess to answer this question you need to think about the first part of the question. Is BPD at 36 weeks a good outcome to look at for benefit? The Canadian Neonatal Network has recently called for a rethink on this The New BPD That Matters. It turns out that it is 40 weeks and not 36 weeks that has the greatest prediction for respiratory morbidity after discharge. If you were to move the goal post to 40 weeks from 36 I strongly suspect one would see the 9% reduction in BPD as shown in the PREMILOC trial vanish. If that is the case, would a slightly earlier extubation time be enough to motivate families to take the plunge?
Although I often cringe at the expression “more trials are needed”, I think at least a combination of studies to achieve greater confidence in outcome may be needed. Barring that, we might just have to sit tight and accept that while there may be a little bit to be gained with the use of the PREMILOC protocol it may just not be enough to be clinically warranted at this time. May want to wait for the next big thing to tackle BPD…
In April of this year the ALPS trial results were published in the New England Journal of Medicine (Antenatal Betamethasone for Women at Risk for Late Preterm Delivery) and I took the time to review the paper at the time Antenatal Steroids After 34 weeks. Believe the hype? In the analysis I focused on an issue which was relevant at the time, being a shortage of betamethasone. In a situation when the drug of choice is in short supply I argued that while the benefits of giving steroid to women at risk of delivery between 34 0/7 to 36 6/7 weeks was there, if I had to choose (as I did at the time) I would save the doses for those at highest risk of adverse outcome. Since the blog post though a couple of things have come out in the literature that I believe are worth sharing as it could truly influence practice.
The American College of Obstetricians and Gynecologists, moved by the results of the ALPS trial issued the following recommendations (shortened in places).
Betamethasone may be considered in women with a singleton pregnancy between 34 0/7 and 36 6/7 weeks gestation at imminent risk of preterm birth within 7 days.
Monitoring of late preterms for hypoglycemia (already being done)
Do not give in the setting of chorioamnionitis.
Tocolysis or delayed delivery for maternal indications should not be done in order to to allow for administration of late preterm antenatal corticosteroids.
Do not provide if the pregnancy was already exposed to antenatal corticosteroids.
The exclusions above such as twins and triplets, diabetic pregnancies and previous receipt of steroids were included since the study had not included these patients. As the ACOG states in the summary, they will be reviewing such indications in the future and providing recommendations. I would imagine that if I were in a US based practice then this post might seem like old news since many centres would have started doing this. Given that the readers of this blog are based in many different countries around the globe and at least in Canada this has not become commonplace I thought it would be worth the update!
I posted the abstract for this review on my Facebook page the other day and it certainly garnered a lot of interest. Some of my readers indicated the practice is already underway. I was curious what a systematic review would reveal about the topic since the ACOG was so moved by the ALPS study in particular. Perusing through the Society of Obstetricians and Gynecologists of Canada (SOGC) I can’t find any commentary on this topic and certainly there are no new clinical practice guidelines since the ALPS study landed on my desktop.
Here are the pooled results from 6 trials:
Lower risk of RDS (relative risk 0.74, 95% confidence interval 0.61 to 0.91)
Mild RDS (0.67, 0.46 to 0.96)
Moderate RDS (0.39, 0.18 to 0.89)
Severe RDS (0.55, 0.33 to 0.91)
Transient tachypnea of the newborn (0.56, 0.37 to 0.86)
Shorter stay on a neonatal intensive care unit (−7.64 days, −7.65 to −7.64)
So across the board patients who receive antenatal steroids after 34 weeks still continue to see a benefit but looked at a different way the real benefit of the intervention is easier to see and that is through looking at the number needed to treat (NNT). For those of you who are not familiar with this analysis, this looks at how many patients one would need to treat in order to avoid the outcome in 1 patient.
For the outcomes above as an example the NNT for RDS overall is about 59 while for TTN 31 patients. Severe RDS which is less common after 34 weeks you might expect to require more patients to treat to help 1 avoid the outcome and you would be correct. That number is 118 patients. It is interesting to look at the impact of steroids in pregnancies below 34 weeks (taken from the Cochrane review on the subject) as the NNT there is 23! If you were to break these benefits down from 23-27 weeks though where the risk of RDS is quite high the NNT would be even lower. Steroids help, no question to reduce neonatal complications but as you can see even when there is a reduction in risk for various outcomes, the number of women you need to treat to get one good outcome is quite different.
Some Discussion With Obstetrics Is Needed Here
As you read through this post you may find yourself saying “Who cares? if there is a benefit at all most moms would say give me the steroids!” The issue here has to do with long term outcome. To put it simply, we don’t know for this type of patient. We know clearly that for patients at high risk of adverse outcomes eg. 24 week infant, the reduction in risks of infection, NEC, PDA, BPD etc from receiving antenatal steroids translates into many long term benefits. What about the patient who say is 35 weeks and would have none of those risks? Yes we are avoiding some short term outcomes that let’s be honest can be scary for a new parent but what are we trading this benefit for. The concern comes from what we know about steroids impact on the developing brain. Steroids lead to a developmental arrest but in very preterm infants there is no doubt that the protective effect on all of these other outcomes more than offsets whatever impact there is there. Incidentally I wrote about this once before and the section of interest appears at the end of the relevant post Not just for preemies anymore? Antenatal steroids for elective c-sections at term. In the absence of these other conditions could there be a long term impact in babies 34 – 36 6/7? My suspicion is that the answer is no but discussion is needed here especially in the absence of an endorsement by our Canadian SOGC. Having said all that I expect the future will indeed see an expansion of the program but then I do hope that someone takes the time to follow such children up so we have the answer once and for all.
