Skull fractures after birth.  Don’t be so quick to blame.

Skull fractures after birth. Don’t be so quick to blame.

Anyone who has watch the delivery of a baby knows that in some cases things go very smoothly and in others every care provider in the room would likely have tachycardia themselves. In some cases where labour is quite prolonged and some degree of cephalopelvic disproportion exists, the fetal head can become quite wedged in the pelvis. When this occurs it is not uncommon to hear of an ob/gyn having to dislodge the entrapped head from below and then perform a c-section to get the baby out safely.

In some of these cases though on the newborn exam a depression of the skull is found such as with the figure on the right. As our brains like to link things together we may jump to the conclusion that the pressure exerted on the head from below led to a fracture. This fracture in turn may lead to injury to the underlying brain. At least that is what our brains want us to think but what if the reason for the fracture has nothing to do with the maneuver as described?

Spontaneous Skull Fractures

This exact situation has been described in two cases and with a review of the literature in a paper entitled Spontaneous Intrauterine Depressed Skull Fractures: Report of 2 Cases Requiring Neurosurgical Intervention and Literature Review. In this report they describe two cases, the first of which was a term infant born via SVD without instrumentation and was described as atraumatic. The figure above was from this infant and thankfully the underlying brain was free of hemorrhage. The second case was also term and again there was no need for forceps or vacuum. In this case there was significant parietal fracture with a small amount of subdural blood collection. This infant unlike the other one due to significant depression required neurosurgical intervention to correct the skull deformity and lift the bone off the brain. As the authors go on to describe there have been 39 other such patients described in the literature with the features as shown in the table from the paper. While there are 4 more in the paper they had vacuum extractions so I wouldn’t count them.

Why Does This Happen?

The short answer in most cases is a tight fit! In the 1960s this was postulated that in the right occiput posterior and and right occiput transverse positions the fetal head becomes compressed between the sacral promontory and pubic bones. Other implicating factors have been maternal fibroids leading to chronic pressure on the developing skull along with oligohydramnios that may lead to fetal compression as well.

When you look at the above table though what stands out is failure to progress as an ethology. One can imagine the contracting uterus attempting to propel the fetus forward and if impacted in the pelvis the pressure on the skull may well lead to fracture.

The other thing of note is the overwhelming involvement of the parietal bone in these cases. A presentation in another bone might lead one to think of a different etiology.

As far as treatment, many of these as you can see are simply observed but in the presence of significant bleeding neurosurgical intervention is needed. At the outset it is sensible to consult neurosurgery as one never knows which ones need intervention and which ones do not.

As you can see, the presence of a fracture and a history of forceful pushing from below MAY be related to a fracture but on the other hand these may occur simply with protracted labours themselves. In these situations while it may be tempting to blame the ob/gyn we also need to ask ourselves what the alternative they had was. Should they have let the mother continue to push with the potential risk of asphyxia or potentially even uterine rupture? At some point the delivering physician needs to get the baby out and if that is what needs to be done to extract the baby then that is what they will need to do. At the end of the day one thing is for sure that we don’t know for sure what caused the fracture and as tempting as it may be to blame the ob/gyn or GP delivering a baby it just might have been spontaneous!

Do antenatal steroids really benefit 22 and 23 weekers?

Do antenatal steroids really benefit 22 and 23 weekers?

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It’s been a while since my last post. Like many centers across North America and worldwide the resuscitation of premature infants as young as 22 weeks is becoming more commonplace. Our own center is in the process of working towards coming up with evidence-based approaches to the care of these fragile infants. One of the questions that has long been asked is whether antenatal steroids really make a difference at these earliest gestational ages. The argument against effectiveness would be that the cards are just so stacked up against these preemies that even steroids may not help. Making matters worse is that the number of babies at this early gestational age included in antenatal steroid trials are extremely small making any conclusions difficult.

A Study To Help Us?

You can imagine my delight and then when I saw the following study published this past week, Association of Antenatal Steroid Exposure at 21 to 22 Weeks of Gestation With Neonatal Survival and Survival Without Morbidities.

