Before getting in to what they did it is important to understand how the mRNA vaccines work as the antibodies that one can look at in mothers and babies are of two types. The mRNA vaccines instruct the body to make anti-bodies against the spike protein (S antibodies) which forms the basis of how the vaccine helps our bodies identify the virus and then destroy it. For those who have actually been exposed to the virus and are not vaccinated, they develop a second antibody to the nucelocapsid protein (N antibody) which is within the viral core so this type will only be present in people who have been infected with the virus and their immune systems have dealt with it on their own. This is an important distinction as it allows you to create pure samples of people who have had the virus as a true infection and those who have been vaccinated and finally those who are neither.
Comparing Three Groups
So the authors here decided to compare three groups of women. Eighty three cord blood samples were divided into three groups (from the paper quoted) based on IgG antibody titres.
Group 1 included 29 samples (37%) from women who were infected with SARS-CoV-2 during pregnancy. Twelve had RT-PCR confirmed Covid-19 infection: three were infected in the first trimester, three in the second trimester and six in the third trimester. The other 17 had no clinical signs of SARS-CoV-2 infection during pregnancy and had a positive serologic test on admission. None of the 17 women had active SARS-CoV-2 infection at the time of delivery. Group 2 included 29 samples (37%) from women who were vaccinated against SARS-CoV-2 in the 3rd trimester.
Group 3 included 21 women (34%) and served as controls.
Looking at antibody levels in Group 1&2, 100% were positive for S antibodies. Interestingly, in group 1, 4 women did not test positive for the N antibody (3 were asymptomatic and one infected in the 1st trimester). In group 3 none of the women tested positive for any antibodies confirming they were neither vaccinated or had the infection previously.
Looking at mean antibody S titres there was a significant difference found in that Group 1 had a mean of 83.7 U/mL vs 225.5 U/mL for the newborns whose mothers were vaccinated. Also notable was the relationship (not surprisingly between antibody levels in the mother at the time of delivery and newborn cord blood titres.
There was a linear correlation between the level in the mother and the level found in the newborn with higher levels presumably better for protecting the infant. Having said that, no infants in this study had neonatal COVID infection. Detractors would be quick to point out that this indicates it doesn’t matter if you get the vaccine since all babies were ok but remember although this may be the biggest study looking at antibodies in cord blood it remains a very small sample and neonatal infection although reported, remains a very rare occurrence.
The Other Side
If you have followed my coverage of the COVID saga from the start you would know that I am in favour of vaccination and in pregnancy as well. The results of this study are encouraging but we need to compare apples to apples. This study compared women who were vaccinated in the 3rd trimester to women who were infected at earlier time points and may have been sick or asymptomatic. The lower antibody levels found in group 1 could represent declining titres as the infection becomes more remote. What we also don’t know is what they antibody levels would have looked like in group 2 if the mothers were vaccinated in the 1st or 2nd trimester as this is now happening. Would the levels be similar? They just might be as the antibody levels do decline with time. We rely on memory cells to reactivate our antibody producing cells if the virus comes along again.
I am not saying this study is meaningless but be prepared if you quote this study for vaccine hesitant to point out that you are comparing recent vaccination to potentially mild cases or remote infections. What is clear and hopeful though is that your newborn is protected by antibodies you make in pregnancy from vaccination at very good levels and until we can vaccinate babies this is the greatest protection we can offer.
When I began my career in Neonatology we initially ventilated primarily with pressure limited time cycled modes of ventilation and only supported some of the breaths as in SIMV modes. With time and emerging research a movement to using set volumes came about and in many centres supporting every breath using an assist control mode or similar version. Although I don’t have access to it in my centre, ventilators such as the Avea also allow for automated FiO2 control in addition to having a choice of two different volume targeting modes. The difference between the modes is the subject of a study entitled Comparison of volume guarantee and volume-controlled ventilation both using closed loop inspired oxygen in preterm infants: a randomised crossover study (CLIO-VG study). I suppose it shouldn’t be a big surprise that as technology advances and we fine tune practice, different modes for volume targeting would arise.
What’s the difference?