It seems like a sensational title I know but it may not be as far fetched as you may think. The pendulum certainly has swung from the days of liberal post natal dexamethasone use in the 1990s to the near banishment of them from the clinical armamentarium after Keith Barrington published an article entitled The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs in BMC Pediatrics in 2011. This article heralded in the steroid free epoch of the first decade of the new millennium, as anyone caring for preterm infants became fearful of causing lifelong harm from steroid exposure. Like any scare though, with time fear subsides and people begin asking questions such as; was it the type of steroid, the dose, the duration or the type of patient that put the child at risk of adverse development? Moreover, when death from respiratory failure is the competing outcome it became difficult to look a parent in the eye when their child was dying and say “no there is nothing more we can do” when steroids were still out there.
Over the last decade or so, these questions in part have been studied in at least two important ways. The first was to ask whether we use a lower dose of dexamethasone for a shorter period to improve pulmonary outcomes without adverse neurodevelopment? The target population here were babies on their way to developing chronic lung disease as they were ventilated at a week of age. The main study to answer this question was the DART study. This study used a very low total dose of 8.9 mg/kg of dexamethasone given over ten days. While the study was stopped due to poor recruitment (it was surely difficult to recruit after the 2001 moratorium on steroids) they did show a benefit towards early extubation. This was followed up at 2 years with no difference in neurodevelopmental outcomes. Having said that the study was underpowered to detect any difference so while reassuring it did not prove lack of harm. Given the lack of evidence showing absolute safety practitioners have continued to use post natal steroids judiciously.
The second strategy was to determine whether one could take a prophylactic approach by providing hydrocortisone to preterm infants starting within the first 24 hours to prevent the development of CLD. The best study to examine this was by Kristi Watterberg in 2004 Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Strangely enough the same issue of early stoppage affected this study as an increased rate of spontaneous gastrointestinal perforation was noted leading to early closure. The most likely explanation is thought to be the combination of hydrocortisone and indomethacin prophylaxis which some centres were using at the same time. An interesting finding though was that in a subgroup analysis, infants with chorioamnionitis who received hydrocortisone had less incidence of chronic lung disease. (more on this later) Although this of course is subject to the possible bias of digging too deep with secondary analyses there is biologic plausibility here as hydrocortisone could indeed reduce the inflammatory cascade that would no doubt be present with such infants exposed to chorioamnionitis in utero.
Has the answer finally come?
The DART study at 360 patients was the largest study to date to look at prophylaxis as a strategy. That is until this past week. The results of the PREMILOC study have been published which is the long awaited trial examining a total dose of 8.5 mg/kg of hydrocortisone over 10 days. We can finally see the results of a trial without the complicating prophylactic indomethacin trials interfering with results. Surprisingly this study was also stopped early (a curse of such trials?!) due to financial reasons this time. Prior to stoppage though they managed to recruit 255 to hydrocortisone and 266 to control groups. All infants in this study were started on hydrocortisone within 24 hours of age and the primary outcome in this case was survival without BPD at 36 weeks of age.
All infants were less than 28 weeks at birth and therefore had a high risk of the combined outcome and despite the study being stopped early there was indeed a better outcome rate in the hydrocortisone group (60% vs 51%). Another way of looking at this is that to gain one more patient who survived without BPD you needed to treat 12 which is not bad at all. What is additionally interesting are some of the findings in the secondary analyses.
The lack of a difference in males may well reflect the biologic disadvantage that us males face overcoming any benefit from the hydrocortisone. In fact for the females studied the number needed to treat improves to 6 patients only! Short term outcomes of less ventilation are sure to please everyone especially parents. Lastly, a reduction in PDA ligation is most probably related to an antiprostaglandin effect of steroids and should be cause for joy all around. Lastly, a tip of the hat to Dr. Watterberg is in order as those infants who were exposed to chorioamnionitis once again show that this is where the real benefit may be.
But what about side effects?
The rate of NEC is quite high but is so for both groups but otherwise there is nothing much here to worry the reader. Once and for all we also see that by excluding concurrent treatment with indomethacin or ibuprofen the rate of GI perforation is no different this time around. Reassuring results indeed, but alas the big side effect, the one that would tip the scale towards us using or abandoning treatment has yet to be presented. Steroids no doubt can do great things but given the scare from 2001 we will need to see how this cohort of babies fares in the long run.
The follow-up is planned for these infants and the authors have done an incredible job of recruiting enough patients to make the results likely believable. I for one can’t wait to see what the future holds. If I was a betting man though I would say this ultra low dose of hydrocortisone may be just the thing to bring this therapy finally into the toolbox of neonatal units worldwide. We have been looking for the next big thing to help improve outcomes and good old hydrocortisone may be just what the doctor ordered.