In short, the goal of the study was to look at survival and survival without major morbidities for infant born between 22 and 0 days to 23 weeks and 6 days gestational age who either received no antenatal steroids, 1 dose or 2 doses 24 hours apart. Only those mothers who received betamethasone were included and the doses were provided at either 21 or 22 weeks of gestation prior to delivery at 22 and 23 weeks of gestation.
The study was retrospective and looked at NICHD neonatal research network data from January 1, 2016 to December 31, 2019. In comparison to all the previous prospective studies in existence which recruited less than 50 preterm infants this young this study managed to recruit 431 infants. In the groups analyzed, there were 25.5% infants who received no antenatal steroids, 18.6% infants receiving a partial course and 55.9% infants receiving complete antenatal steroids.

What did they find?

The authors found evidence that I believe will be reassuring to practitioners deciding whether to provide a course of steroids at these gestational ages. There are questions though that will be raised when looking at this data as well.

The data in table to show a number of interesting findings. Most notably a primary outcome of survival at hospital discharge was improved with a complete course of steroids but not with partial or none. Similarly there were reductions in severe intracranial hemorrhage and survival at 36 weeks postmenstrual age without major medical morbidities.

Figure 2 shows survival to hospital discharge and survival without major neonatal morbidities graphically. What one can more clearly see is that if you are going to give steroids the outcome is best if the mother receives both doses.

Challenges

On the one hand you might say that this is a slam dunk finding and we should be giving antenatal steroids to all women presenting at 21 and 22 weeks gestational age. I mentioned there would be questions and one of them will have to do with the avoidance of a repeat course of antenatal steroids. There is some literature that suggests repeat dosing of antenatal steroids later in pregnancy is associated with adverse developmental outcomes and also structural changes to the developing brain. This then leads the practitioner and a bit of a quagmire. If the woman presents at 21 or 22 weeks with threatened preterm labor do give her the steroids knowing that only a full course will help her versus waiting to see if she is truly in labor as you are considering whether you should save dosing for a later time in pregnancy. I have no doubt there will be some providers that we will hesitate to give the 1 course if that is their institution practice at this gestational age. This will not be an easy selection to make.

The other question that we will come up as we start to see a single dose antenatal steroid trials coming out is whether such infants will be included in prospective trials. The upcoming SNACS trial which we are participating in is one such trial that will include infants as young as these. It will be interesting to see if prospectively collected clinical trials with adequate numbers of such small infants will demonstrate similar findings that 2 doses really are required to make a meaningful reduction in adverse outcomes. As we have seen with many retrospective studies though such as this one the outcomes may in fact be different when you randomize patients in a prospective fashion.

For now I think the evidence as good as it is we will favor giving steroids to mother’s presenting at these gestational ages. Curious what you think?

Skull fractures after birth.  Don’t be so quick to blame.

New evidence to support mid line head positioning after birth in preemies?

In an effort to reduce the incidence of IVH many patient care bundles in the last number of years have advocated for minimal handling. As part of approach to minimal handing an effort to keep the head straight and in some centres elevated has been postulated to help with enhancing venous outflow from the head. By reducing the passive gravity aided flow from the brain back into the thorax the theory would be that this would help minimize venous pressure in the draining cerebral system. Lowering pressure would in turn theoretically reduce the risk of IVH and hopefully the most severe types. The evidence to support this practice has largely been observational in the sense that those units practising this sort of intervention have published reductions in rates of severe IVH such as reported for small baby units. The fly in the ointment however is that many changes occur in the care of these infants so definitively attributing the difference in outcomes to just one intervention such as midline head positioning with elevation of the head can be challenging.

A Study to Sort It Out

Researchers in Iran sought to answer this question with an elegant study in which 39 patients served as their own controls and had NIRS monitoring through different head positions. This study entitled The effect of head positioning on brain tissue oxygenation in preterm infants: a randomized clinical trial study by Mohamammadie et al looked at these infants over the first 48 hours of life. Each infant went through NIRS monitoring and were randomly placed in six different positions as shown in the figure.

The infants studied were those who would be most vulnerable to IVH so were all <=32 weeks and < 1500g. The authors acknowledged that they would have liked to record over the first 72 hours as this has traditionally become the period of minimal handling in care bundles but claim that they did not have enough data past 48 hours to comment.

Prior to starting positional changes ten minutes of baseline recording was done in the midline position without elevation. Each position was used for a period of 2 hours during which NIRS monitoring was performed. The goal here was to see if the amount of oxygen extraction changed with different head positions and elevations. If the extraction increased in one head position it would be thought to reflect slowed return of venous blood with further extraction of oxygen from the brain.

What did the authors find?