Volume Controlled Ventilation (VCV) – flow based on a set volume and measurement of the PIP every 2 ms. Next breath is given the greater of PEEP+2 cm H2O or PIP-2 cmH2O. The ventilator at the end of each breath is able to determine if the baby is still demanding flow and continues providing flow but stops when inspiratory flow is <25% of peak set flow. There is constant inspiratory flow and peak volumes.
Volume Guarantee (VG)- inspiratory pressure is adjusted breath to breath. These breaths have a decelerating flow instead of a fixed flow as in VCV.
Using automated FiO2 control for both groups the study design was a crossover one. The concept was that better ventilation would help to keep O2 saturations more reliably in a target range of 90-95% and that one of these modes might be superior than the other in doing so. Infants in the study were born at 23+0 – 36+6 weeks and had to be intubated and on >21% FiO2 to be part of the study. Each group spent 12 hours in each arm with the starting mode randomly chosen before switching over to the other mode.
Based on a power calculation in which the authors selected looking for a 5% difference they determined they needed 19 patients in the study overall. The median GA of the infants was 25 weeks (IQR 24-28) with a BW of 685g.
On a personal note, I use only VG in my centre so I am pleased to see there is really no difference in the primary outcome but the trend in the secondary outcomes at least puts a slight smile on my face as well!
I have written a lot over the years on the topic of BPD. It isn’t by chance as it is a condition that Neonatologists have put a lot of weight on. In many ways it is a benchmark that is often the go to condition when comparing one unit to another. When two Neonatologists get together their first question isn’t what’s your rate of ROP or severe developmental delay but more often comparing rates of BPD. We like to compare this as a metric as it’s something we can see as compared to say rates of late onset sepsis. You can see a patient on a ventilator or on CPAP at 36 weeks but you can’t see bacteria coursing through veins.
Not all BPD is the same though. in 2000 the NIH produced a new consensus definition of BPD as shown below.
What stands out for the babies <32 weeks is how severe BPD is defined. Babies who are ventilated are classified in the same severity group as those who are on CPAP. Somehow that doesn’t seem quite right intuitively but alas that is what they decided at the time.
Type 1 sBPD: patients on nasal cannula or noninvasive positive pressure support (i.e., high flow nasal cannula (HFNC), nasal continuous positive airway pressure (nCPAP), noninvasive intermittent positive pressure ventilation (nIPPV)) Type 2 sBPD: infants receiving iMV
The authors then looked at a sample of 564 patients from 2015-2019 in the BPD collaborative registry and subdivided them into 429 (76%) Type 1 vs 135 (24%) Type 2 sBPD and compared outcomes between the two. The differences between the two types of BPD are quite significant and shown in Table I. Babies who went on to develop sBPD as Type 2 were younger and smaller than those with Type 1. Medication use within the NICU and after discharge was markedly different as were the total ventilator days which is likely not surprising since by definition they were still intubated at 36 weeks. Importantly if you were still intubated at 36 weeks PMA almost one quarter of the patients went on to receive a tracheostomy.
Looking at it another way using relative risks the signifance of having Type 2 sBPD is impactful.
Taking Meaning From This
You might be quick to say, Michael this is absolutely no surprise. On the other hand if you have read this blog for some time you may remember this piece The New BPD That Matters. This study looked at what gestational age really mattered when looking at long term pulmonary outcomes in a Canadian cohort. When you take all comers it was 40 weeks and not 36 weeks that really mattered. The likely differernce here though is that by selecting out only the severe patients in this current study it is indeed the 36 week mark that still has relevance. I actually think the two papers together are not contradictory but rather additive.
What I think one takes away from the current study is that failure to extubate by 36 weeks does in fact carry with it significant long term risk to the patient. It would be easy enough to say that these babies should be extubated but as you see from table I it isn’t that they didn’t try. From a medication standpoint it would appear that they ” threw the kitchen sink” at these babies. The only thing I find a little surprising is that only 47% of babies in the collaborative with type 2 sBPD received systemic steroids. If they were that sick I would have expected it to be higher although that also may just be a reflection of my own practice.