Since I am reporting the findings it shouldn’t surprise you that they found something here. What might surprise you though is the actual difference in what they found. If one would have to guess before sharing the results it would seem that laying the head of the bed flat would not help with venous drainage as much as a 15-30 degree elevation so let’s guess that they would find that. Also, based on a belief that the jugular veins might be kinked if you turn your head to one side or the other let’s guess that midline head positioning does make a difference. Looking at the results below, let’s see if this actually happened.

As you can see the highest NIRS recordings were found in the baseline position and in general the three positions with the head of bed elevated (Position 4-6) and when flat in the midline (Position 1). It would seem then that the anticipated benefit was shown! From a statistical standpoint the third position was found to be different as was the fourth compared to the first position.

What does it all mean though?

A statistically different finding was achieved which shows the 3rd and 4th positions are not as good as baseline for sure but what about clinical significance. The lower limit of normal for NIRS readings is about 60. The means for all of these positions were in the 70s. In fact the difference between the mean of the 3rd and 4th positions and the others were only about 2%. Is this enough to make a difference? I honestly am not sure. There is a difference that reaches statistical significance so if we accept that there may have been some disruption of venous flow is this enough evidence to totally explain the reductions in IVH that have been seen with bundles for minimal handling with positioning? There were a lot of variables here that could not be controlled such as time of day that a baby was in one position or another since it was random. Was there a lot of noise in the unit at the time of one position or another? Depending on circadian rhythms what would the cortisol levels be and might mild changes in blood pressure explain the findings since they are so small?

I don’t want to totally dismiss the findings but suspect that it isn’t just the positioning that is leading to reductions in IVH. The same units that promote small baby care are also pushing breastfeeding rates up, skin to skin care and trying to harmonize other aspects of care. If we are seeing reductions in IVH which is a wonderful thing is it all related to this? Probably not but what this study does in my mind is support the theories about enhancing venous drainage through positioning and I see no reason not to continue this practice and try to keep these infants in the mid line and avoid bothering them as much as possible as they transition from the in-utero to ex-utero environment.

Should we feed insulin to preemies?

Should we feed insulin to preemies?

It isn’t often that something comes along that causes me to raise not one but two eyebrows but I suppose the idea of adding insulin to preemies feeds is just such a thing. Apparently this research isn’t that new as there has been some previous animal research and human testing of breastmilk that revealed insulin is present in milk at concentrations of 46 microunit/mL. Testing of amniotic fluid has found even higher levels at 2500 microunits/mL! All of this insulin can’t be there by accident. If you believe in evolution as I do it can’t be by chance that all that insulin doesn’t have a role to play. By extension, since babies swallow amniotic fluid and therefore bath the developing intestine in insulin containing fluid there must be a benefit right?

Let’s do a study looking at benefits of oral insulin added to formula!

Researchers in Israel thought the same thing as they postulated that since insulin is a growth factor in the intestine that adding an oral formulation to formula may confer benefits. We know that breastmilk is better tolerated by preemies and might it be that the growth promoting effects of insulin in breastmilk is a contributing factor? There had already been a proof of concept Phase 1 study to test the use of oral insulin at 400 microunit/mL so on this go around the authors sought to perform a larger Phase 2 study looking at the primary outcome of time to full feeds. The paper is entitled Efficacy and Safety of Enteral Recombinant Human Insulin for Reduction of Time-to-Full Enteral Feeding inPreterm Infants: A Randomized, Double-blind, Placebo-Controlled Trial.

Infants included in this study were from 26-33 weeks GA with a birth weight greater than or equal to 750g and postnatal age < 7 days. Since breastmilk has insulin in it already all infants were fed formula. The insulin was NTRA as a dry powder with the dose of 400 microunit/mL chosen based on the amount known to be in amniotic fluid. The study required 76 patients but was stopped after 33 patients when a planned interim analysis found a benefit already to the intervention without any safety concerns identified.

The Results

The primary outcome was the time it took to reach full feedings defined as 150 mL/kg/d of enteral formula intake.

As you can see there was about a 1.6 day advantage favouring the group receiving insulin. This represents a 20% reduction in time to full feedings

In terms of secondary outcomes the results were also impressive even more so when one considers the small sample size. While we don’t routinely measure gastric residuals in our centre the authors did these measurements as a proxy for feeding tolerance. They defined low residuals as a goal of < 2 mL/kg in 24 hours. In the insulin group this goal was reached in 1.67 days vs 5.09 days in the placebo group. While this result had a p Value of 0.056 so therefore just missed being significant it is an interesting trend for sure. Again owing to small size while a difference in time to wean off TPN was 2.4 days shorter in the insulin group it was not significantly different. No difference it time to discharge was found but again the difference favoured the insulin group with a mean reduction of about 9 days for singletons.