One thing that I think will be a hot topic moving forward is the use of higher levels of CPAP than what many units are accustomed to. This has also been recently discussed in High CPAP vs NIPPV. Is there a winner? There may be a reluctance by some units to use CPAP levels in the +9-12 cm H2O range but when looking at these downstream complications for patients who remain ventilated at 36 weeks I think people need to seriously consider their biases and whether they are based on science or what they were taught. I can’t help but think of the oft used expression absence of evidence is not evidence of absence and think that if we can all be a little humble who knows what we may discover that can help this population.
Who doesn’t love a good match up?! Supporting neonates in need of resuscitation after delivery has been the subject of many studies over the years. The movement has certainly been to non-invasive support with CPAP or NIPPV but some babies need some degree of support with PPV after delivery when they simply won’t breathe. Prior to intubation the rise of the t-piece resuscitator has meant that practitioners can set a PIP and PEEP and with only a finger press to deliver a tidal volume at set pressure and with the finger released provide CPAP through the same device. The only problem potentially with use of these devices is the imposed work of breathing (iWOB) which has been measured in other studies. Any device I have used has provided ventilation through a mask so imagine my surprise to come across a new device called rPAP using prongs from the original infant flow design. From the manufacturers website the company claims that their design used with either a mask or nasal prongs reduces iWOB by 92% compared to other comparable machines! Imagine my greater surprise to see a head to head RCT comparing this new device to standard t-piece resuscitators with a mask.
The intervention was completed with one of three outcomes were met.
Stable and breathing on method of support after a minimum of 10 minutes of support.
At 30 minutes when respiratory support could continue as decided by the clinician without crossover allowed.
Looking at the appendices for the trial it appears that one could use either device to administer PPV or CPAP but the point of the trial was that the devices would be used to support the infants until one of the three above criteria were met. If the claims about reduced iWOB were true compared to other devices in use then one might expect to see a difference in the primary outcome of incidence of intubation or death within 30 minutes of birth.
In total there were 250 infants recruited with 127 assigned to the rPAP and the other 123 to t-piece resuscitation. The mean GA in the trial was 24.8 weeks and the baseline characteristics between groups were similar although the group randomized to the rPAP has more c-sections and more general anesthetic exposure compared to the t-piece group. Lastly, humidification of gases during resuscitation was similar between the two groups.
How Did They Compare?
It just might be that the claims of decreased iWOB might have merit. In Figure 2 below the Kaplan-Meier curves show a difference favouring the rPAP device when looking at the primary outcome. This difference was significant with 41 of 124 infants (33.1%) in the rPAP group and in 55 of 122 infants (45.1%) in the T-piece group having the primary outcome of intubation or death within the first 30 minutes of life. Moreover when looking at the adjusted odds ratio it was still significant at 0.53; 95% CI, 0.30-0.94. The incidence of intubation and death in the first 72 hours although trending towards favouring the new system did not reach statistical significance.
Finally, none of the secondary outcomes reached statistical significance which included such things as death in the delivery room, use of surfactant, or PPV in the DR.
Does it make sense?
If you had asked me to tell you prior to the study whether resuscitation with nasal prongs vs a mask would be different I would have said a mask would be better due to less leak. Turns out based on this data that I would be wrong in that guess. A look at the website though for the rPAP device indicates that it can be used with a mask or nasal prongs. It would have been nice in the study presented here to have used a mask as a third arm with the rPAP device as it leaves me wondering a bit whether it was the interface that mattered more than the type of driver used? Maybe I am wrong and by using prongs it allows the infant to have less iWOB than with a mask over the mouth and nose? Could it be that it has more to do with that that the type of driver whether it is a traditional t-piece resuscitator or the new rPAP device? Regardless, I have a suspicion that these results will resonate with people. A posting of the abstract alone has garnered a lot of attention on twitter this week so clearly this is of interest.
I don’t think there is much fault to find in this study other than my question of why they didn’t choose to have a head to head comparison with masks as well but perhaps that is for another study. I imagine we will see this approach adopted in many centres around the world as they replace their traditional t-piece resuscitators in need of replacement. I also suspect there will be many that will want a larger study before adopting this strategy to look more closely with come faith in the results at secondary outcomes in particular having to do with safety.
One thing is for certain. There will be more studies to come!