Below are the growth curves for the first 28 days reflecting a mean weight increase of 768.9g in the insulin group and 643.6g in the placebo arm.

So What’s Next?

I would like to start of by saying I hope one day you say you saw it here first! I think this research is very promising and no doubt a phase 3 trial with larger numbers is on the way. This isn’t quite ready for prime time as the saying goes based on small numbers but it is reassuring. Keep in mind this isn’t for everyone. We want as much as possible to provide breastmilk to our infants as it is more than just growth that we think about and time to full feeds. The question though for the future is whether for mothers who can’t produce enough or don’t want to breastfeed whether a little insulin sprinkled into their infant’s feeding will be just what the doctor ordered. My bet is that in the future you will see this indeed come into practice but we will need to certainly wait for bigger trials to confirm the trends that we are seeing here!@

Poractant alpha and Bovine lipid extract surfactant go head to head!

Poractant alpha and Bovine lipid extract surfactant go head to head!

This is the one as the saying goes that you have all been waiting for! Poractant entered the scene in Canada a few years ago with a lot of promise as a great alternative to the bovine source generally used here. The volume of administration was about half and as the use of MIST/LISA rose in popularity the option to use the lower volume was of interest to many. A study out of London Ontario demonstrated however that the bovine form could be used for LISA/MIST successfully and was written about in Less Invasive Surfactant Administration with High Volume Surfactant.

What about if we look at a real head to head comparison looking at meaningful outcomes like length duration of respiratory support? To do so would require a fairly large sample and would generally be difficult to accomplish but us Canadians opted for a study design to allow this to move forward with a sample size that for a neonatal study I think at least were admirable!

The Study

The study design here was a prospective comparative effectiveness cohort study of babies all born under 32 weeks at 13 NICUs across Canada. The study in question was entitled Poractant alfa versus bovine lipid extract surfactant: prospective comparative effectiveness study and is authored by many I consider colleagues and friends! To do this study each centre agreed to start off for 6 months with the bovine surfactant for any baby that had respiratory distress syndrome and in the opinion of the team needed surfactant. After that period each centre switched to poractant for an additional 6 months. This was a pragmatic trial designed to be less rigid with respect to criteria for intubation and allow for a “real world” determination of effect of using one surfactant vs another. While the study was not randomized the collection of outcome data relied on trained abstractors for the Canadian Neonatal Network in each centre. The authors determined that to see a difference in the primary outcome would require 484 patients per surfactant group. What they obtained in terms of recruitment is shown below.

The Results Please

I realize you have been waiting with excitement about what they could have found. Sadly they didn’t find too much!

There was no difference in length of ventilation or for that matter some important outcomes like number of doses of surfactant needed (if one group needed more might they be less effective), BPD, mortality and length of stay. The authors did note a difference in rates of MIST/LISA favouring the poractant group but when they controlled for that variable still found no difference in outcomes. Important to note that though since use of MIST/LISA may reduce the outcome of interest itself but alas no difference.

As with many studies people start digging and looking at secondary outcomes to see if there is anything of interest that pops up. It is worth noting here that whatever is found based on this study design would be an association so one must be careful not to jump to causation which may or may not be at play. For fun though let’s look at a couple of things that cropped up.

When you look at the subgroup of babies 28 +0 to 31+6 weeks an increased rate of pneumothorax creeps into the picture if you received poractant. On the other hand a reduction in days of non-invasive ventilation in favour of poractant comes into play for the same cohort. There of course is the possibility given these are secondary outcomes that these came about by chance. I did find it interesting about the pneumothorax issue though as early in the study when our centre was using poractant questions came up from our staff about a perceived increase in pneumothoraces with use of poractant. In other words the findings are in keeping with what our own units experience was so I can’t help but wonder if there is something there!

What the study does in my mind is demonstrate that if you wish to use either surfactant you may. I suppose then it comes down to comfort and in part whether you believe that use of a lower volume surfactant is better for administration with MIST/LISA. If that is the case then your choice would be poractant. If you don’t care however then it may come down to cost. There has been a difference in cost but I do wonder if the gap may close with demonstration of similar efficacy in this study. If people are indifferent to utility of the two then cost will certainly be a variable to consider!