If there is a country that leads this site in terms of mentions it has to be Sweden. This isn’t just because I happen to know some Neonatologists from there who are fine people but because of the fantastic research that spills forth from their national registry of births. Surfactant is one of the oldest treatments we have in Neonatology and we know that in babies with RDS giving it early within 2 hours has benefits such as reduction in pneumothorax. The reality though is that as we have become familiar with the therapy its use has spilled over to other conditions. Years ago use of surfactant in meconium aspiration syndrome was shown to reduce need for ECMO. It has also been shown to imrove clinical condition in babies with pneumonia. Interestingly as a fellow I was criticised one call night for wanting to give a three day old baby with a history of RDS and high FiO2 requirements a repeat dose of surfactant. That was in 2001 and at that time no one could believe I was suggesting such an odd thing to give a dose after 48 hours yet now this is commonplace. Again as we have become more comfortable with surfactant such “off label” use spreads. I am not being critical of my colleagues back in 2001 as that was what the “conventional wisdom” was with respect to surfactant but that was then and this is now.
Looking at their registry data for 97377 infants born from 2009-2018 they found 7980 surfactant administrations to 5209 infants. The reasons for surfactant administration are shown in the table 1 below from the paper. Clearly and not surprisingly the bulk of surfactant administration is for RDS especially as gestational age declines. Given that so few preterm infants will pass meconium in-utero it also is understandable why MAS clusters in the more mature babies.
When it comes to multiple surfactant administrations they found 59.2% received 1 administration, 25.8% received 2, 7.3% had 3, and 2.8% had 4 or more administrations. Not surprisingly the more immature infants were more likely to receive multiple administrations. I have to say at this point that I feel vindicated with that suggestion for late surfactant administration all those years ago as these extra doses would have been given up to days after the first dosing.
Now Here Comes The Interesting Part
Much like previous work before this study, delivery of surfactant within the first 2 hours of age was associated with a reduction in very important outcomes of pneumothorax, IVH and need for ventilation beyond 7 days.. In short, improving compliance has a lot of benefits! The surprise was the in-hospital survival which favoured giving surfactant late. Put another way, if you receive surfactant in the first two hours you are more likely to die in hospital.
How can that possibly be if provision of surfactant has all those benefits outlined in table 3? More on that in a bit.
The next table addresses another question which is what if you don’t get surfactant at all? Interestinly the in-hospital survival is better for that group as well. On the other hand no difference exists for pneumothorax or IVH and ventilation beyong 7 days is improved with no surfactant at all!
The Difference Between Association and Causation
Ultimately that is what I think is at play here. You could look at the information quickly and conclude that giving surfactant late or not at all improves your chances of survival! Maybe aggressive use of surfactant isn’t such a good thing after all. I think you would be wrong there though based on prospective randomized trials. What is happening here is that the baseline characteristics are not likely equal and you are really looking at three different groups of patients.
Group 1 – These are the ones who get surfactant early within 2 hours of life. My suspicion is that the number of babies in this group that are really sick who may also have other comorbid issues is higher. There might be some babies with servere IUGR, pulmonary hypoplasia, meconium aspiration or pleural effusions that made the resuscitating team so nervous that they in advance of delivery had surfactant thawing and ready to go. Yes overall this group might benefit from better compliance and have less pneumothoraces for example but their comorbid conditions put them at higher risk of death.
Group 2 – Surfactant given after 2 hours of age. These are likely babies who are not as sick as group 1. Maybe they are babies initially managed with CPAP or NIPPV who due to escalating FiO2 requirements get surfactant. Much less likely to die.
Group 3 – No surfactant needed at all. The reason there might not be a difference in the major morbidities is that while they have RDS, TTN or MAS they are mild in nature. Clearly very low risk of death here and for that matter complications.
It might have been helpful to have some meaures of acuity documented such as SNAPPE-II (Score for Neonatal Acute Physiology with Perinatal Extension-II) used as it would help us in figuring out such differences.
Overall I think the message remains the same. Give surfactant early for those with significant lung disease. What I think it adds is an awareness that repeat dosing even if off-label is being done in Neonatology. The next question will be whether this repeat dosing makes the babies better or just us!